Core Human Physiology

INTRODUCTION
PHYSIOLOGY
- Physiology is the study of normal functions of living organisms. It
includes many branches like viral physiology, bacterial physiology,
cellular physiology, plant physiology, animal physiology and human
physiology.
- Human physiology is the branch of physiology which is concerned
with the functions of the entire human body; from the sub-cellular
components to the organs and organ systems. It is also concerned
with how these functions are performed and how they are integrated.
HOMEOSTASIS
- All living organisms are composed of cells. Cells of the body do not
only contain water, but also surrounded by water (= intracellular and
extracellular fluid compartments). The extracellular fluid is the link
between the external world and the cells. It carries nutrients to the
cells and eliminates their waste products. It circulates between all
cells in the body and provides for them a homogenous environment.
In other words, it is essential for survival of cells. Disturbance of this
extracellular fluid impairs functions of cells and results in disease. For
this reason it is described as the "internal environment" (Claude
Bernard, 19th century). Later on, the term "Homeostasis" was
applied. It indicates that: "all systems in the body, however various,
they have one goal; to maintain the constancy of the internal
environment (which is the ECF)". Therefore each organ in the body
participates in homeostasis by maintaining constant ECF volume,
osmolarity, pH, pressure or temperature).
The core of medical physiology (1) – 3rd edition Page 1
CELL STRUCTURE
- Cells are the building blocks of the body (the basic units of each
tissue). The entire body contains about 75 to 100 trillion cells.
Although these cells are highly specialized in various organs to
perform specific functions, the structures inside their cytoplasm (i.e.
the organelles) are almost identical in all types of cells. These include
the following:
 The cell membrane:
- Phospholipid bilayer (about 25%) with proteins (about 50%); plus
some cholesterol (13%), carbohydrates (3%) and other lipids.
- The phospholipids have hydrophilic parts "phosphate" facing
outside and the hydrophobic parts "fatty acids" in the interior of the
membrane.
- Thickness = 7.5 nm (75 Angstrom)
- It is a semi-permeable membrane (allows passage of lipid soluble
substances and prevents passage of water and water soluble ones).
However, the protein channels and carriers in the membrane
facilitate passage of many substances- see below.
- It contains two types of protein:
o Peripheral proteins: attached to one surface of the cell
membrane (usually the inner surface)
o Integral proteins: extends throughout the cell membrane
- Functions of proteins in the cell membrane:
o Offer structural support to the membrane (cytoskeleton)
o Act as adhesion molecules (connect cells together)
o Act as enzymes (catalyze chemical reactions on the cell
membrane)

o Act as antigens (usually glycoproteins; like the blood
group antigens on surface of red blood cells and the “HLA”
antigens (human leukocyte antigens) on surface of all
nucleated cells.
Notes about the HLA antigens:
 They are encoded by group of genes in the short arm (P
arm) of chromosome 6. These genes are known as the
genes of the major histocompatibility complex (MHC). They
include different classes (e.g. MHC class I, MHC class II &
MHC class III).
 HLA antigens (also known as MHC antigens) are unique
for every person; that’s why they are used by the immune
system to distinguish self cells or antigens from non-self
(they are considered in selection of a donor in organ
transplantation).
o Act as ion channels for movement of water and ions
across the cell membrane (osmosis and simple diffusion)
o Act as carriers for passive transport of certain substances
across the cell membrane (facilitated diffusion; see below)
o Act as pumps for active transport of certain substances
across the cell membrane (active transport; see below)
o Act as receptors for hormones and neurotransmitters
 Remember that peripheral proteins act as enzymes
whereas integral proteins carry out the other functions.
 Carbohydrates on the surface of a cell membrane (=
glycocalyx) are either attached to proteins (forming
glycoproteins) or to lipids (forming glycolipids).

Fig 1: The cell membrane
 The nucleus
- Contains chromatin (DNA) which condenses to form chromosomes
before cell division. The DNA replicates during cell division to carry
genetic information from the mother cell to the daughter cells.
- The nucleus also contains one or more nucleoli rich in ribosomal
RNA (the RNA is synthesized from DNA by transcription). The
ribosomal RNA diffuses to the cytoplasm to be translated into
proteins (in the ribosomes of the rough endoplasmic reticulum).
- The proteins may act within the cell or may be packed within
vesicles (in the Golgi apparatus) for secretion to the outside.
 The endoplasmic reticulum
- Complex meshwork of canals and vesicles, extending from the
nucleus to the exterior of the cell.
- Two types:
o Smooth endoplasmic reticulum:
- Has no ribosome on its surface
- For synthesis of lipids and steroids
- Contains enzymes for certain metabolic functions within
the cell (e.g. detoxification of foreign substances)
o Rough endoplasmic reticulum:
- Has ribosomes on its surface
- For protein synthesis
 The Golgi apparatus
- Closely associated with the rough endoplasmic reticulum.
- For processing and package of proteins synthesized in the rough
endoplasmic reticulum into secretory vesicles (most of the packed
proteins act as enzymes).
 The mitochondria
- The power houses of cells (provide the energy used by the cell to
perform its functions). They are abundant in certain cells like
endocrine cells, parietal cells and renal cells (because these cells
need energy for synthesis of hormones or active transport of ions).
- Each mitochondrion is surrounded by two phospholipid bilayer
membranes; the inner one is folded to produce cristae. The cristae
and the inner cavity of the mitochondrion (the matrix) contain the
respiratory enzymes needed for oxidative phosphorylation of glucose
to release large amount of energy in form of ATP (Adenosine
diphosphate).
- Each mitochondrion contains DNA that plays a role in formation of
few intra-mitochondrial proteins (using mitochondrial ribosomes) and
in its own replication.

- Abnormalities of mitochondrial DNA may result in certain diseases,
usually affecting the high energy tissues (muscle, heart and brain).
These diseases are always inherited from mothers (this is because
the defective mitochondria are inherited through ova of mothers;
whereas sperms of fathers do not contain mitochondria).
 The lysosomes
- Vesicles formed from the endoplasmic reticulum and Golgi
apparatus. They contain hydrolytic enzymes (proteases, lipases,
carbohydrases & nucleases) that are used in hydrolysis or digestion
of engulfed material (e.g. digestion of bacteria within vacuoles of the
white blood cells).
Fig 2: The cell organelles

TRANSPORT MECHANISMS ACROSS CELL MEMBRANES
- There are constant movements of O2, CO2, nutrients, electrolytes
and waste products across cell membranes. A variety of transport
mechanisms are involved, these are generally classified into passive
and active transport mechanisms.
 Passive transport mechanisms:
- Do not consume energy in transport.
- Transport substances from areas of higher concentration to
areas of lower concentration (i.e. down the concentration or
electrical gradient).
- Either do not use carrier (= simple diffusion) or use carrier (=
facilitated diffusion).
 Active transport mechanisms:
- Consume energy in transport.
- Transport substances from areas of lower concentration to
areas of higher concentration (i.e. against the concentration or
electrical gradient).
- Always need carrier for transport.
- Transport of a substance against its chemical or electrical gradient,
with consumption of energy and usage of a carrier is known as
primary active transport.
- Transport of a substance with an other one that’s transported
actively is known as secondary active transport. Here the substance
uses the same carrier that’s used by the other substance.
- Secondary active transport (also known as co-transport) may occur
in the same direction of the primary substance (= symport), or in the
opposite direction (= antiport).

 Substances transported by simple diffusion
- Diffusion is the process by which a substance expands, because of
the random movement of its particles to fill the available volume.
- Non-polar substances transported by simple diffusion include:
o Fatty acids
o Steroid hormones (synthesized from cholesterol)
o Gases (O2 and CO2)
- Simple diffusion of polar substances (water soluble substances) like
ions is low. However, it can occur through certain "ion channels"
(integral proteins in the cell membrane).
- Passive diffusion of water through cell membranes is known as
osmosis. It occurs through certain water channels known as
aquaporins. Water moves from the side of lower concentration of a
solute to the side of higher concentration of the solute.
Fig 2: Passive transport

 Substances transported by facilitated diffusion
- Do not consume energy in the process of transport.
- Have a maximum rate of transport that depends on the density of
carriers on the cell membrane. The maximum rate is reached when
all the carriers are saturated.
- Examples include transport of glucose through the basolateral
membranes of renal and intestinal cells and its absorption from the
ECF by most cells of the body.
Substances transported actively
- The well known example of primary active transport is the pump
that transports sodium and potassium against their concentrations (=
The Na+ / K+ pump). It transports three atoms of sodium from ICF to
ECF in exchange to two atoms of potassium from ECF to ICF.
Fig 3: Active transport

- The well known example of secondary active transport is the
transport of glucose (coupled to sodium) through the luminal
membranes of intestinal and renal cells.
- Secretion of hydrogen by renal cells is another example of
secondary active transport. However, hydrogen moves in the
opposite direction to sodium (anti-port).
 Other transport mechanisms

o Endocytosis (active vesicular transport)
- Endocytosis is the uptake of molecules into cells. Here a molecule
fuses with the cell membrane, invaginates it and then the invagiation
is separated from the cell membrane to form of a vesicle.
- Special proteins may facilitate the process of endocytosis (clathrin
and dynamin).
- When the engulfed substance is dissolved in fluid, the process is
known as pinocytosis (cell drinking); and when it is a particulate
matter or bacteria, the process is known as phagocytosis (cell
eating).
o Exocytosis (active vesicular transport)
- Exocytosis is the release of substances from cells. (i.e. opposite to
endocytosis). Proteins synthesized within the cell are usually packed
into secretory vesicles and secreted by exocytosis.
- Notice that exocytosis requires calcium, energy and certain
proteins.
o Solvent drag (passive transport)
- During diffusion of a solvent, it tends to drag some solute with it.
This occurs in capillaries.

Fig 3: Endocytosis & Exocytosis
 Transport proteins "carriers, pumps & ion channels"

- These are highly specialized transmembrane proteins that allow
passage of water, ions, glucose, urea and other substances through
cell membranes.
- The carriers change their shape (configuration) when they bind
their substances to move them from one side of the cell membrane to
the other side, usually down the chemical or electrical gradients (=
facilitated diffusion).
- The pumps act as ATPase enzymes to catalyze hydrolysis of ATP.
The released energy is used in active transport of substances,
against their chemical or electrical gradients. Examples include the
Na+/ K+ ATPase pump, the proton pump and the Ca2+ ATPase pump.

(Remember that the active transport is either primary active or
secondary active, see above).
- The ion channels allow simple diffusion (down chemical or
electrical gradients). They include:
 Leak channels
- Always open
- Example: Potassium leak channels which are responsible
for the resting membrane potentials
- Resting membrane potentials are found in almost all cells
in the body (see chapter two)
 Voltage gated channels
- Have gates that open or close in response to changes in
voltage "or potential" in the cell membrane
- Examples: voltage gated sodium channels & voltage
gated potassium channels which are responsible for the
depolarization and the repolarization phases of action
potentials respectively
- Action potentials are only found in excitable tissues
(nerve and muscle)
 Ligand gated channels
- Have gates that open when certain membrane receptors
bind to specific neurotransmitters or hormones, and close
when these chemicals are released from the receptors
 Mechano-sensitive channels
- Have gates that open in response to direct mechanical
stimulation of the cell membrane
- They are involved in movement of some cells

QUESTIONS FOR SELF ASSESSMENT-1 (BEST OF FIVE)
1- Concerning the cell organelles:
a. mitochondria synthesize proteins
b. endoplasmic reticulum is needed for cell division
c. nuclei are the power houses of cells
d. lysosomes contain hydrolytic enzymes
e. Golgi apparatus translates RNA into proteins
2- Water passes through cell membranes by:
a. facilitated diffusion
b. primary active transport
c. osmosis
d. co transport
e. none of the above
3- Maintenance of constant internal environment is known as:
a. endocytosis
b. feedback mechanism
c. physiology
d. homeostasis
e. haemostasis
4- Facilitated diffusion:
a. occurs against the electrical gradient
b. requires energy
c. not influenced by the concentration gradient
d. has no transport maximum capacity
e. mediated by a protein carrier
5- Which of the following can cross the cell membrane passively?
a. Proteins
b. carbon dioxide
c. potassium ions
d. calcium ions
e. glucose
6- Facilitated diffusion differs from simple diffusion in that it:
a. does not require energy
b. occurs against the electrical gradient
c. is not influenced by the concentration gradient
d. is mediated by a protein carrier
e. has no transport maximum capacity
7- Which of the following is a passive type of transport:
a. solvent drag
b. endocytosis
c. exocytosis
d. co-transport
e. antiport

8- Concerning transport of ions across cell membranes, which of
the following is not true:
a. secondary active transport requires energy
b. simple diffusion occurs down the concentration gradient
c. facilitated diffusion occurs against the electrical gradient
d. active transport is mediated by a protein carrier
e. secondary active transport has a transport maximum capacity
9- Concerning transport across cell membranes, all the following
require integral proteins to cross cell membranes except:
a. water
b. glucose
c. oxygen
d. potassium ions
e. calcium ions
10- Leak channels:
a. are present in almost all cells in the body
b. have gates that open or close in response to changes in potential
c. open when a hormone binds to a nearby membrane receptor
d. are responsible for the depolarization phase of action potentials
e. are activated by mechanical stimulation of cell membranes
11- All of the following substances cross the cell membrane
through channels or transporters except:
a. sodium
b. bicarbonate
c. oxygen
d. water
e. potassium
12- Homeostasis is:
a- arrest of bleeding
b- maintenance of constancy of the external environment
c- formation of a blood clot
d- normal pH
e- represented by control of body temperature
Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Answer d c d e b d a c c a c e

CHAPTER 1
BODY FLUIDS
TOTAL BODY WATER (TBW)
-Body composition in a 70 Kg young adult male:
– Water = 60% (of the total weight which is 70 kg)
– Proteins = 18%
– Fats = 15%
– Minerals = 7%
– Carbohydrates < 1%
-Therefore: water is the most important constituent in the body.
-With total deprivation of water, survival is limited to a few days,
whereas total food deprivation is tolerated for at least a month.
-Total body water (in a 70 kg, young adult male):
= 60 % of the total body weight
= 42 Kg (60/100 x 70) = 42 L (because density of water = 1)
 Variation in the % of TBW among different subjects
-The % of TBW varies according to:
1) Age
- TBW decreases with age (e.g. in an embryo it is near to
100%, in a neonate = 80%, in an adult male = 60% and above
the age of 60 years = 52% in males).
2) Sex
- The % of TBW is higher in males when compared to
equivalent females. This is because the female has higher
percentage of fat in her body, compared to an equivalent male,
with the same age and weight.

- The higher percentage of fat is associated with less
percentage of water because fat cells contain less water than
other types of cells. For example, water in a fat cell is about
13% whereas in a muscle cell is about 75%.
3) Body size
- The % of TBW is higher in thin-tall subjects compared to
obese-short subjects.
- This is also explained by the higher percentage of fat in the
obese subject, and therefore less percentage of water.
Table1.1: % of TBW in males and females of different ages

Age % of water in a male % of water in a female
Embryo Almost 100% Almost 100%
Neonate 80% 80%
Adult 60% 51%
Elderly 52% 46%
 Body Fluid Compartments

- As mentioned in the introduction of this book, cells of the body do
not only contain water, but also surrounded by water.
- Therefore, total body water is divided into two compartments:
– 1) Intracellular fluid (ICF): = 2/3 of the total body water or 40%
of the total body weight (TBwt).
– 2) Extracellular fluid (ECF): = 1/3 of the total body water or 20%
of the total body weight (TBwt).
- ECF is further divided into:
– a) Interstitial fluid: = 75% of ECF or 15% of TBwt.
– b) Intravascular fluid (plasma): = 25% of ECF or 5% of TBwt.
– c) Trans-cellular fluid: Negligible.
Notes about trans-cellular fluid:
 It includes synovial fluid, pleural fluid, pericardial fluid,
peritoneal fluid, cerebrospinal fluid...
 Its volume is very low, that’s why it is not included in
calculations of ECF.
 In abnormal conditions (like pleural effusion, pericardial
effusion and ascites) its volume becomes very high.
- In a 70 Kg adult male:
– Total body water = 42 L (60% of the total body weight)
• ICF = 28 L (= 40% of total body weight)
• ECF = 14 L (= 20% of total body weight)
– ISF = 10.5 L (= 15% of total body weight)
– IVF (Plasma) = 3.5 L (= 5% of total body weight)
Question: Calculate the expected body fluid compartments in an
average 60 kg adult male
Answer: Total body weight= 60Kg, therefore: Total body water =
60/100 x 60 = 36L, ICF = 40/100 x 60 = 24 L, ECF = 20/100 x 60 =
12 L, ISF = 15/100 x 60 = 9 L and IVF = 5/100 x 60 = 3 L.
Notes about body fluid compartments in neonates:
 Total body water constitutes a very high proportion of the total
body weight (about 80%)
 ECF exceeds 30% and ICF volume is less than 40% of total
body weight. Therefore, ECF/ICF volume ratio is very high

 Differences between ECF & ICF:
 ECF has: lower volume, higher pH and higher concentrations of
sodium, calcium, chloride & bicarbonate. Sodium is the main
cation and chloride is the main anion.
 ICF has: higher volume, lower pH and higher concentrations of
potassium, magnesium, phosphate, sulphate and protein.
Potassium is the main cation and non-diffusible anions (like
organic phosphate and protein) are the main anions.
Table 1.2: Differences between ECF and ICF in a 70 kg adult male
Difference Extracellular fluid Intracellular fluid
Volume 15L 25L

Conc. Of Cations:
Sodium (Na+) 142.0 mmol/L 10 mmol/L
Potassium (K+) 4.0 mmol/L 140 mmol/L
+2
Calcium (Ca ) 2.5 mmol/L Negligible (0)
Magnesium (Mg+2) 2.0 mmEq/L 26 mmEq/L
Conc. Of Anions:
Chloride (Cl-) 105.0 mmol/L 4 mmol/L
Bicarbonate (HCO3-) 25.0 mmol/L 10 mmol/L
Phosphate (PO4-3) 2.0 mEq/L 100 mEq/L
Protein 17.0 mEq/L 65 mEq/L
pH 7.4 7.2
Temperature 37 c 37 c
Osmolarity 280-300 mOsm/L 280-300 mOsm/L

 Measurement of body Fluid Compartments
- Volumes of body fluid compartments can be measured using the
indicator (dye) dilution method.
- In this method, a known quantity of a substance (e.g. a dye) is
injected and allowed to distribute in the compartment of interest. After
distribution, a sample of fluid is taken from the same compartment to
measure the final concentration of the dye. Then the volume of the
compartment (known as the volume of distribution of the dye) is
calculated using the formula:
Volume of distribution = Q-e /C
Where:
- Q is the quantity of the dye injected
- e is the amount of the dye excreted or metabolized by cells
- C is the concentration of the dye after equilibration
- Substances used for measurement of body fluid compartments
should have the following characteristics:
- Non toxic
- Easily measured
- Their amounts are not altered by the body (not stored,
metabolized, excreted or produced by the body) or the
altered amount can be calculated easily
- Distribute only in the compartment being measured
- Do not affect water distribution in other compartments
Remember that:
 Leakage of a substance into other compartment decreases its
final concentration and therefore increases the calculated
volume of distribution.

Examples for substances used in measurement of body fluids:
Substances used in measurement of total body water:
-Deuterium oxide (heavy water)
-Tritium oxide (3H2O = an isotope of water)
-Antipyrine
-Aminopyridine
Substances used in measurement of extracellular fluid:
-Saccharides (inulin, manitol & sucrose)
These fail to penetrate the trans-cellular fluid
Therefore they underestimate the ECF
-Radioactive electrolytes (sodium, chloride & bromide)
These easily penetrate the entire ECF and may
escape into cells
Therefore they overestimate the ECF
-Thiosulphate & thiocynate
Substances used in measurement of plasma:
-Radioactive iodine used to label serum albumin (RISA)
-Evan’s blue dye (which binds to plasma protein and stay in
plasma)
-Labeled macroglobulin
Substances used in measurement of Blood:
-Blood volume can be calculated from plasma and packed cell
volume (PCV) by the formula: Blood = Plasma X 100/100-PCV
-The PCV is measured by centrifugation of a sample of blood
in a capillary tube, and then the percentage of the packed
cells at the bottom of the tube is calculated (read about the
PCV in chapter 5).

-It is also calculated from red blood cell volume and plasma
volume by the formula: Blood = plasma + red blood cell
volume.
-The red blood cell volume is obtained from the volume of
distribution of re-injected red blood cells labeled with
radioactive chromium (51Cr).
Intracellular fluid and interstitial fluid:
- Are measured indirectly by two substances, for two
compartments. Then ICF or ISF can be subtracted as follows:
ICF = TBW - ECF
ISF = ECF - plasma
Factors Affecting Body Fluid Compartments

Body fluid compartments are affected by:
1. Osmosis
2. Diffusion
3. Gibbs Donnan equilibrium
4. Sodium-potassium pump
5. Starling's forces
6. Abnormalities of water balance
1- Osmosis
- Osmosis is the movement of water molecules across a semi-
permeable membrane, from a region of lower concentration of a
solute to a region of higher concentration of the solute (see the
introduction).

- All cell membranes and capillaries are semi-permeable membranes
(permeable to water and generally not permeable to solute).
- For osmosis to occur there should be a difference in solute
concentration between the two sides of the membrane, i.e. difference
in osmolarity.
Fig 1.1: Osmosis
1
Solution A has the same
concentration as solution B
= No osmosis
2
Solution A has higher
concentration than solution B
= Osmosis from B to A
_______________________________________________________
Osmolarity, Osmolality & Tonicity

Osmolarity
- Osmolarity is the number of osmoles of solute per one liter of
solution.
- It is used to describe concentrations of osmotically active particles in
a solution.
- If a solute dissociates into ions to form an ideal solution, each
liberated ion is an osmotically active particle.

- For example: dissociation of one mole of (NaCl) gives one osmole of
sodium and one osmole of chloride (i.e. 2 osmoles).
- However, one mole of glucose (C6H12O6) in a solution gives one
osmole; because organic substances like glucose are non-ionizable.
- Remember that one mole of a substance contains the same number
of molecules that are found in one mole of any other substance (=
Avogadro's number = 6.061 x 1023).
- The osmotically active particles can exert osmotic pressure if they
are in contact with another solution, but separated from it by a semi-
permeable membrane (permeable to the solvent but not to the
solute).
- Osmotic pressure is defined as the pressure necessary to prevent
solvent migration (i.e. prevent osmosis).
Fig 1.2: The osmotic pressure
Osmotic pressure prevents

osmosis from solution B to
solution A

Osmolality
- Osmolality is the number of osmoles per one kilogram of solvent.
- It is more accurate than osmolarity since it depends on mass (which
is constant) rather than volume (which is affected by changes in
temperature and pressure).
- In body fluids, where the solvent is water, the concentration of
solutes is very low (highly diluted); therefore one liter and one
kilogram are equal. More over, temperature and pressure are
constant under normal physiological conditions; that’s why osmolality
and osmolarity are equal in body fluids.
- Because of this similarity between osmolality and osmolarity, you
may find osmolality expressed in (mosm/L) rather than (mosm/Kg).
- Osmolality of plasma = (280-300) mosm/L. Na+ and its anions are
responsible for most of this value (Na+ determines ECF osmolality).
- Osmolality of intracellular fluid = (280-300) mosm/L. K+ and its anions
are responsible for most of this value (K+ determines ICF osmolality).
Tonicity
- This term is used when describing osmolality of a solution relative to
osmolality of the plasma.
- Accordingly, solutions may be:
o Isotonic (with osmolality similar to plasma)
o Hypotonic (with osmolality lower than plasma)
o Hypertonic (with osmolality higher than plasma)
- Intravenous (I.V.) infusion of each type of these solutions affects
volumes and osmolarities of body fluid compartments. These effects
can be studied from the following figure and table:

Fig 1.3: The effects of different types of solutions on cells:
Table 1.3: Effects of I.V. solutions on volumes and osmolarities

ECF ICF
Solution Osmosis
Vol. Osmol. Vol. Osmol.
Isotonic The same The same The same
Hypotonic
Hypertonic
- From the above table:

- I.V. infusion of an isotonic solution increases volume of ECF
with no effect on its osmolarity, and no effect on volume or
osmolarity of ICF (i.e. no effect on cells).
- I.V. infusion of a hypotonic solution increases volumes of ECF
and ICF and decreases osmolarities of ECF and ICF.
- I.V. infusion of a hypertonic solution increases volume and
osmolarity of ECF, and decreases volume of ICF while its
osmolarity is increased.

Calculation of osmolality:
A. From the Freezing Point Depression
- One osmole depresses the freezing point of a solution by 1.86 οc
- One milliosmole depresses the freezing point by 0.00186 οc
- Number of milliosmoles per liter in a solution =
The freezing point depression/0.00186
Q: Calculate the osmolality of normal human plasma if the freezing
point = - 0.55 οc
Answer: Plasma osmolality = 0.55/0.00186 = 295 mosm/L
B. From the Molarity

Number of osmoles = Number of moles x number of particles
(liberated by a single molecule)
Q: Calculate the osmolarity of 0.9% NaCl solution and mention the
effect of this solution on volume and osmolarity of ICF after its
infusion in the plasma? (Molecular weight of NaCl = 58.5).
Answer: 0.9% NaCl = 0.9 g/dL, (x 10) = 9 g/L
Molarity = [conc. g/L] / MWt of NaCl = 9 / 58.5 mol/L
= 0.154 mol/L, (x 1000) = 154 mmol/L
Osmolarity = 154 x 2 = 308 mosm/L
(Isotonic, has no effect on ICF)
(Remember that: This solution is regarded as isotonic solution
although its osmolarity is higher than plasma Osmolarity (> 300
mosm/L). This is because the dissociation of NaCl in plasma is not
as complete as in true ideal solutions (dissociation is about 93%).
Therefore the osmolarity of 0.9% NaCl solution in plasma is actually
less than 308 mosm/L; that’s why it is isotonic).

Q: Calculate the osmolarity of 5% glucose solution. If one liter of this
solution is infused intravenously, mention the immediate and the later
effects on the cells? (MWt glucose = 180).
Answer: 5% glucose = 5g/dL = 50 g/L
Molarity = [Conc. g/L]/MWt
= 50/180 = 0.278 mol/L
(x 1000) = 278 mmol/L
Osmolarity = 278 x 1 = 278 mosm/L (Isotonic)
Immediate effect on cells: no effect because it is isotonic
Later effect on cells: After uptake of glucose by cells the solution
becomes hypotonic; water enters cells, it increases volume &
decreases osmolarity of ICF.
Q: Calculate the osmolality of a solution containing 110 mmol NaCl,

25 mmol NaHCO3, 2.5 mmol CaCl2, 5 mmol urea & 5 mmol glucose
Answer: Plasma osmolality = (110x2) + (25x2) + (2.5x3) + (5x1) +
(5x1) = 287.5 mosm/L.
(Remember that glucose and urea are non-ionizable).
C. Using a formula
Osmolarity of the plasma can be calculated using the following
formula: Plasma Osmolarity = 2([Na] + [K]) + [glucose] + [urea]
(All concentrations are in mmol/L)
Q: Calculate the osmolarity of the plasma if [Na] = 140 mmol/L, [K] =
4 mmol/L, [Glucose]= 5 mmol/L and [Urea]= 7 mmol/L.
Answer: Osmolarity = 2(140 + 4) + 5 + 7
= 300 mosm/L (isotonic).

2- Diffusion
- It is expansion or passage of a substance through a cell membrane
down its chemical or electrical gradient, due to continuous random
movement of its molecules.
- Water follows osmotically active particles to inside or to outside the
cell, this affects volumes of body fluid compartments.
Fig 1.4: Diffusion
3- Gibbs Donnan equilibrium

- The presence of non-diffusible anions (protein and organic
phosphate) within the cell affects distribution of diffusible ions (both
anions and cations); it allows entry of diffusible cations (e.g. Na+) into
the cell and prevents entry of diffusible anions (e.g. Cl-).
Fig 1.5: Gibbs Donnan equilibrium

- The concept was shown theoretically by Gibbs and confirmed
experimentally by Donnan (= known as Gibbs Donnan equilibrium).
- At equilibrium:
1- Total cations = total anions (on either side of the membrane)
2- The product of diffusible ions on one side equals the product of
diffusible ions on the other side of the membrane (This holds for
cations and anions of the same valence).
- Take this example of two solutions “a” and “b”; in which Na+ and Cl-
are diffusible cations and anions respectively; X- indicates non
diffusible anions.
Solution (a) Solution (b)
+
Na Na+
Cl- Cl-
X-
At equilibrium:
1- [Na+]a = [Cl-]a + [X-]a (i.e. cations in a = anions in a)
+ -
[Na ]b = [Cl ]b (i.e. cations in b = anions in b)
2- [Na+]a x [Cl-]a = [Na+]b x [Cl-]b
[Na+]a/ [Na+]b = [Cl-]b / [Cl-]a
From the above relationships:

 [Na+]a > [Cl-]a
(Cations on the side of X- are greater than anions on the same side)
 [Cl-]a < [Cl-]b
(Diffusible anions on the side of X- are less than on the other side)
 [Na+]a > [Na+]b
(Cations on the side of X- are greater than cations on the other side)

 [Na+]a + [Cl-]a + [X-]a> [Na+]b + [Cl-]b
(There is greater number of ions on the side of X- than on the other
side).
Remember that:
 The greater number of particles in compartment “a” exerts an
osmotic effect resulting in swelling of this compartment.
 A similar effect occurs in body fluids, i.e. cells tend to undergo
swelling but this is prevented by the Na+/K+ pump.
Effects of Donnan equilibrium in the body:

1- Swelling of cells
The ICF contains higher concentration of non diffusible anions than
the ECF and therefore more particles. This may result in swelling of
the cells and eventually their rupture. However, swelling of cells is
prevented by the action of the Na+/K+ pump and other ion channels.
The Na+/K+ pump transports 3 sodium ions to outside of the cell and
2 potassium ions to inside; this decreases the total number of ions
inside the cell and prevents its swelling (see below).
2- Electrical difference across the cell membrane
The asymmetrical distribution of diffusible ions across the cell
membrane generates an electrical difference that can be determined
for each ion by the Nernst equation. In addition the asymmetrical
distribution of non diffusible anions participates in genesis of the
resting membrane potential (see chapter two).
3- Slight difference in concentration of ions between plasma and ISF
Since plasma contains higher concentration of protein than the
interstitial fluid (ISF), it contains slightly higher concentration of

cations (like sodium and potassium) and lower concentration of
anions (like chloride and bicarbonate).
4- Slight difference in concentration of ions between the plasma and
the glomerular filtrate
At the kidney, proteins are not filtered out of the glomerular
capillaries. The filtrate is free of plasma protein. Therefore the
plasma contains slightly higher concentration of cations (like sodium
and potassium) and lower concentration of anions (like chloride and
bicarbonate) than in the filtrate.
Table 1.2: Differences between plasma and ISF in an adult male
Difference Plasma Interstitial fluid
Volume 5% of body weight 15% of body weight

Conc. Of Cations:
Sodium (Na+) 145 mmol/L 140 mmol/L
+
Potassium (K ) 4.1 mmol/L 4 mmol/L
Calcium (Ca+2) 2.5 mmol/L 2.1 mmol/L
Magnesium (Mg+2) 1 mmol/L 1 mmol/L
Total cations 152.6 mmol/L 147.1 mmol/L
Conc. Of Anions:
Chloride (Cl-) 105 mmol/L 110 mmol/L
Bicarbonate (HCO3-) 25 mmol/L 30 mmol/L
Phosphate (PO4-3) 1 mmol/L 1 mmol/L
Organic acids 5 mmol/L 5 mmol/L
Protein 16.6 mmol/L 1.1 mmol/L
Total anions 152.6 mmol/L 147.1 mmol/L

4- The Sodium-Potassium Pump
- Found in all cells of the body.
- Transports sodium and potassium actively against their chemical
gradients (3 Na+ ions to outside and 2 K+ ions to inside the cell).
Fig 1.6: The sodium potassium pump
- It accounts for 20-45% of the total metabolic energy expended by

the cell.
- Consists of alpha and beta subunits extending through the cell
membrane. The beta subunit is a glycoprotein, whereas the alpha
subunit is a protein with extracellular binding sites for K + and
intracellular binding sites for Na+ and ATP.
Fig 1.7: Subunits of the sodium potassium pump

- It is the alpha subunit that transports Na+ and K+; however,
separation of the two subunits inactivates the pump
- The Na+/K+ ATPase enzyme releases energy from ATP that’s used
in transport of 3 sodium ions to outside the cell and 2 potassium ions
to inside. This results in accumulation of negative charges inside the
cell (i.e. it is an electrogenic pump).
Functions of the Na+/K+ pump
- Participates in genesis of the resting membrane potential (i.e.
generates negative charges towards the inner side of the cell
membrane (see chapter two)).
- Prevents swelling and rupture of cells by removing excess sodium
ions to outside (see Donnan effect).
Regulation of the pump
- The pump is activated by accumulation of Na+ ions intracellularly.
- Activity is increased by:
o Insulin, Aldosterone and thyroid hormones
- Activity is inhibited by:
o Dopamine and digitalis
5- Starling's forces
- As mentioned above, movement of water across cell membranes
depends on osmosis. However, movement of water across the walls
of capillaries depends, in addition to that, on 4 primary forces (known
as Starling’s forces) that control fluid exchange between plasma and
interstitium.
- Although Starling’s forces act in all blood vessels, they cause fluid
exchange only in capillaries.

- This is because the walls of capillaries, unlike arteries and veins,
are characterized by pores between the endothelial cells that allow
movement of water (for this reason capillaries are called “the
exchange vessels”).
- Starling forces include:
1- Capillary hydrostatic pressure (HPc)
- It is the pressure of plasma acting on the lateral wall of the
blood vessel
- For filtration (from plasma to ISF)
= 35 mmHg at the arteriolar end of capillaries
= 15 mmHg at the veniolar end of capillaries
2- Capillary oncotic pressure (OPc):
- The osmotic pressure of plasma proteins (also known as
colloid osmotic pressure or oncotic pressure)
- It is exerted mainly by albumin
- For absorption (from ISF to plasma)
= 25 mmHg throughout the capillaries (proteins are not filtered
and therefore their oncotic pressure is not changed)
3- Interstitial fluid hydrostatic pressure HPISF:
- Acts in the opposite side to HPC;(i.e. against filtration)
4- Interstitial fluid oncotic pressure OPISF:
- Acts in the opposite side to OPC; (i.e. against absorption)
Notes about osmotic pressure of proteins (Oncotic pressure)
 Oncotic pressure is mainly exerted by albumin because it is
the smallest plasma protein and therefore it has the highest
number of particles than other types of plasma proteins.
 Osmolarity depends on “number” not “size” of particles.

- Calculation of filtration pressure:
- Both hydrostatic pressure of ISF and oncotic pressure of ISF are of
low magnitude, they act against each other and therefore they cancel
each other. That’s why they are not considered in calculation of the
filtration pressure.
- The filtration pressure is calculated by subtracting the capillary
oncotic pressure from the capillary hydrostatic pressure as follows:
o At the arteriolar end= (35-25)= +10 mmHg (i.e. net filtration)
o At the veniolar end= (15-25)= -10 mmHg (i.e. net absorption)
Fig 1.8: Starling's forces
- A filtration pressure of + 10 mmHg indicates that Starling’s forces

cause filtration of plasma at the arteriolar end of capillaries to the
interstitium. The filtered plasma carries nutrients to the surrounding
cells & then the fluid is absorbed back at the veniolar end with the
waste products.

 About 90% of the filtered fluid at the arteriolar end of capillaries is
absorbed back to the capillaries at their veniolar end; the remaining
10% of the filtered fluid is also absorbed but by the lymphatics.
 The lymphatic vessels also absorb small amount of protein that
may escape out of the plasma to the interstitium.
 The lymphatics return this protein together with the 10% of the
filtered fluid back to the circulation at the neck where the main
lymphatic duct drains into the jugular vein. This keeps balance
between filtration and absorption of fluid at the capillaries.
 Disturbance of this balance between filtration and absorption may
result in accumulation of fluid in the interstitium causing edema.
Edema
- Edema is defined as abnormal accumulation of fluid in the
interstitial space. It is caused by many diseases through one or more
of the following mechanisms:
1- Increased capillary hydrostatic pressure (HPC)
- Some diseases may cause accumulation of blood in veins; thus
increasing the HPC at the veniolar end of capillaries.
- When the HPC becomes higher than the OPC , the return of the
filtered fluid to the capillaries is prevented causing edema.
- Examples include:
o Heart failure
 Left sided heart failure results in accumulation of blood in
the lung veins causing pulmonary edema whereas right
sided heart failure causes accumulation of blood in
systemic veins causing generalized edema.

o Venous obstruction
 Results in accumulation of blood proximal to the site of
obstruction causing localized edema
Remember that:
 Oedema is not caused by hypertension because the
hydrostatic pressure of capillaries is not increased at the
veniolar end of capillaries, which is the site of absorption
 Oedema is not caused by arterial obstruction because this
decreases blood flow to the capillaries and therefore
decreases HPC
2- Decreased oncotic pressure (OPC)

- Some diseases may lower the level of proteins in the plasma. This
decreases OPC.
- The low OPC prevents absorption of the filtered fluid back to the
intravascular space causing edema.
- Examples include:
o Malnutrition
 Decreased protein intake (e.g. Kwashiorkor)
 Results in generalized edema
o Malabsorption
 Decreased absorption of protein (e.g. due to chronic
pancreatitis)
o Liver disease (chronic disease like liver cirrhosis)
 Decreased synthesis of plasma proteins

o Renal disease (nephrotic or nephritic syndromes or renal failure)
 Loss of plasma proteins in urine
3- Lymphatic obstruction
- Obstruction of lymphatics results in accumulation of the fluid that’s
supposed to be absorbed by the lymphatics to be removed from
the interstitium. Therefore, it accumulates causing edema.
- The obstruction is caused by:
o Filaria (worms that live within the lymphatic vessels)
 Filariasis results in localized edema (very large swelling
proximal to the site of obstruction known as elephantiasis)
o Surgical removal of lymph nodes (which drain a site of cancer)
 This is done to prevent spread of secondaries from the
cancer
o It interrupts the lymph flow resulting in localized edema
4- Increased permeability of capillaries:

- Some diseases may increase the permeability of capillaries and
allow filtration of plasma proteins to the interstitium thus increasing
the OPISF which absorbs fluid to the outside causing edema.
- The capillary permeability is increased by:
o Inflammation
 The increased permeability is due to mediators of
inflammation released by white blood cells and the nearby
tissues
 Results in localized edema

o Burn
 The increased permeability is due to the high temperature
 Results in localized edema
o Allergy
 The increased permeability is due to histamine which is
released by mast cells and basophils
 Results in localized or generalized edema
Types of edema:
- Edema can be classified into 2 types (by applying pressure on it in
one site using one finger “the thumb” against bone, for a minute):
1- Pitting edema
- The finger leaves a mark (a pit) on the skin
- The mark appears because the fluid escapes away from the
site of pressure and returns slowly
- Causes of pitting edema include:
 All causes of high capillary hydrostatic pressure
 All causes of low capillary oncotic pressure
2- Non pitting edema
- The finger does not leave a mark on the skin because the
escaped fluid returns rapidly.
- This is because it is attracted by proteins that are filtered to
the interstitium
- Causes of non pitting edema include:
 All causes of increased permeability
 All causes of lymphatic obstruction

6- Abnormalities of water balance
 Water balance
- In normal physiological conditions, the body loses water in urine to
excrete waste products of metabolism and in addition to that, there is
insensible loss of water through the skin and in expired air.
- These water losses should continuously be replaced by water
intake to maintain normal water content of the body.
- On the other hand, if water intake is higher than the daily
requirement of the body, the excess water should be excreted.
- In summary: water loss should equal water intake (= water balance)
Fig 1.9: Water balance
- Abnormalities of this balance between water intake and output

cause disturbances in volumes and osmolarity of body fluid
compartments.

Normal water intake occurs through:
o drinking 1.3L/day
o solid food 0.9L/day
o metabolism 0.3L/day
Net = 2.5L/day
Normal water output occurs through:
o urine 1.5 L/day
o stool 0.1 L/day
o sweating & insensible loss 0.9 L/day
Net= 2.5 L/day
Note
- The average water intake = the average water loss = 2.5 L/day
- The above values vary greatly in different physiological and
pathological conditions:
Examples of the physiological conditions:

1- Type of work
E.g. heavy work increases sweating= increased water loss
2- Exercise
E.g. strenuous exercise increases sweating and causes
hyperventilation (increases insensible water loss in expired
air) = increased water loss
3- Degree of water intake
Affects urine volume as follows:
- High water intake increases urine volume
- Low water intake decreases urine volume
 Remember that the minimum volume of urine required for
excretion of waste products of metabolism is 500 ml/day

4- Variation in body temperature and environmental temperature
Both affect the amount of sweating, the rate of metabolism
and the rate of respiration (see chapter 4)
Examples of the pathological conditions:

1- Abnormal water intake through:
- increased metabolism (fever, hyperthyroidism)
- increased drinking (psychogenic polydypsia)
- excess intravenous fluids (fluid overload)
- complete water deprivation
2- Abnormal water loss through:
- vomiting
- diarrhea
- polyuria (diabetes mellitus, diabetes insipidus)
- excessive sweating (heat exhaustion)
- hyperventilation (metabolic acidosis)
Regulation of water balance

- As mentioned earlier, maintenance of constancy of ECF is the goal
of all systems in the body.
- Variation in water intake or water loss produces minor changes in
extracellular fluid volume and osmolarity. These changes stimulate
certain receptors (e.g. volume receptors & osmoreceptors) that
activate multiple regulatory mechanisms to restore back the
constancy of the ECF.

- The regulatory mechanisms include:
1- Mechanisms for control of water intake
- act principally through control of thirst
2- Mechanisms for control of water loss
- act principally through control of urine volume
Control of water intake

- Under normal environmental and physiological conditions, the
amount of water gained by metabolism or solid food is almost
constant whereas the amount gained by drinking may be variable.
That’s why water intake is generally regulated through regulation of
drinking (= regulation of thirst). On the other hand, water intake
through solid food and metabolism is a non-regulatory component.
Thirst
- Defined as the subjective perception that provides the urge for
humans and animals to drink fluids.
- Also defined as the conscious desire for water.
- Regulated by thirst center located in the hypothalamus.
- There are 4 major stimuli to thirst:
 Angiotensin II: This is an octa-peptide hormone produced in the
plasma following release of renin enzyme from the "Juxta-
glomerular apparatus" in the kidney (see below).
- It acts directly on specific receptors located in
circumventricular organs in the brain (neural organs that lie
outside the blood-brain barrier) to stimulate thirst. The
neuronal pathway from the circumventricular organs to the
hypothalamus also uses angiotensin II as a neurotransmitter.

 Hypertonicity: Small increases of 1-2% of the effective osmotic
pressure of plasma causes shrinkage of osmoreceptors in the
hypothalamus (due to osmosis from the osmoreceptors to the
ECF).
- Shrinkage of the osmoreceptors results in direct mechanical
stimulation of the thirst center because its dendrites which are
attached to the osmoreceptors are stretched by the shrinkage.
 Hypovolemia: The volume of ECF is sensed via volume
receptors located at the low pressure side of the circulation (i.e.
the venous side, at the junction of the right atrium and the vena
cava and at the entry of the pulmonary vein into the left atrium).
- Hypervolemia stretches these receptors which send inhibitory
impulses through the vagus nerve to inhibit thirst. On the other
hand, hypovolemia stimulates thirst through reduction of the
inhibitory discharge from the volume receptors to the thirst center.
 Hypotension: The blood pressure is sensed via baroreceptors
located at the high pressure side of the circulation (i.e. the arterial
side, at the carotid sinus and the aortic sinus which are found at
the bifurcation of the common carotid artery and the aortic arch
respectively).
- Hypertension stretches these receptors which send inhibitory
impulses through the vagus and the glossopharyngeal nerves to
inhibit the thirst center. On the other hand, hypotension stimulates
thirst through reduction of the inhibitory discharge from these
receptors to the thirst center.
Remember that:
 Thirst is one of the symptoms of dehydration and shock

The hormone atrial natriuretic peptide (ANP) inhibits thirst!
ANP is a peptide hormone released by atria in response to
hypervolemia. It inhibits the effect of angiotensin II on thirst to
decrease ECF volume. It also decreases ECF volume through
inhibition of aldosterone action on the kidney, increasing the rate of
glomerular filtration and increasing the rate of sodium excretion in
urine (notice that loss of sodium is followed by loss of water).
Important note: Drinking stimulates mechanoreceptors in the mouth
and pharynx which provide input to the hypothalamus to attenuate
the sensation of thirst. This occurs before any reduction in plasma
tonicity; thus acting as a safeguard against over-ingestion of water.
Control of water loss

- Under normal environmental and physiological conditions, the
amount of water lost by sweating, respiration and through the skin is
almost constant whereas the amount lost by urine is variable. The
minimal volume of urine that can be excreted to eliminate the
metabolic waste products = 0.5 L/day. The maximal volume depends
on water intake.
- For this reason water loss is controlled through regulation of urine
volume. This involves the kidney and the hormones acting on it.
Renal function
- The functional unit of the kidney is the "nephron" which consists of:
glomerulus, for filtration & tubules: for reabsorption and secretion.
- About 180 L of fluid pass through the glomeruli of the kidney each
day. However, only 1.5 L is excreted in urine indicating that the renal
tubules reabsorb more than 99% of the filtered fluid.

Fig 1.10: The nephron
- Reabsorption of water in the renal tubules occurs as follows:

- The PCT: reabsorbs 70% of the filtrate following sodium
reabsorption. The filtrate remains isotonic
- The loop of Henle: water reabsorption occurs in the thin
descending limb without sodium reabsorption. The filtrate becomes
hypertonic; however it becomes hypotonic at the end of the thick
ascending limb because it reabsorbs solutes without water.
- The DCT: relatively impermeable to water. About 5% of the
filtrate may be reabsorbed. The filtrate remains hypotonic.
- The CDs: Completely impermeable to water except at the
presence of ADH (see ADH below).

Hormonal activity
 ADH
- Antidiuretic hormone, also known as vasopressin
- It is a nona-peptide hormone synthesized in the hypothalamus and
stored in the posterior pituitary gland
- It is released in response to the same major stimuli of thirst, through
similar mechanisms:
o Hyperosmolarity (detected by osmoreceptors located at the
hypothalamus. They cause mechanical stimulation of ADH)
o Hypovolemia (results in less stretch of the volume receptors at
the low pressure side of the circulation and therefore less
inhibition of ADH release)
o Hypotension (results in less stretch of the baroreceptors at the
high pressure side of the circulation and therefore less
inhibition of ADH release)
o Angiotensin II (stimulates ADH release, see below)
o Drugs (drugs that stimulate ADH release include barbiturates,
clofibrate, nicotine, acetylcholine and others)
Functions of ADH
- ADH acts on the collecting ducts in the kidney causing water
retention. It facilitates reabsorption of 7-13% of the filtrate
- When ADH level in plasma is high, it also causes vasoconstriction
resulting in elevation of the blood pressure
Abnormalities of ADH:
- Deficiency of ADH causes polyuria and excessive thirst due to
hypovolemia. Urine volume may reach up to 23 L/day. The condition
is known as diabetes insipidus (DI). It may result from a problem in

the hypothalamus (neurogenic DI) or a problem in the renal receptors
for ADH (nephrogenic DI)
- Excessive ADH secretion causes reduction in urine volume,
hypertension and edema due to water retention. The condition is
known as syndrome of inappropriate ADH secretion (SIADH). It is
caused by many problems; these include head trauma, lung tumors,
pneumonia and pancreatitis.
 Aldosterone
- Steroid hormone synthesized in the adrenal cortex
- It is released in response to the following stimuli:
o Hyperkalemia
Directly stimulates aldosterone release from the adrenal cortex.
o High level of ACTH
The adrenocorticotrophic hormone (ACTH) is released by the
anterior pituitary gland to stimulate secretion of cortisol (not
aldosterone) by the adrenal cortex. But, in high levels (due to
endocrine abnormalities) it also stimulates release of aldosterone.
o The renin-angiotensin-aldosterone system
In this system, renin enzyme which is produced by the Juxta-
glomerular apparatus in the kidney results in formation of
angiotensin II. The later stimulates aldosterone secretion from the
adrenal cortex.
The Juxta-glomerular apparatus (JGA) is formed by:
- Cells of the afferent arteriole (juxta-glomerular cells)
- Cells of the DCT (macula densa cells)
- Lacis cells (= extra-glomerular mesangial cells)

Fig 1.11: The juxta-glomerular apparatus (JGA)
- This apparatus (specifically the juxta-glomerular cells) secretes

renin in response to one of the following stimuli;
o Hyponatremia (low [Na])
o Renal ischemia (e.g. due to hypotension or hypovolemia)
o Sympathetic stimulation
- Renin acts on a plasma peptide known as angiotensinogen (14
amino acids) produced by the liver to form angiotensin I (10 aa).
- Angiotensin I is converted to angiotensin II (8 aa) by the action of
angiotensin converting enzyme (ACE).
- This enzyme is produced by the pulmonary endothelial cells. It is
also released to the circulation by lung macrophages.

- Angiotensin II increases ECF volume & pressure because it causes:
1- Vasoconstriction
2- Stimulation of the sympathetic (this stimulates release of
renin and renin forms angiotensin I and then angiotensin II
and the cycle repeats itself in a positive feedback mechanism)
3- Stimulation of thirst
4-Stimulation of ADH
5- Stimulation of aldosterone
- Aldosterone acts on the DCT and CDs in the kidney to stimulate
retention of sodium and secretion of potassium. Water follows
sodium resulting in increased ECF volume and pressure.
- Unlike excessive ADH secretion, excessive aldosterone secretion
due to adrenal tumors results in hypervolemia and hypertension but it
does not cause edema. The explanation involves ANP as follows:
 Hypervolemia caused by sodium and water retention
stimulates release of ANP from the atria. ANP acts in the
kidney to increase sodium and water excretion. This prevents
development of edema. This phenomenon is known as
“aldosterone escape phenomenon”.
 Atrial natriuretic peptide (ANP)
- A peptide hormone released by atria in response to hypervolemia.
- It reduces ECF volume through the following effects:
o Inhibition of the effect of angiotensin II on thirst
o Inhibition of the effect of aldosterone on the kidney
o Increasing the rate of glomerular filtration
o Increasing excretion of sodium in urine (= natriuresis; notice
that loss of sodium is followed by loss of water).)

1. The percentage of total body water is higher in:

a. females compared to equivalent males
b. old subjects compared to children
c. infants compared to neonates
d. thin subjects compared to obese ones
e. male children compared to female children
2. Using the indicator dilution method, ECF volume is measured by:
a. heavy water
b. RISA
c. inulin
d. heavy water and RISA
e. Evan’s blue dye
3. The volume of distribution of substance A in an average adult
male was found to be 3.5 litres. This substance could be:
a. distributed to all body fluid compartments
b. highly exchangeable between plasma and interstitium
c. tightly bound to plasma proteins
d. rapidly metabolised by cells
e. all the above are correct
4. The ECF differs from the ICF because it contains:
a. less concentration of sodium
b. lower pH
c. higher temperature
d. osmolarity of about 300 mosm/L
e. higher concentration of chloride
5. The interstitial fluid:
a. constitutes about 5% of total body weight in adults
b. temperature is less than that of the plasma
c. osmolarity is determined by Cl- concentration
d. volume can be measured by using inulin and manitol
e. contains slightly higher concentration of Cl- than plasma
6. In a twenty years old man, the following volumes of distribution
are obtained using the indicator dilution method: inulin = 14L and
Evan’s blue dye = 3L; which of the following is not true:
a- intravascular fluid volume is about 3L
b- ECF volume is about 14L
c- ICF volume cannot be calculated from this data
d- ISF volume cannot be calculated from this data
e- blood volume cannot be calculated from this data

7. The osmolarity of plasma is a function of:
a. calcium concentration
b. protein concentration
c. sodium concentration
d. urea concentration
e. glucose concentration
8. The concentration of calcium in the extracellular fluid is about:
a. 10 mg/dL
b. 5 mmol/L
c. 1.5 meq/L
d. 1.0 %
e. 0
9. Filtration of fluid from plasma to interstitium is increased by:
a. increased capillary oncotic pressure
b. increased capillary hydrostatic pressure
c. increased interstitial hydrostatic pressure
d. decreased interstitial oncotic pressure
e. lymphatic obstruction
10. Edema due to high capillary permeability results from:
a. filariasis
b. renal failure
c. burn
d. hepatic failure
e. deep vein thrombosis
11. Gibbs Donnan equilibrium is responsible for:
a. higher concentration of Na+ in ICF than in ECF
b. lower concentration of K+ in plasma than in ISF
c. slightly higher concentration of HCO3- in ISF than in plasma
d. lower concentration of Cl- in intracellular fluid than in plasma
e. higher volume of interstitial fluid than plasma
12. The ECF/ICF volume ratio is highest in:
a- lean males
b- obese males
c- male children
d- female children
e- newborns
Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Answer d c c e e d c a b c c e

CHAPTER 2
EXCITABLE TISSUES
- Nerves and muscles are said to be excitable because they are
capable of generating electrical signals known as action potentials.
- In addition to action potentials, excitable tissues are also
characterized by resting membrane potentials. However, unlike
action potentials, resting membrane potentials are found in almost all
cells of the body.
THE RESTING MEMBRANE POTENTIAL (RMP)

- It is the difference in electrical potential between the interior and the
exterior of cell membranes at rest, with the interior being more
negative relative to the exterior.
- The cell membranes are said to be “polarized”; i.e. negative inside
and positive outside.
Fig 2.1: The polarized cell membrane
- The difference in potential across the cell membrane can be

measured by special devices (e.g. the Cathode Ray Oscilloscope),
using electrodes placed in the two sides of the cell membrane.
Fig 2.2: Measurement of the resting membrane potential

- The magnitude of the RMP differs in different types of cells, for
example:
In a skeletal muscle cell = - 90 mv
In a cardiac muscle cell = - 90 mv
In a nerve cell = - 70 mv
Causes of the RMP:
a- Potassium efflux
b- The Sodium- potassium pump
c- ICF non diffusible anions
a- Potassium efflux
- This is the major cause of RMP.
- The cell membrane is more permeable to potassium than sodium
(because the hydrated atom of potassium is smaller than the hydrated
atom of sodium).
- Therefore potassium diffuses to the outside down its concentration
gradient through potassium leak channels.
Fig 2.3: Potassium efflux
- For each atom of potassium that diffuses to the outside, a negative

charge is generated inside and a positive charge is generated outside
the cell membrane.

- The positive charges outside the cell membrane rebel the potassium
ions, forcing them back to the inside through the leak channels (down
their electrical gradient from the positive side to the negative side).
However, net potassium efflux continues until the chemical gradient
which drives potassium to the outside is equal to the electrical
gradient that drives potassium to the inside (= stage of equilibrium).
b- The Sodium- potassium pump
- An electrogenic pump that pumps 3 sodium ions to outside and 2
potassium ions to inside, thus generating negative charges within the
cell.
Fig 2.4:The sodium potassium pump
- Sodium and potassium ions are transported actively against their

concentration gradients, using energy released by hydrolysis of ATP
(see chapter 1).
c- ICF non diffusible anions
- Presence of non diffusible anions inside the cell (protein and organic
phosphate) contributes to the genesis of RMP by increasing the
number of negative charges inside the cell (= very low contribution).

The equilibrium potential:
- The equilibrium potential (E) for an ion gives an idea about its role in
genesis of the resting membrane potential. Here the ion is placed in a
medium similar to ECF and allowed to pass into or out of the cell to
reach equilibrium, without contribution of other ions. The membrane
potential generated due to difference in concentrations of that ion in
ECF and ICF is called the equilibrium potential. However, it does not
occur normally because of the contribution of other ions.
- The equilibrium potential can be measured by the Nernst equation

as follows:
 for cations: E = 61 log [cation]ECF/[cation]ICF

 for anions E = 61 log [anion]ICF/[anion]ECF
- Examples:
 E for K+ = 61 log 4/140 = - 90 mv (close to the RMP, indicating

a major role of K+ in the genesis of RMP).
 E for Na+ = 61 log 150/15 = + 61 mv (very far from the RMP,
indicating a minor role of Na+ in genesis of the RMP).
 E for Cl- = 61 log 110/8 = - 70 mv (However, there is no
evidence that Cl- has an active transport similar to Na+ and K+;
so it does not contribute to the RMP).
- The Goldman equation can be used for direct calculation of the
RMP. It includes the effects of the major ions and their permeabilities
(P) across the cell membrane; as follows:
RMP (mv) = 61 log PK [K]ECF + P Na [Na]ECF + PCl [Cl]ICF
PK [K]ICF + P Na [Na]ICF + PCl [Cl]ECF

THE ACTION POTENTIAL (AP)
- Occurs only in excitable tissues (nerve & muscle).
- Involves alterations in the membrane potential (depolarization and
repolarization) following sufficient mechanical, electrical or chemical
stimulation.
- The action potential can be recorded by special devices (e.g. the
cathode ray oscilloscope).
- The recorded action potential can be: Monophasic in which the

recording electrodes are placed on the surface of cell membrane; or
Biphasic in which they are placed on the two sides of cell membrane.
Components of the action potential
1- Stimulus artifact
- Occurs at the time of stimulation (marks the point of stimulation)
- Due to current leakage from the stimulus electrode
2- Latent period
- The isopotential interval from the point of stimulation to the start of

action potential.
- Can be used for measurement of the conduction velocity (CV) in an

axon. Conduction velocity = (the distance between the stimulating
and recording electrodes) divided by (the latent period).
3- Threshold
- The voltage at which the "fast voltage gated sodium channels"

open. If not reached, action potential never occurs.

- It is usually about 15 mv less than the resting membrane potential
(e.g. -75 mv when the RMP is -90 mv).
4- Depolarization
- Due to sodium influx through the "fast voltage gated sodium

channels".
- The membrane potential moves towards the equilibrium potential

for sodium (+60 mv) but it does not reach it because opening of the
sodium channels is short lived (the channels rapidly become
inactivated and will never open again unless the membrane potential
returns back to the resting level); (see the refractory period below).
5- Repolarization
- Due to potassium efflux through "voltage gated potassium

channels".
- Opening of the "voltage gated potassium channels" is slower than

sodium channels; that’s why potassium efflux occurs after sodium
influx. Opening is also more prolonged than sodium channels and
this explains the occurrence of after-hyperpolarization (see below).
- Additional factors that facilitate repolarization are the inactivation of

the "fast voltage gated sodium channels" and the reversal of the
membrane potential (becomes positive inside); thus limiting further
sodium influx.
6- After- depolarization
- The slower fall in the rate of repolarization.
- occurs when repolarization is 70% completed.

7- After-hyperpolarization
- Slight overshooting in the hyperpolarizing direction, due to excess

potassium efflux through the "voltage gated potassium channels",
and then restoration of the membrane potential to the resting level
(due to the activity of the Na/K pump).
Fig 2.5: The action potential
Characteristics of action potentials

1- All or none law
- Sub threshold stimuli can never generate an action potential
whereas threshold and supra threshold stimuli can generate action
potentials of the same magnitude (i.e. full action potential).
- This indicates that action potentials either occur in a full form or do
not occur at all (i.e. all or none).

2- Refractory period
- Period of time during which a cell membrane is refractory to
excitation, because it is already in a state of excitation. During this
period the "fast voltage gated sodium channels" are inactivated
- The refractory period is divided into:
 Absolute refractory period:
o Action potential can never be generated even with supra-
threshold stimulation.
o Its duration from the firing level to the end of one third of
repolarization.
 Relative refractory period:
o Action potential can not be generated by ordinary stimulation
but it can be generated by supra-threshold stimulation.
o Its duration from the end of absolute refractory period to the
end of repolarization (i.e. to the start of after-depolarization).
Fig 2.6: The refractory period

3- Conduction
- Action potential can be propagated (conducted) through axons of
neurons.
- Conduction is an active, self propagating process that occurs with
no change in amplitude or velocity of the action potential.
- There are two types of conduction:
 Conduction in unmylinated nerves (continuous conduction)
 Conduction in myelinated nerves (saltatory conduction)
(jumping of action potential from a node of Ranvier to
another).
Fig 2.7: Types of electrical conduction
_______________________________________________________

- The velocity of conduction depends on:
 Degree of myelination:
- Faster in thick myelinated > thin myelinated > un-myelinated
 Distance between nodes of Ranvier:
- Faster when the distance is increased
 Diameter of the axon:
- Faster when the diameter is larger
The compound action potential

- The above description of action potential refers to action potential
that’s recorded from a single axon. It differs from an action potential
recorded from a peripheral nerve (which contains many axons).
- The action potential that’s recorded from a peripheral nerve is
called the compound action potential and it is characterized by
multiple peaks.
Fig 2.8: The compound action potential
- It represents algebraic summation of action potentials of many

axons in the nerve. The multiple peaks appear because a peripheral
nerve contains different types of fibers with different sizes, thresholds
and peaks.

Effects of ECF electrolyte disturbances on excitability
Disturbances in sodium ions
- Have little effect on the resting membrane potential (RMP).
- Hyponatremia decreases the amplitude of the action potential.
Disturbances in potassium ions
- Affect the resting membrane potential because potassium efflux is
the main cause of the resting membrane potential.
- Hypokalemia causes hyperpolarization (because it allows more K
efflux and therefore the resting membrane potential gets away from
the threshold; this decreases excitability.
Fig 2.9: Hyperpolarization caused by excessive K efflux
- Mild to moderate hyperkalemia limits potassium efflux and therefore

the RMP is elevated to become closer to the threshold, this
increases excitability. However, severe hyperkalemia elevates the
RMP to the level of the threshold and therefore it inhibits excitability
(the cell can not respond to stimulation since its RMP is not below
the threshold; that’s why hyperkalemia prevents excitation of the
heart and stops it in diastole).
Fig 2.10: Effect of hyperkalemia on the RMP
Disturbances in calcium ions

- Calcium ions guard the sodium leak channels, thus preventing
sodium influx through these channels during the resting state.
- In hypocalcemia sodium ions enter the cells because the leak
channels are not guarded, this elevates the RMP and makes the
cells more excitable (for this reason hypocalcaemia is characterized
by high excitability in neuromuscular junctions resulting in
involuntary contraction of some muscles (= this is known as tetany).
- Hypercalcemia has an opposite effect; it prevents influx of sodium
ions through their leak channels; therefore, it stabilizes cell
membranes and decreases excitability.
- Severe hypercalcemia may interfere with the normal function of
nerves and may result in coma.
- Hypercalcemia increases contractility of cardiac muscle but not
skeletal muscle; that’s because calcium ions in ECF enter cardiac
muscle cells and increase contraction (they do not enter skeletal
muscle cells). Severe hypercalcemia stops the heart in systole.

Action potential of the cardiac muscle
Fig 2.11:
- There are two types of muscle in the heart:

 The cardiac muscle proper: whose AP is characterized by the
plateau phase (due to calcium influx). The plateau prolongs the
refractory period.
 The conductive system: whose AP is characterized by the
prepotential (unstable resting membrane potential, mainly due to
slow potassium efflux).
NERVE
- Nerves are distributed throughout the body to form the nervous
system. The nervous system is subdivided into:
 Central nervous system (CNS = the brain and the spinal cord).
 Peripheral nervous system (PNS = the spinal and cranial nerves).
- Each nerve consists of many nerve cells (neurons).

- A neuron is the main functional cell in the nervous system.
- It consists of:
o Cell body (or soma)
o Dendrites
o Axon
Fig 2.12: The neuron
- There are about 100 billion neurons in the CNS and about 10-50
times this number glial cell (neuroglia).
- - Neuroglia (= non-excitable cells) are 3 types in the CNS:
o Microglia
- Phagocytic cells in the brain (resemble tissue
macrophages)
o Astrocytes (= macrglia)
- Provide a supportive matrix around the neurons
- Form part of the blood brain barrier (BBB)
- Maintain stable ECF concentration of ions (by taking
up K+)
- Two types: fibrous astrocytes (in the white matter) and
protoplasmic astrocytes (in the gray matter)
o Oligodendrocytes (= macroglia)
- Form myelin sheath around axons in the CNS

- There is one type of glia in the peripheral nervous system (PNS):
o Schwann cells
- The only glial cells in the PNS
- Form myelin sheath around axons in the PNS
- Each cell wraps its membrane around axons up to
100 times to form a myelin sheath
Fig 2.13: Myelination
Types of nerve fibers

- Nerve fibers are divided into 3 groups: (A, B and C).
- These groups differ in the axon size and degree of myelination.
- The A group is subdivided into: (A, A, A and A).
Group A
 Thick myelinated = The fastest (especially the A type)
 Has the largest diameter
 Carries touch, proprioception and motor impulses
 Most susceptible to pressure
 Least susceptible to local anesthetics, that’s why touch
sensation, which is carried by type A fibers, is not completely
depressed by local anesthetics

 Conduction velocity of type A fibers:
- A = 70-120 m/s
- A = 30-70 m/s
- A = 15-30 m/s
- A= 12-30 m/s
Group B
 Thin myelinated
 Found in the preganglionic autonomic neurons
 Most susceptible to hypoxia than to pressure or local
anesthetics
 Conduction velocity= 3-15 m/s
Group C
 Un-myelinated
 Mainly carries pain and cold sensations
 Also found in the postganglionic sympathetic neurons
 Most susceptible to local anesthetics (that’s why local
anesthetics depress pain sensation which is carried through
type C fibers)
 Least susceptible to hypoxia and pressure
 Conduction velocity= 0.5-2 m/s
Important note
- There is another method of nerve fiber classification (Ia, Ib, II, III
and IV) However, it is rather confusing.
- Here Ia, Ib, II and III are equivalent to the subdivisions of group A
fibers whereas IV is equivalent to type C fibers.
- This classification is used to describe afferents of the muscle
spindle & the Golgi tendon organ (see the motor system).

SYNAPTIC TRANSMISSION
THE SYNAPSE
- It is a junction between two neurons. It allows transmission of
electrical impulses from one neuron to another.
- The transmission is called "chemical transmission" because a
chemical substance "a neurotransmitter" is released by the first
neuron (the pre-synaptic neuron) to bind receptors in the second one
(the post-synaptic neuron). However, direct electrical transmission
can occur through special synapses.
- Unlike electrical transmission through the axons, chemical
transmission is uni-directional (i.e. allows conduction in one way only;
from the pre-synaptic neuron to the post-synaptic neuron).
- The total number of synapses in the CNS is very large; a single
axon may divide to form over 2000 synaptic endings.
- Most synapses occur between the axon terminals of the pre-
synaptic neuron and the cell body or dendrites of the post-synaptic
neuron (axo-somatic and axo-dendritic connections). However, other
types of connection may occur (e.g. axo-axonal).
Fig 2.14: Synapses

General structure of the synapse
Fig 2.15:
The presynaptic neuron:

 Releases a neurotransmitter (NT) through the presynaptic
membrane
 The NT is synthesized in the cell body, packed into vesicles in
the Golgi apparatus and then transported through the axon to
be stored at the terminal end of the axon.
 The terminal end of the axon is slightly dilated for storage of
the NT. It is called the synaptic knob or button.
The postsynaptic neuron:
- Contains receptors for the NT.
- The receptors are located on the postsynaptic membrane.

The synaptic cleft:
- The area that separates the pre and post synaptic neurons
- It is about 20-40 nm wide
- The NT has to cross this area to bind its receptors on the
postsynaptic membrane
- It may contain an enzyme for hydrolysis of the NT and
therefore terminates its action (e.g. acetylcholine esterase
enzyme for hydrolysis of acetylcholine).
Steps of neurotransmitter release to the synaptic cleft

1- Arrival of the action potential to the terminal end of the axon
2- Opening of voltage-gated Ca++ channels, allowing Ca++ influx
3- Ca++ stimulates release of the neurotransmitter (NT) from the
vesicles by exocytosis (it increases movement of the vesicles
to fuse with the pre-synaptic membrane and facilitates the
process of exocytosis)
4- The NT within the vesicles is released to the synaptic cleft.
- Note: Ca++ is then removed from the knob by "Ca2+/Na+ antiport "
Fate of the neurotransmitter at the synaptic cleft

 Neurotransmitters at the synaptic cleft may:
1- Combine with receptors on the post-synaptic membrane (to
exert their effects)
2- Be hydrolyzed by an enzyme in the synaptic cleft
3- Return back to the synaptic knob by endocytosis
4- Diffuse to the plasma (where it is catabolized there or in other
tissues)

Fig 2.16: Fate of neurotransmitters at the synapse
Notes to remember:
 Not all of these options are applicable for all types of
neurotransmitters.
 For example: acetylcholine is hydrolyzed in the cleft by
acetylcholine-esterase into acetate and choline. Therefore it
does not return back to the synaptic knob by endocytosis;
however, its metabolite choline returns back.
 Another example: noradrenaline is not hydrolyzed in the cleft.
Therefore it returns back to the synaptic knob by endocytosis
and packed again into vesicles to be released later (recycling).
 Because it is not hydrolyzed in the cleft, the amount of
noradrenaline that diffuses to plasma is higher than that of
acetylcholine.

ELECTRICAL EVENTS IN THE POSTSYNAPTIC NEURON
- When a neurotransmitter combines with its specific receptor, it
results in opening or closure of some "ligand gated channels" on the
postsynaptic membrane.
- This changes the permeability of the postsynaptic membrane to
specific ions and results in a postsynaptic potential.
- The postsynaptic potential is a local potential that can be excitatory
or inhibitory (depending on which type of ion channels is opened).
Excitatory post synaptic potential (EPSP):
 This is a depolarizing potential that increases excitability of the
post-synaptic neuron
 It does not cause a response because it does not reach the
threshold
 It is caused by an excitatory neurotransmitter that opens:
- sodium channels causing sodium influx
- or calcium channels causing calcium influx
Inhibitory post synaptic potential (IPSP):
 This is a hyperpolarizing potential that decreases excitability of
the post-synaptic neuron
 It is caused by an inhibitory neurotransmitter that opens
potassium or chloride channels causing potassium efflux or
chloride influx respectively or closes: sodium or calcium
channels preventing their influx.
Summation of local potentials:
- For an EPSP to reach a threshold and cause a response, it should
summate with other EPS potentials.
- There are two types of summation: spatial and temporal.

Spatial summation: Occurs when multiple EPSPs arrive
simultaneously, at the same time, on the post-synaptic neuron. The
potentials when added together reach the threshold and produce an
action potential.
Temporal summation: Occurs when a single synaptic knob is
stimulated repeatedly to produce successive EPSPs. These when
added together reach the threshold and produce an action potential.
Fig 2.17: Summation of local potentials
Action potential in the post-synaptic neuron

- Summation of several EPSPs generates an action potential in the
post-synaptic neuron.
- The action potential starts in the generator zone which is situated
at the origin of the axon (axon hillock).
- It is more excitable than the rest of the axon because:
 It contains higher number of voltage-gated Na+ channels
 Its threshold is more near to the RMP (-59 mV)

Inhibition and facilitation at synapses
Direct inhibition
 Occurs directly by releasing an inhibitory NT from a
presynaptic neuron into a postsynaptic neuron.
 This direct inhibition on the postsynaptic neuron is called
postsynaptic inhibition.
Fig 2.18: Direct inhibition
Indirect inhibition
 Occurs indirectly on the neuron
 Has many forms; for example:
o it follows a previous discharge on the postsynaptic neuron (=
here the already excited postsynaptic cell is in a refractory
period or in after-hyperpolarization (Periods of low excitability)
o it occurs in a postsynaptic neuron if the release of the
excitatory NT coming from its presynaptic neuron is prevented
by direct inhibition from another neuron (this is known as
presynaptic inhibition)

Fig 2.19: Indirect inhibition
Properties of synapses
a- Transmission is uni-directional
- From the presynaptic neuron to the postsynaptic neuron.
b- Synaptic delay
- The minimum time required for chemical conduction from a synaptic
knob to its postsynaptic neuron is a bout 0.5 ms.
- Measurement of synaptic delay within the CNS gives information
about the number of synapses in a pathway. For example if the delay
is about 1.2 ms, the number of synapses is probably two.
c- Synaptic fatigue
- Failure or decrease in frequency of conduction in a synapse
following repetitive stimulation.
- Due to exhaustion of the NT (release of all vesicles at the synaptic
knob) or inactivation of the receptors at the postsynaptic membrane.
d- Post-tetanic facilitation
- Increased frequency of conduction in a synapse following repeated
stimulation.
- Caused by increased availability of calcium in the synaptic knob
due to repeated stimulation.

e- Convergence and divergence
- Most of the inputs to the postsynaptic neurons are multiple
(convergence).
- Most of the outputs from the presynaptic neurons are multiple
(divergence)
Fig 2.20: Convergence and divergence
The Neuromuscular junction (NMJ)

- Special type of synapse (between a neuron and a muscle cell).
- The muscle cell membrane that receives the terminal end of the
neuron is known as the motor end plate. It is characterized by
multiple invaginations (junctional folds) that increase its surface area.
- Transmission through the NMJ is similar to chemical transmission
through other synapses.
- The neurotransmitter is acetylcholine and the receptors are
nicotinic.
- The local potential produced by binding of acetylcholine to its
nicotinic receptors at the NMJ is called the end plate potential.
- The end plate potential is always excitatory (caused by sodium
influx) and it is regularly capable of generating an action potential
(the high amount of acetylcholine released in the cleft is 10 times
sufficient for generation of an action potential).

Fig 2.21: The neuromuscular junction
Factors affecting neuromuscular transmission

 Autoimmune destruction of acetylcholine receptors at the NMJ (=
Myasthenia gravis): characterized by weak skeletal muscles.
 Autoimmune destruction of calcium channels at the synaptic knob
of the NMJ (= Lambert-Eaton syndrome): similar to Myasthenia
but unlike it, the weakness of skeletal muscles is improved by
repeated contractions, due to increased Ca++ level in the knob.
 Blockers of acetylcholine receptors (e.g. curare and
succinylcholine): cause paralysis of skeletal muscles.
 Snake venoms: block acetylcholine receptors causing paralysis.
 Organophosphorus compounds (OPC e.g. parathion) & nerve
agents (e.g. Sarin, Tabun and VX): inhibit acetylcholinesterase to
allow acetylcholine to act for prolonged periods in both nicotinic
receptors (causing fasciculations, tachycardia & mydriasis) and
muscarinic receptors (causing bradycardia, bronchospasm,
salivation, lacrimation, diarrhea and vomiting). OPC are used as
insecticides whereas nerve agents are military weapons.
 Botulinum toxin: released by bacteria (Clostridium botulinum):
Prevents release of acetylcholine from neurons causing paralysis.

MUSCLE
Types of muscle
- There are 3 types of muscle:
 Skeletal muscle
- Striated
- Under voluntary control (somatic nervous system)
- Has no anatomical connection between fibers
- Does not contract in the absence of external stimulation
Fig 2.22:
 Cardiac muscle
- Striated
- Under involuntary control (autonomic nervous system)
- There are connections between fibers (gap junctions and
intercalated discs)
- Contracts rhythmically in the absence of external stimulation
Fig 2.23:

 Smooth muscle
- Non striated
- Under involuntary control (autonomic nervous system)
- Connections between fibers may be present (e.g. smooth
muscle in viscera) or absent (e.g. smooth muscle in the eye).
Fig 2.24:
Structure of skeletal muscle

- Each muscle consists of bundles of fibers
Fig 2.25:
- Each fiber is a single cell, composed of myofibrils

Fig 2.26:

- Each myofibril consists of filaments, the filaments are:
 Thick filaments: myosin II
 Thin filaments: actin, tropomyosin and troponins (I, T & C)
 Others: actinin and titin
Fig 2.27:
Striations
- Appearance of alternate light and dark bands in skeletal or cardiac
muscle fibers when examined under direct polarized light, using the
microscope.
- Are due to differences in refractive indexes of thick & thin filaments
- The light area (I band):
 Is isotropic to polarized light
 contains actin only
 divided into two halves by the Z line
- The dark area (A band):
 is anisotropic to polarized light
 contains myosin + ends of actin
 contains lighter area in the middle (H band) that contains
myosin only and divided by the M line

- The area between two Z lines is called sarcomere
- The sarcomere is the functional unit of muscles. It contains an A
band + two halves of I band.
Fig 2.28:
The thick filaments:

Myosin II
- Each has 2 heavy chains and 4 light chains forming a tail and 2
globular heads.
- Each head of myosin has:
 Actin binding site
 ATPase activity
Fig 2.29:

The thin filaments :
a- Actin:
- Consists of two chains that form double helix
- Has active sites that act as targets for myosin heads
Fig 2.30:
b- Tropomyosin:
- Lie in the groove between the two filaments of actin
- Hides the actin active sites during relaxation of muscle
- This prevents binding of myosin heads to actin
Fig 2.31:

c- Troponins:
- Troponin T: binds other troponin units to tropomyosin
- Troponin I: inhibits interaction between actin and myosin
- Troponin C: binds calcium which initiates contraction
Fig 2.32:
The sarcotubular system

- Membranous structures in the muscle fiber
- Made up of: T tubules & sarcoplasmic reticulum
Fig 2.33:

The T tubules:
- Are transverse tubules that arise as invaginations from the cell
membrane.
- Located at the A-I junctions in skeletal muscles (= two per cell); and
at the Z lines in cardiac muscles (one per cell).
- Inside the cell they are perforated by the myofibrils.
- They transmit action potentials from the sarcolemma to the interior
of the cell.
The sarcoplasmic reticulum:
- Forms irregular curtain around the myofibrils.
- Has an enlarged terminal on each side of the T tubule "the
sarcoplasmic cisternae". These form with the T tubule a triad (T
tubule + 2 cisternae on each side).
- It stores calcium to be released to the sarcoplasm when an action
potential arrives through the T tubule.
Molecular basis of contraction (Sliding theory)

- Contraction occurs by sliding of the thin filaments over the thick
filaments, thus shortening the sarcomers.
Steps of muscle contraction:
 Depolarization of the sarcolemma (by an action potential
coming from the neuromuscular junction).
 Transmission of the action potential to interior of the muscle
cell via the T tubules.
 The passage of the depolarization wave through the T tubules
induces opening of dihydropyridine receptors in the membrane
of the T tubules.

 The dihydropyridine receptors:
o in the cardiac muscle they allow influx of calcium & this
triggers release of stored calcium in the terminal cisterns.
o in skeletal muscle fibers they act as sensors that detect
arrival of the depolarizing wave & trigger release of stored
calcium.
 Release of stored calcium from the terminal cisterns to the
sarcoplasm occurs via the ryanodine receptors
 Calcium in the sarcoplasm binds to troponin C
 This results in:
o Weakness of the binding of troponin I to actin
o Conformational changes in tropomyosin
 Tropomyosin moves laterally to uncover the actin active sites
 Myosin heads bind the uncovered actin active sites
 ATP is hydrolyzed and the energy released by hydrolysis
causes flexion of myosin heads inwards.
 This causes sliding of actin on myosin resulting in shortening
of the sarcomers (= contraction).
Fig 2.34:

Notes to remember:
- The process by which depolarization of the muscle cell results in
contraction is known as excitation-contraction coupling.
- Seven active sites in actin are uncovered for each molecule of
troponin C that binds a calcium ion.
- Contraction of skeletal muscle depends on release of stored
calcium from the sarcoplasmic reticulum whereas contraction of
cardiac and smooth muscles requires influx of calcium from the
ECF.
- The calcium binding protein in smooth muscle is known as
calmodulin. Unlike troponin, calmodulin initiates contraction
immediately. First it activates a kinase enzyme that’s needed for
phosphorylation of myosin head. This phosphorylation triggers the
ATPase activity of the head and this is followed by contraction.
Steps of muscle relaxation:
 Shortly after releasing calcium to the sarcoplasm, the
sarcoplasmic reticulum begins to transport it back actively by
the Ca-Mg ATPase pump
 When the level of calcium in the sarcoplasm is lowered
sufficiently, calcium is released from troponin C
 This causes actin & myosin interaction to stop, tropomyosin
returns to its position & the muscle relaxes.
Remember that:
 ATP is consumed for both contraction & relaxation.
 If calcium transport back to the sarcoplasmic cisterns is inhibited,
relaxation will never occur (= contracture)

 If no energy is available for relaxation (no ATP), the muscle
becomes rigid (= rigor). A common example is (rigor mortis) which
occurs after death.
- Relaxation in smooth muscles follows de-phosphorylation of myosin
heads by a phosphatase enzyme. However, contraction may
continue in spite of that for some time; this is due to the latch bridge
mechanism.
- In the latch bridge mechanism, myosin remains attached to actin
resulting in a sustained contraction with minimal energy expenditure;
as in the vascular smooth muscle.
Types of contraction
Isotonic contraction:
- Isotonic contraction (the same tension) is contraction against a
constant load that results in shortening of a muscle.
- The muscle develops a constant tension throughout the range of
movement (e.g. when lifting a light object).
Isometric contraction:
- Isometric contraction (the same length) is contraction without
appreciable shortening of a muscle.
- The tension developed by the muscle is not constant, it is
increasing (e.g. when trying to lift a very heavy object).
- Since there is no distance of movement (the same length of
muscle); no work is done during the isometric contraction (remember
that work = force times distance, which is zero).
- Standing involves isometric contraction of muscles whereas walking
involves both isometric & isotonic contractions.

Single muscle twitch and summation of contractions
- A single sufficient stimulation of a muscle fiber results in a single
action potential that results in a single contraction followed by
relaxation (= single muscle twitch).
- The duration of the single muscle twitch is longer than the duration
of the action potential.
- Repeated stimulation of a muscle fiber results in repeated action
potentials that are followed by successive contractions.
- Since there is no refractory period for contractions, each new
contraction starts before completion of the previous one. This results
in summation of these contractions.
- The tension developed by summation of contractions is greater than
that’s developed by a single contraction.
- Summation of contractions into one continuous contraction is called
tetanus.
Tetanus
- Tetanus may be complete (with no any relaxation between
contractions) or incomplete (with some incomplete relaxations
between contractions).
- The frequency of stimulation that results in tetanus is determined by
the duration of the single muscle twitch.
- With a frequency of stimulation just below the frequency of
summation, the tension developed is increased by each new stimulus
until a uniform tension per contraction is reached. This is called
treppe or staircase phenomenon.
- Here the increase in tension is not due to summation, it is due to
increased availability of calcium to troponin C.

Types of muscle fibers
There are two types of muscle fibers:
Type one fibers:
 Called red muscles (darker than other types)
 Respond slowly to stimulation (i.e. have long latency)
 Have high oxidative capacity
 Contract to maintain posture
 E.g. muscles of the back
Type two fibers:
 Called white muscles
 Have short twitch duration
 Respond rapidly (i.e. have short latency)
 Have high glycolytic capacity
 Specialized for fine skilled movement
 E.g. muscles of the hand
The oxygen debt mechanism

- During severe exercise, the amount of oxygen delivered to skeletal
muscle by the circulation is not enough for aerobic metabolism; for
this reason skeletal muscle has to find extra oxygen or additional
sources of energy; this is achieved as follows:
 It takes oxygen from myoglobin
 It metabolizes glucose anaerobically to lactic acid to synthesize
ATP
 It uses phosphorylcreatine to synthesize ATP
- Hyperventilation after exercise provides extra amount of oxygen
that can be used to repay oxygen taken from myoglobin, to

catabolize lactic acid to carbon dioxide and water, and to replenish
phosphorylcreatine.
- This extra amount of oxygen consumed after exercise is described
as the oxygen debt.
- The mechanism of oxygen debt does not occur in the cardiac
muscle because it depends exclusively on aerobic metabolism for
energy production.

1- The resting membrane potential is generated by:
a. opening and closure of ligand gated channels
b. passage of ions through voltage gated channels
c. selective permeability of the cell membrane to potassium
d. closure of sodium leak channels by calcium
e. the high concentration of phosphates in the cell
2- The following is true about the action potential:
a. an external stimulus is not always needed for its initiation
b. the depolarization phase is always due to Na+ influx
c. its duration is equal in all types of excitable cells
d. after-depolarization phase is due to activity of the Na+/K+ pump
e. it can be summated in skeletal but not in cardiac muscle
3- Concerning myelination, which of the following is not true:
a. synthesized from phospholipids and protein
b. found in preganglionic sympathetic neurons
c. found in postganglionic sympathetic neurons
d. found in the central nervous system
e. formed by oligodendroglial cells
4- If ECF K+ concentration is increased from 3.5 to 5.0 mmol/L:
a. the resting membrane potential becomes less negative
b. the resting membrane potential will not change
c. fast voltage gated sodium channels will open
d. an action potential will occur spontaneously
e. the cell membrane becomes hyperpolarized
5- Leak channels:
a. are present in almost all cells in the body
b. have gates that open or close during action potentials
c. have gates that open when a hormone binds to its receptor
d. are responsible for the depolarization phase of action potentials
e. gates are closed by the end of the action potential

6- Calcium channels in synaptic knob:
a. Allow release of neurotransmitter through them
b. Are voltage gated
c. Are ligand gated
d. Are opened when acetylecholine is released
e. Cause termination of the action potential
7- These proteins are involved in skeletal muscle contraction except:
a. calmodulin
b. actin
c. tropomyosin
d. myosin
e. troponin C
8- The A band in a striated muscle
a. is a light area
b. contains thick filaments only
c. is divided by the M line
d. is longer during relaxation than during contraction
e. appears due to overlapping between actin and myosin
9- Concerning chemical conduction, which of the following is not
true:
a. it is unidirectional (one way direction)
b. excitatory neurotransmitters open Na+ channels
c. inhibitory neurotransmitters open Ca++ channels
d. GABA opens CI- channels in the postsynaptic neurons
e. the post-synaptic neuron is influenced by many pre-synaptic
neurons
10- Ryanodine receptors:
a. allow influx of calcium from ECF to ICF in cardiac muscle
b. allow release of calcium from the sarcoplasmic cisternae to ICF
in skeletal muscle
c. are found in skeletal but not cardiac muscle
d. act as sensors for arrival of excitation through the T tubule
e. allow pumping back of calcium to sarcoplasmic cisternae
11- Isometric contraction differs from isotonic contraction in that:
a- it does not occur in cardiac muscle
b- it occurs during walking
c- it does not involve interaction between actin and myosin
d- the muscle tension applied is increased during the contraction
e- the force applied equals zero
Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Answer c a c a a b a c c b d

CHAPTER 3
THE AUTONOMIC NERVOUS SYSTEM
INTRODUCTION
- The nervous system can be classified into two physiological
divisions: The somatic nervous system (SNS) and the autonomic
nervous system (ANS)
Table 3.1: Comparison between the SNS and the ANS:
The somatic nervous system The autonomic nervous system

- Controls voluntary functions - Controls involuntary functions
e.g. limb movements e.g. cardiac beats
- Supplies skeletal muscles - Supplies smooth and cardiac
muscles
- One neuron connects the - Two neurons connect the central
central part with the target part with the target muscle
muscle - The two neurons are:
preganglionic & postganglionic
neurons connected by a ganglion
Fig 3.1 Peripheral neurons of the SNS and the ANS

Divisions of the autonomic nervous system
- The autonomic nervous system (ANS) is divided into:
 Sympathetic division
 Parasympathetic division
Differences between the sympathetic and the parasympathetic
divisions:
* Activators
- Stressful stimuli (e.g. fear, pain, exercise…) activates the
sympathetic while complete physical and mental rest (e.g. sleep)
activates the parasympathetic.
* Metabolism
- The sympathetic nervous system causes catabolism for immediate
release of energy that’s used for fight or flight; whereas the
parasympathetic is associated with anabolic reactions that store
energy until needed by the body.
* Anatomical points
- The peripheral parts of the ANS are made up of preganglionic
(myelinated, type B) and postganglionic (unmyelinated, type C)
neurons.
- The cell bodies of the preganglionic neurons are located in the
lateral horn of the spinal cord or the motor nuclei of the cranial
nerves 10, 9, 7 and 3 (= 1973). Their axons pass through the ventral
horns to the spinal nerves and then they follow the blood vessels to
the target organs.
- The preganglionic neurons of the sympathetic are short. They leave
the spinal nerve through white rami communicantes to synapse in
sympathetic ganglia with postganglionic neurons that return back to

the spinal nerve via gray rami communicantes to be distributed to
their targets. They are longer than the preganglionic neurons.
Fig 3.2: Origin and course of a preganglionic neuron
- The sympathetic ganglia, the site of cell bodies of the

postganglionic neurons, are connected together to form the
sympathetic trunk that extends parallel to the thoracic and upper
lumbar spinal segments. Additional sympathetic ganglia are also
found in the neck (superior, middle and stellate ganglia) and in the
abdomen (collateral ganglia).
- On the other hand, the preganglionic parasympathetic neurons are
longer than the postganglionic. The ganglia are found near or within
the wall of the target organs.
Fig 3.3: The output of autonomic neurons

Output from the CNS
- The central parts of the sympathetic and parasympathetic nervous
systems originate from certain autonomic centers at the brain (e.g.
the hypothalamus or the brain stem) and then descend through the
spinal cord.
- The peripheral part of the sympathetic passes out through the
spinal nerves that originate from the thoracic and some lumbar
segments (from T1 to L2); whereas the peripheral part of the
parasympathetic passes out through some cranial nerves (number
10, 9, 7 and 3) and some sacral spinal nerves (S2, S3 and S4).
- For this reason the outflow of the sympathetic is described as
thoraco-lumbar and that of the parasympathetic as cranio-sacral.
* Effects
- The ratio of a preganglionic neuron to postganglionic neurons is
about 1:20 for the sympathetic neurons and 1:1 for the
parasympathetic neurons. This indicates that the effects of the
sympathetic are generalized (because of divergence of its
preganglionic neurons) while those of the parasympathetic are
localized.
* The neurotransmitters released by the neurons
- All preganglionic neurons whether sympathetic or parasympathetic,
and all postganglionic parasympathetic neurons release
acetylcholine whereas most postganglionic sympathetic neurons
release noradrenaline. Others release acetylcholine.
- Postganglionic sympathetic neurons that release acetylcholine
supply the sweat glands, arterioles of skeletal muscles and pilo-
erectror muscles.

Table 3.2: Comparison between the symp. and the parasymp.
Difference Sympathetic Parasympathetic
Activator* Stress Rest
Metabolism* Catabolic to release Anabolic to store
energy for fight or flight energy until needed
Pregan. neurons Short Long
Postga. neurons Long Short
Ganglia Near the spinal cord Near or within the
(paravertebral) wall of the organ
Output from the Thoracolumbar Craniosacral
CNS*
Effects* Generalized Localized
Neurotransmitter Pregananglionic: Preganglionic
released by the = Acetylcholine = Acetylcholine
neurons Postganglionic Postganglionic
= Noradrenaline = Acetylcholine
THE NEUROTRANSMTTERS
- The principal neurotransmitters (NT) in the autonomic nervous
system are acetylcholine and noradrenaline.
Acetylcholine:
- Synthesized from acetyl co A and choline in the cell body of
cholinergic neurons (i.e. neurons that release acetylcholine).
- Synthesis is catalyzed by the enzyme choline acetyltransferase.

- Acetylcholine is released by:
o All preganglionic parasympathetic neurons
o All postganglionic parasympathetic neurons
o All preganglionic sympathetic neurons
o Some postganglionic sympathetic neurons (those
supplying sweat glands, arterioles of skeletal muscles and
pilo-erector muscles)
- When released at the synaptic cleft, acetylcholine acts on its
receptors. However, its action is terminated by the
acetylcholinesterase enzyme which converts it to acetate and
choline. Therefore generally no acetylcholine diffuses to plasma.
Noradrenaline (= norepinephrine):
- Synthesized from the amino acid tyrosine in noradrenergic
neurons (i.e. neurons that release noradrenaline)
- Steps of synthesis:
 Tyrosine (from diet or from phenylalanine) is hydroxylated to
dopa (by tyrosine hydroxylase in the cytoplasm).
 Dopa is decarboxylated to dopamine (by dopa decarboxylase
in the cytoplasm).
 Dopamine is converted to norepinephrine (by dopamine beta
hydroxylase in the vesicles).
- Noradrenaline is also synthesized in the adrenal medulla (an
endocrine gland regarded as a modified sympathetic ganglion
that lost its postganglionic axons). However, in this gland most of
the synthesized noradrenaline (= norepinephrine) is converted to
adrenaline (= epinephrine) by the enzyme phenylethanolamine-N-
methyltransferase (PNMT).

- Adrenaline, noradrenaline and dopamine are called
catecholamines.
- In summary, noradrenaline is released by:
o Most postganglionic sympathetic neurons (excluding
those which release acetylcholine).
o The adrenal medulla (releases adrenaline plus some
noradrenaline).
- When released at the synaptic cleft, noradrenaline acts on its
receptors. There is no enzyme for its hydrolysis in the cleft.
However, after its diffusion into the plasma, it is hydrolyzed by two
enzymes:
 Monoamine oxidase (MAO)
 Catechol-O-methyl-transferase (COMT)
- The most important metabolite is vanillylmandelic acid (VMA),
which is excreted in urine.
- Excretion of high amount of this metabolite in urine indicates
hyper-production of catecholamines (e.g. by a tumor in the
adrenal medulla (= pheochromocytoma)).
Fig 3.4: Cholinergic and noradrenergic neurons

Other neurotransmitters:
Dopamine: Released by some interneurons in symp. ganglia
GnRH: Released by some preganglionic neurons
Co-transmitters:
(VIP): May be found with acetylcholine
(ATP, Neuropeptide Y): may be found with noradrenaline
AUTONOMIC RECEPTORS
- These are the receptors for the neurotransmitters in the autonomic
nervous system (i.e. receptors for acetylcholine and noradrenaline)
Acetylcholine receptors
1- Nicotinic receptors (N)
- Stimulated by small amount of nicotine (a chemical substance
found in tobacco).
- Found at the following sites:
 Sympathetic ganglia
 Parasympathetic ganglia
 Neuromuscular junction
 Adrenal medulla
 The brain
2- Muscarinic receptors (M)
- Stimulated by small amount of muscarine (a chemical substance
excreted in urine of tadpoles).
- Found at the following sites:
 All organs supplied by postganglionic cholinergic nerves
(these include all organs in the body supplied by autonomic
neurons except ventricles of the heart and blood vessels of

the skin, abdominal viscera and the kidney which are supplied
only by sympathetic, without parasympathetic supply).
 The brain
Noradrenaline receptors
1- Alpha receptors
Sites of alpha receptors:
Alpha 1:
Blood vessels
Dilator pupillae muscle
Sphincters
Alpha 2:
Pancreas
Presynaptic membranes
2- Beta receptors
Sites of beta receptors:
Beta 1:
The heart
Renin secreting cells
Adipose tissue
Beta 2:
Bronchi
Uterus
Pancreas
Beta 3:
Adipose tissue
-

Remember that:
 Both noradrenaline and adrenaline act on α and β receptors.
 Noradrenaline acts better on α receptors than on β receptors
while adrenaline acts better on β receptors than on α
receptors.
Fig 2.5: Autonomic receptors
 N = Nicotinic receptors M= Muscarinic receptors
EFFECTS OF SYMP. AND PARASYMP. STIMULATION

- All postganglionic parasympathetic neurons are cholinergic and
most postganglionic sympathetic neurons are noradrenergic.
- Therefore sympathetic effects are generally mediated by
noradrenaline and parasympathetic effects are generally mediated by
acetylcholine.
- Examples of these effects on various organs in the body:
Organ Sympathetic effect Parasympathetic effect
Eye pupil Dilation (it contracts the Constriction (it contracts
dilator pupillae muscle/ the constrictor pupillae
alpha receptors) muscle/ muscarinic Rs)
Salivary Stimulates secretion Stimulates secretion
glands (small amount, mucus in (large amount, watery in
consistency) consistency)
Bronchioles Bronchodilation/ Bronchoconstriction/
through beta 2 Rs through muscarinic Rs
Heart rate Increased (Positive Decreased (Negative
chronotropic)/ beta 1 chronotropic/ Muscarin.
Contractility Increased No direct effect on
of the heart Positive inotropic contractility (it does not
supply the ventricles)
GIT motility Decreased (inhibitory, Increased (excitatory, it
& contracts the sphincters relaxes the sphincters
Secretions and relaxes the walls) and contracts the walls)
Blood - Vasoconstriction - Does not supply and
vessels (mediated through alpha therefore has no effect
receptors) on blood vessels of the
- Vasodilatation of some skin, abdominal viscera
blood vessels like the and the kidney.
coronary artery - Causes vasodilatation
(mediated through beta 2 in some blood vessels
receptors). like the coronary artery)

Organ Sympathetic effect Parasympathetic effect
Micturition & Not involved in the Excitatory (contracts the

Defecation reflex; but, its walls of the bladder &
reflexes stimulation inhibits rectum & relaxes their
these reflexes sphincters)
Sex organs Mediates the Mediates the erection reflex
ejaculation reflex
Sweat glands Causes sweating No effect (does not
supply sweat glands)
BLOCKERS
- Block the actions of neurotransmitters at their receptors
- Two types:
 Competitive blockers
- Compete with the neurotransmitter (NT) for binding with its
receptors.
- The affinity of the receptor for the blocker is higher than for the
NT.
- The blocker occupies the receptor without producing any
response.
 Depolarizing blockers
- Causes prolonged depolarization of the receptor.
- The receptor becomes in state of refractory period, therefore it
does not respond to the neurotransmitter.

Blockers of Acetylcholine
 Nicotinic blockers:
- Blockers of acetylcholine at nicotinic receptors
- Competitive blockers:
o Curare (at the neuromuscular junction)
o Hexamethonium (at the ganglia)
- Depolarizing blocker:
o Large amount of nicotine
 Muscarinic blockers:
 Competitive blockers:
o Atropine
o Scopolamine (hyoscine)
 Depolarizing blocker:
o Large amount of muscarine
Blockers of noradrenaline
 Alpha blockers:
o Phentolamine
o Prazosin (alpha 1)
o Yohimbine (Alpha 2)
 Beta blockers:
o Propranolol
- (non selective blocker; blocks beta 1 & beta 2 receptors)
o Atenolol
- (selective blocker; blocks beta 1)
o Butoxamine
- (selective blocker; blocks beta 2)

ABNORMALITIES
 Horner’s Syndrome
- Results from damage to sympathetic neurons that supply the face
- The damage may occur at any site along the course of sympathetic
neurons which originate from the hypothalamus, descend through the
brain stem, emerge from the upper thoracic segments, synapse at
the superior, middle or inferior cervical ganglia and then pass with
blood vessels to supply the face. However, the damage usually
occurs at the neck (cervical sympathectomy).
- Examples of the causes:
o Apical lung tumor
o Surgical trauma at the neck
o Hypothalamic lesions
- The syndrome is characterized by the following signs (on the
affected side of the face):
o Ptosis (drooping of the upper eye lid)
o Meiosis (constriction of the eye pupil)
o Anhydrosis (dryness, due to loss of sweating)
o Enophthalmos (abnormal recession of the eyeball in the
orbit)
o Rubor (redness, due to vasodilatation)
o Calor (hotness, due to vasodilatation)
 Myasthenia Gravis
- Results from damage to acetylcholine receptors at the
neuromuscular junctions.
- The damage is caused by auto-antibodies induced by unknown
mechanism

- Develops in females more than males.
- It is characterized by:
o Muscle weakness (especially after repeated movement)
o Ptosis (drooping of the upper eye lid)
o Weakness of respiratory muscles (the patient may die
due to respiratory failure).
- Treatment:
- By anti- acetylcholine esterase (e.g. neostigmine); to decrease
break down of acetylcholine at the neuromuscular junction and allow
it to act on the remaining receptors.
- Other modalities of treatment include:
o Use of steroids to inhibit production of the auto-antibodies by
lymphocytes
o Decrease of further breakdown of acetylcholine receptors by
plasmapheresis (a machine that eliminates the autoantibodies
from plasma).
Table 3.3: Effects of drugs acting on autonomic receptors
ATROPINE PROPRANOLOL SALBUTAMOL
Mechanism of Muscarinic β1 & β2 blocker β2 agonist
action blocker (antagonist) (stimulant)
Effects Heart rate Heart rate & - Bronchodilation
GIT motility & contractility Heart rate (side-
secretion Cardiac output effect, because
- Bronchodilation Blood pressure although it is β2
- Dilatation of the - Vasoconstriction agonist, it may
eye pupil - Broncho- react with β1
- Dries mouth constriction receptors resulting
( saliva) in tachycardia)

1. The somatic nervous system differs from the autonomic nervous

system because:
a- it has sensory and motor neurons
b- its neurons release acetylcholine
c- some of its neurons arise from the spinal cord
d- it has nicotinic receptors
e- it causes skeletal muscle contraction
2. Effects of the parasympathetic nervous system include all the
following except:
a- meiosis
b- penile erection
c- increased gastrointestinal motility
d- decreased airway resistance
e- bradycardia
3. Stimulation of the sympathetic nervous system results in:
a- bradycardia
b- recruitment in the cardiac muscle
c- dilatation of skeletal muscle arterioles
d- excessive salivary secretion
e- negative inotropic effect
4. Acetylcholine:
a- is released by all postganglionic sympathetic neurons
b- is released from the adrenal medulla
c- causes contraction of skeletal muscles
d- is blocked by propranolol
e- has alpha and beta receptors
5. The drug that blocks muscarinic receptors results in:
a- tachycardia
b- excessive salivation
c- elevation of blood pressure
d- micturition
e- sweating
6. Nicotinic receptors are found in:
a- arterioles of skeletal muscle
b- motor end plates of skeletal muscles
c- sweat glands in the skin
d- small intestine
e- ventricles of the heart

7. The nicotinic cholinergic receptors at the autonomic ganglia are:
a- blocked by curare
b- stimulated by salbutamol
c- stimulated with noradrenaline
d- blocked by hexamethonium
e- identical to those in skeletal muscles
8. Stimulation of beta 1 receptors results in all the following except:
a- breakdown of adipose tissue
b- increased cardiac output
c- release of renin from the juxta-glomerular cells
d- tachycardia
e- vasoconstriction
9. Adrenal medullary cells are stimulated by:
a- dopamine
b- GABA
c- adrenaline
d- acetylcholine
e- nor-adrenaline
10. Dopamine is:
a- released by all autonomic ganglia
b- an excitatory neurotransmitter
c- an acetylcholine derivative
d- a noradrenaline precursor
e- the main neurotransmitter released by the adrenal medulla
11. Sympathetic nerves
a- release noradrenalin from pre-ganglionic fibres
b- release adrenalin from postganglionic fibres
c- are stimulated during sleep
d- release of acetylcholine by some postganglionic fibres
e- are mostly myelinated
12. Stimulation of the sympathetic nervous system results in:
a- tachycardia through β2 receptors
b- constriction of skin blood vessels through β1
c- dilatation of the eye pupil through β1 receptors
d- contraction of intestinal wall through alpha receptors
e- sweating through muscarinic receptors
Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Answer e d C c a b d e d d d e

CHAPTER 4
TEMPERATURE AND METABOLIC RATE
TEMPERATURE
Normal body temperature
- The temperature of the internal structures of the body is called the
core body temperature.
- It equals 37oC (± 0.5oC) or 98.6oF (± 1.3oF)
- The core body temperature differs from the temperature of the skin
because:
 The temperature of the skin is affected directly by the temperature
of the external environment.
 The subcutaneous fat layer beneath the skin acts as insulator. It
preserves the core body temperature and prevents the effect of
the external environment.
Remember that:
 Skin vasodilatation (as occurs when the core body temperature
rises) allows blood to pass through the subcutaneous fat layer
and comes under the skin to facilitate heat loss to the outside.
The opposite occurs when the core body temperature falls.
Measurement of the core body temperature

- The device used is the clinical thermometer
- The sites used for measurement are:
The rectum
 The most accurate site
 Not socially acceptable
 Used in children and unconscious patients
The mouth (under the tongue)
 The most frequently used site (Socially acceptable)
 Differs slightly from the core body temperature (less by 0.5oC )
 Affected by hyperventilation, smoking and recently ingested food
or drink.
Other less frequently used sites:
o The axilla (less accurate; affected by the external environment)
o The ear (less accurate; affected by the external environment)
o Freshly passed urine (more accurate “but used for research
purposes only”)
Regulation of body temperature

- Maintenance of normal body temperature is an important goal in
homeostasis.
- This is because disturbance in body temperature affects:
 Activity of enzymes
 Speed of metabolic reactions within the body
 Activity of the various systems in the body. For example:
o The nervous system: higher body temperature increases
conduction in neurons whereas lower body temperature
decreases conduction.
o The cardiovascular system: higher body temperature causes
tachycardia and increases contractility whereas lower body
temperature does the reverse.
o The respiratory system: higher body temperature causes
hyperventilation whereas lower body temperature causes
hypoventilation.

o The endocrine system: higher body temperature decreases
release of thyroid hormones whereas lower body temperature
increases release of thyroid hormones.
- Regulation of body temperature within narrow limits is not only a
characteristic of humans; it is also a characteristic of birds and
mammals. For this reason they are described as "warm blooded" or
homeothermic.
- Other vertebrates like reptiles, amphibia and fish are "cold blooded"
or poikilothermic because the range of their body temperature is
rather wide.
- Invertebrates, on the other hand, can not regulate their body
temperature.
The temperature regulatory center:
- There is a center specialized for control of body temperature located
in the hypothalamus, known as the temperature regulatory center.
- This center controls heat loss & heat gain (the anterior
hypothalamus controls heat loss & the posterior hypothalamus
controls heat gain.
- Notice that: to maintain constant body temperature, the degree of
heat loss should always be balanced by an equivalent degree of heat
gain.
Heat loss:
- Heat is lost from the body by:
1. Conduction
- Transfer of heat between objects in contact with each other
(From an object with higher temperature to another with lower
temperature).

- Conduction occurs for either heat loss or heat gain,
depending on the level of body temperature.
2- Convection
- Transfer of heat away from a surface by successive currents
of air or water (from the object to the air or water currents, if
they have temperature lower than that of the object).
- Convection occurs for either heat loss or heat gain, depending
on the level of body temperature.
3- Radiation
- Transfer of heat between objects not in contact with each
other (from that of higher temperature to another with lower
temperature).
- Radiation occurs for either heat loss or heat gain, depending
on the level of body temperature, compared to the
temperature of the water or air currents.
4- Evaporation
- Vaporization of water molecules from a surface, taking heat.
- For example, evaporation of sweat from the surface of the
body or evaporation of water from the mucus membranes
during respiration.
- Notice that vaporization of 1g of water removes about 0.6 kcal
of heat.
- During exercise, sweat secretion may reach 1.6 L/h.
Evaporation of this volume results in loss of more than 900
kcal of heat per hour.
- Evaporation occurs for heat loss only (heat is always lost, not
gained by evaporation).

Heat gain
- The body gains heat by:
1- Metabolism
- Metabolism of all types of energy substrate, especially brown
fat, produces considerable heat.
- Brown fat is more abundant in infants than adults. It is found
mainly between scapulae and at the nape of the neck. Unlike the
white fat, it has rich sympathetic innervation and high metabolic
activity.
2- Muscular activity
- Contraction of muscles is a major source of heat. This may be
induced voluntarily (e.g. exercise) or involuntarily (e.g. shivering)
- Shivering is stimulated when the body temperature reaches
35.5oC.
3- Food intake (Specific dynamic action of food)
- Obligatory energy release that occurs during assimilation of food
within the digestive system (i.e. before absorption).
- The energy release of specific dynamic action of food is highest
for proteins than for carbohydrates or fats.
4- From the environment
- By conduction, convection or radiation (notice that these
mechanisms are suitable for both heat loss and heat gain).
- Remember that: In a hot weather, the mechanisms of conduction,
convection and radiation are all for heat gain; the only way for heat
loss is through evaporation of sweating. However, in a very humid
environment sweating occurs without evaporation. Therefore the
temperature of the body is not decreased.

Body responses to a hot environment
- Due to the direct effect of a hot environment, the temperature of
the body starts to rise.
- This rise is detected by thermoreceptors located peripherally in
the skin and centrally in the spinal cord and hypothalamus.
- The peripheral and central chemoreceptors send their impulses to
the temperature regulatory center in the hypothalamus.
- The center, to correct the body temperature, increases heat loss
(by the anterior hypothalamus) & decreases heat gain (by the
posterior hypothalamus).
- Heat loss is increased by:
o Sweating (to increase evaporation from the skin)
o Vasodilatation (to increase blood supply to the skin, for
radiation)
o Increased respiration (to increase evaporation from the mucus
membranes).
o Behavioral changes to increase heat loss, these include:
 Stretching at sleep (to increase surface area for radiation)
 Light clothes and cold drinks
- Heat gain is decreased by:
o Decreased metabolism, decreased food intake and decreased
muscular activity.
 Body responses to a cold environment

- Due to the direct effect of the cold environment, the temperature
of the body starts to drop.
- This drop is detected by peripheral and central thermoreceptors.
- The thermoreceptors send impulses to activate the temperature
regulatory center in the hypothalamus.
- The center increases heat gain (by the posterior hypothalamus) &
decreases heat loss (by the anterior hypothalamus).
- Heat gain is increased by:
o Increased metabolism
o Increased food intake (the body temperature rises due to the
specific dynamic action of food).
o Increased muscular activity (shivering and exercise)
- Heat loss is decreased by:
o Decreased sweating (to decrease evaporation from the skin)
o Vasoconstriction (to decrease blood flow to the skin)
o Decreased respiration (to decrease evaporation through the
mucus membranes)
o Behavioral changes that include:
 Curling up at sleep (to reduce the surface area). Other
behavior changes like heavy, dark-colored clothes and
hot drinks increase heat gain.
Physiological variation in body temperature

- Body temperature varies physiologically according to:
Age
- Higher in neonates> children > adults
- The higher temperature in neonates and children is due to heat
released by metabolic reactions of the growing tissues
Gender
- Higher in males than females of the same age and weight

- Due to presence of higher percentage of inactive tissues (fats) in
females
At and following ovulation
- Due to release of progesterone which has thermogenic effect
Pregnancy
- Due to higher rate of metabolism (fetal tissues) & higher level of
progesterone
Lactation
- Due to higher rate of metabolism (breast tissue)
Circulating hormones
- Normal variation in levels of thyroid hormones and catecholamines
results in equivalent variation in body temperature
Circadian fluctuation
- Body temperature fluctuates normally throughout the day of 0.5- 0.7
o
C. It is lowest early in the morning and highest at the evening.
Emotions
- Due to unconscious tensing of muscles.
Sleep and exercise
- Body temperature rises with muscular activity and drops at sleep.
Abnormalities of temperature regulation

Fever (Pyrexia)
 An important sign of disease (e.g. tonsillitis, pneumonia, typhoid,
malaria, malignancies …)
 Caused by endogenous pyrogens (e.g. cytokines released by
phagocytic cells, such as interleukin-1 (IL-1), IL-6 and tumor
necrosis factor (TNF ), which act to increase body temperature).

 Release of the endogenous pyrogens is induced, in most times, by
exogenous pyrogens (substances not synthesized by the body
such as bacterial toxins).
 Interleukins, which can not cross the blood brain barrier to reach
the preoptic area in the hypothalamus, induce synthesis of a
substance (most probably prostaglandin E2) to reach that area
which is the site of temperature setting in the body (= Thermostat).
 Prostaglandin E2 resets the thermostat from 37oC to a higher
level (e.g. 40oC). The subject feels cold, and therefore he
develops changes that elevate the body temperature such as
shivering, non-shivering thermogenesis (breakdown of brown
fat) and skin vasoconstriction; these result in fever.
Remember that:
 Immediately following loss of the prostaglandin effect, the
temperature setting point returns back to 37oC. Since the body
temperature is still higher than 37oC, the subject develops
changes to decrease the body temperature such as sweating and
vasodilatation of skin blood vessels.
 Drugs that decrease synthesis of prostaglandins can treat fever
(e.g. Aspirin).
Heat stroke
 In a hot dry environment, the only way to lose heat is through
evaporation of sweating.
 Therefore, failure of sweating results in abnormal elevation of
body temperature to a degree that affects the activity of the
nervous system, resulting in convulsions, coma and even death.

 In heat stroke, there is damage to the temperature regulatory
center caused by the high environmental temperature. This was
confirmed at autopsy. However, the exact mechanism of damage
is not well understood.
 Sometimes, as in severe exercise, heat stroke may result from
failure of the temperature regulatory mechanisms to maintain
normal body temperature (i.e. inadequate sweating); due to high
rate of heat production by the exercising muscles.
 Failure to reduce body temperature is followed by complications of
high temperature (convulsions, coma and death).
 Treatment should start immediately (e.g. electrical beds to reduce
the body temperature gradually or if not available: ice water;
However, body temperature should not be lowered quickly).
Heat exhaustion
 In a hot humid environment, even sweating can not reduce body
temperature because it fails to evaporate. For this reason subjects
should keep themselves in a cold and well ventilated area to lose
heat.
 In heat exhaustion, there is excessive sweating but with no
evaporation.
 The body temperature becomes elevated, the activity of the
nervous system is affected and the patient develops dehydration
(due to the excessive sweating).
 If not treated, the temperature regulatory mechanisms eventually
fail and the heat exhaustion becomes complicated by heat stroke
(permanent damage to temperature center).

 Therefore it is important to treat the condition immediately by
taking the patient to a well ventilated, cold room and giving him IV
fluids (in form of normal saline).
Table 4.1: Differences between heat stroke and heat exhaustion

Difference Heat stroke Heat exhaustion
Classical environment Hot dry Hot humid
Temperature center Abnormal Normal
Sweating Absent Excessive
Skin Hot & dry Hot & wet
Dehydration Absent Present
Effects of the high temperature
- Tachycardia Present Present
- Hyperventilation
- Convulsions & coma
Hypothermia
 Diagnosed when rectal temperature is < 35oC.
 Characterized by loss of consciousness, bradycardia and
decreased respiration.
 Occurs due to the direct effect of cold environments on slim
subjects with thin subcutaneous fat layer (e.g. malnourished
children and old people); or subjects with immature temperature
regulatory mechanisms (e.g. pre-term babies).
 Treatment by stepwise elevation of body temperature using heavy
clothes or electric blankets (because sudden elevation of body
temperature is dangerous).

Lesions of the hypothalamus
- The anterior hypothalamus controls heat loss (e.g. vasodilatation
and sweating) whereas the posterior hypothalamus controls heat
gain (e.g. shivering).
- Damage involving the anterior hypothalamus causes hyperthermia
in hot environments (due to failure of heat loss) whereas damage
involving the posterior hypothalamus causes hypothermia in cold
environments (due to failure of heat gain).
Malignant hyperthermia
- This is a life threatening condition that occurs due to a mutation in
the gene coding for the ryanodine receptors in skeletal muscles.
- Anesthetic drugs such as halothane and suxamethonium trigger
excessive release of calcium through these receptors from the
sarcoplasmic cisternae into the sarcoplasm, causing prolonged
contraction. Calcium causes contraction of muscles, this results in
sudden rise in body temperature and eventually death.
Heat cramps
- These are brief, painful muscle spasms occurring in the abdomen,
thigh or calf muscles.
- They occur during or after exercise, especially in the un-acclimatized
subjects, due to loss of large amounts of water and salts in sweat.
- Acclimatization involves elevation of aldosterone level which
reabsorbs sodium from sweat glands to prevent its loss in sweat.
- Treatment measures include resting of the muscles, rehydration and
correction of sodium and potassium loss.

THE METABOLIC RATE
- The word metabolism refers to all chemical transformations that
occur within the body.
- It includes:
 Anabolic reactions:
o Synthesis of complex molecules from simpler ones
o Example: glycogen from glucose, protein from amino acids…
o Involves consumption of energy for synthesis
 Catabolic reactions:
o Degradation of complex molecules to simpler ones
o Example: glycogen to glucose, protein to amino acids…
o Involves release of energy during degradation
THE BASAL METABOLIC RATE

 The metabolic rate is defined as the rate of energy release per unit
time.
 If it is measured at certain standard conditions; it is called the
basal metabolic rate (BMR).
 The standard conditions for its measurement are:
o Complete physical and mental rest
o Fasting for at least 12 hours
o Comfortable temperature
 The energy released by the body at these standard conditions is
used to maintain basal functions in the body such as:
o Beating of the heart
o Respiration

o Activity of the nervous system
o Sodium-Potassium ATPase pump
Measurement of the BMR

 Normal BMR = 2000 kcal/day or 40 kcal/m2/h
 Measurement of the BMR was formerly used to diagnose thyroid
problems:
o If increased by 15% = it indicates hyperthyroidism
o If decreased by 15% = it indicates hypothyroidism
BMR is measured by 2 methods:
 Direct Calorimetry
(Not preferred because it is difficult and needs special laboratories)
 Indirect Calorimetry
(Preferred)
Direct Calorimetry
 Involves incubation of a subject in a vessel container for a certain
period of time.
 The vessel container is surrounded by a known volume of water
and covered from outside by insulator.
 The energy released during this period of time, in the form of heat,
will raise the temperature of the water around the container.
 This change in temperature is used to calculate the BMR.
Indirect Calorimetry
 Involves indirect measurement of the BMR by measuring certain
substances consumed or produced during the catabolic reactions.
 For example, take the reaction:

C6 H12 O6 + (6) O2 = (6) CO2 + (6) H2 O + energy (heat)
 Here the amount of energy released is known
 Using the above information, the metabolic rate can be calculated
indirectly by measuring any of the following during a certain period
of time:
o the amount of oxygen consumption
o the amount of glucose consumption
o the amount of carbon dioxide production
o the amount of water production
Using the oxygen consumption:

 The amount of energy produced when one liter of oxygen is
consumed is called the joule equivalent (JE)
 It differs according to difference in the foodstuff being oxidized.
This is because the ratio of carbon to oxygen atoms differs in
different types of foodstuff.
 The difference in the ratio of carbon to oxygen atoms also results
in difference in the respiratory quotients (RQ) of foodstuffs.
 The RQ of each foodstuff is defined as the ratio of carbon dioxide
produced to oxygen consumed in the steady state, when
equilibrium is reached at rest.
 It differs from the respiratory exchange ratio (R) which is the
ratio of CO2 to O2 at any given time (see below).
 The RQ for;
o CHO = 1, Protein = 0.82, Fat = 0.7, Mixed diet = 0.85
 The RQ can be used to calculate the joule equivalent (JE) for each
foodstuff as follows: JE = 17.15 + (RQ x 3.5)

 Now the BMR can be calculated as follows:
 BMR = oxygen consumption x joule equivalent
(in joule/unit time)
 BMR = oxygen consumption x joule equivalent/surface area x 4.2
(in kcal/m2 /h).
Note: The volume of oxygen consumption should be corrected for

standard temperature & pressure (STP) by multiplying it by a factor,
obtained from nomograms (e.g. the correction factor at STP when air
temperature = 21◦c & ambient pressure = 741 mmHg equals 0.883)
Notes to remember about the respiratory exchange ratio (R)
 It is affected by hyperventilation (e.g. during exercise or metabolic
acidosis); here R is increased (due to expiration of more CO2 by
the hyperventilation). Then following exercise, R is decreased
(due to the oxygen debt mechanism).
 The respiratory quotient (RQ) and the respiratory exchange ratio
(R) of individual organs give information about their activities.
 For example the RQ for the brain (measured during the steady
state) = 0.99; indicating that its main source of energy is glucose.
 The R for the stomach (measured during active secretion of HCl)
is negative, indicating that more CO2 is consumed than produced;
this is used in synthesis of HCL (see the GIT in volume 2).
Measurement of oxygen consumption

 Requirement
 Bell-type spirometer (Benedict’s Roth)
 Kymograph

 Method
 The subject puts the mouth piece of the spirometer in his mouth
 Firstly, the spirometer is connected to the atmosphere to familiarize
the subject to the procedure before recording
 Then the atmospheric opening is closed to allow the subject to
consume the oxygen inside the cylinder of the spirometer
 Oxygen consumption is obtained from a recording on a kymograph
paper of a spirometer by measuring the slope of the line A-B as in
this example:
Fig 4.1: Measurement of oxygen consumption
 Calculation
 BMR = oxygen consumption x correction factor for STP x Joule
equivalent/ Surface area x 4.2

Remember that:
 If the standard conditions mentioned above are not fulfilled; the
value obtained is a metabolic rate (not BMR)
 To calculate the joule equivalent using the formula (JE = 71.15 +
(3.5 x RQ)), the type of foodstuff consumed by the subject over
the past few days should be known; this gives the RQ
 The surface area can be obtained, using the height and weight of
a subject, from nomograms or certain equations
Factors affecting the metabolic rate

 Age
- Higher in neonates> children > adults> old subjects
- Due to increased metabolism of the growing tissues. Here the
metabolic rate should be expressed per surface area for comparison.
 Gender
- Higher in males than females of the same age and weight.
- Due to presence of higher percentage of fats in females.
 At and following ovulation
- Due to the higher body temperature caused by progesterone.
 Pregnancy and lactation
- Due to presence of more metabolically active tissues (fetal and
breast tissues); & higher level of progesterone.
 Circulating hormones
- Normal variation in levels of thyroid hormones and catecholamines
results in equivalent variation in the metabolic rate.
 Emotions
- Due to unconscious tensing of muscles.

 Sleep and exercise
- The metabolic rate rises with activity.
 Recent ingestion of food (SDA)
- Due to the specific dynamic action of food (SDA). As mentioned
earlier it is the obligatory energy release following ingestion of food,
due to its assimilation within the GIT. However, its exact cause is
unknown. It lasts for 6 hours. The rise in metabolic rate is highest
following protein ingestion and lowest following fat ingestion.
 Body temperature and environmental temperature
- The relation between environmental temperature and the rate of
metabolism is generally an inverse relationship (increased
environmental temperature = decreased metabolic rate). However,
the relation between body temperature and the rate of metabolism is
a direct relationship (increased body temperature = increased
metabolic rate).
- The relation between the environmental temperature and the rate of
metabolism is explained by the body responses to hot or cold
environment. - For example, the rate of metabolism rises in a cold
environment and drops in a hot one (see above).
- However, when the environmental temperature rises enough to
elevate the body temperature or drops enough to decrease the body
temperature, the metabolic rate increases or decreases respectively
(i.e. the relation becomes a direct relationship).
- It is calculated that for each one Celsius degree rise in body
temperature, the metabolic rate increases by 14%.

1. The most accurate site for measurement of body temperature is:
a. The mouth
b. The axilla
c. The rectum
d. The nose
e. The skin
2. Whenever the body temperature is lower than the set point of the
thermostat in the hypothalamus:
a. Sweating is increased
b. Skin blood vessels dilate
c. Rate of metabolism is increased
d. Subjects feel hot sensation
e. Appetite to food is inhibited
3. Features of heat stroke include all the following except:
a. Hypotension
b. Dehydration
c. Low urine output
d. Absence of sweating
e. Convulsions
4. Heat exhaustion:
a. Occurs in hot dry environments
b. Is due to failure of sweating
c. Is best treated with ice water immersion
d. Is associated with low plasma osmolarity
e. Is associated with dehydration
5. At the onset of fever, patients develop:
a. Hot sensation
b. Sweating
c. Convulsions
d. Skin vasoconstriction
e. Nausea and vomiting
6. Exposure to a cold environment is not excepted to cause:
a. Release of thyroid hormones
b. Peripheral cyanosis
c. Acceleration of metabolism
d. Reduction in blood pressure
e. Reduction in heart rate
7. The main way for heat loss from a body in a hot dry environment is
through:
a. Sweating
b. Hyperventilation
c. Evaporation

d. Radiation
e. Conduction
8. Concerning regulation of body temperature:
a. Birds and mammals are poikilothermic
b. The temperature regulatory centre is located in the medulla
c. Convection never causes heat gain
d. Shivering occurs when body temperature falls below 36.5 ◦C
e. Damage to the posterior hypothalamus is expected to cause
hypothermia
9. Heat stroke differs from heat exhaustion because it:
a. Usually occurs in both dry and humid environments
b. Is associated with elevated core body temperature
c. Causes tachycardia and impaired level of consciousness
d. Is not characterized by dehydration
e. Is not associated with sweating
10. Measurement of the basal metabolic rate requires:
a. fasting for two hours
b. ingestion of a heavy meal
c. moderate exercise during measurement
d. normal body temperature
e. suitable environmental temperature
11. Basal metabolism is mainly accounted for by:
a. Energy spent by cardio-respiratory functions
b. Secretions in the endocrine system
c. The sodium-potassium pump
d. Maintenance of body temperature
e. Renal tubular mechanisms
12. In the body the metabolism of 10 grams of protein would produce
approximately:
a. 10 kcal
b. 53 kcal
c. 41 kcal
d. 90 kcal
e. 20 cal
13. For measurement of the basal metabolic rate all the following
conditions are required except:
a. mental rest
b. physic rest
c. normal body temperature
d. 12 hours fasting prior to measurement
e. comfortable room temperature
14. The specific dynamic action of food is due to:
a. an increase in core body temperature
b. amino acid metabolism in the liver

c. energy expenditure during digestion
d. hypothalamic sympathetic stimulation
e. secretion of insulin
15. The basal metabolic rate:
a. is about 500 kcal/ kg body weight / day
b. is measured during exercise
c. is measured during exposure to cold environment
d. rises during menstruation and lactation
e. is usually measured two hour following a meal
16. All the following conditions are expected to increase the rate of
metabolism in a young woman EXCEPT:
a. Fasting
b. Fever
c. Menstruation
d. Second trimester of pregnancy
e. Cold environment
17. The respiratory exchange ratio is:
a. The ratio of CO2 production to O2 consumption during steady
states
b. Used to calculate the joule equivalent
c. Used to calculate oxygen debt of organs
d. Negative for the stomach during active secretion of HCL
e. Negative for the brain at rest
18. The metabolic rate is increased by all of the following except:
a. Rise in body temperature
b. Rise in environmental temperature
c. Increased sympathetic outflow
d. Stress
e. Hyperfunction of the thyroid gland
19. Which of the following is the main consumer of energy under
basal conditions?
a. Heart activity
b. Respiratory muscle activity
c. Sodium-potassium pump
d. Skeletal muscle activity
e. Liver metabolism
Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Answer c c b e d d c e e e
Question 11. 12. 13. 14. 15. 16. 17. 18. 19. 20.
Answer c c c c d a d b c

CHAPTER 5
HEMATOLOGY
BLOOD
- Blood is a type of connective tissue.
- Like other types of connective tissue it consists of:
– Cells and intercellular substance
- The cells are:
– Red blood cells (RBCs) or erythrocytes
– White blood cells (WBCs) or leukocytes
– Platelets or thrombocytes
- The intercellular substance is called plasma
- Volume of blood is about 5L in an average adult male (= 8% of total
body weight).
- Volume of plasma is about 3.5L (= 5% of total body weight).
- The cells in blood can be separated from plasma by centrifugation.
- The percentage of cells in blood is called the packed cell volume
(PCV) or the hematocrit.
The PCV
• PCV is the percentage of blood occupied by cells.
• Most of these cells are RBCs (more than 90%).
• Normal values = 40-50% in males [average = 45%]

= 37-47% in females [average = 42%]
• Low PCV indicates anemia
• High PCV indicates polycythemia.

Fig 5.1: The packed cell volume
Functions of blood
1. Transport of:
– Gases (e.g. oxygen and carbon dioxide)
– Nutrients (e.g. glucose, amino acids and free fatty acids)
– Waste products (e.g. urea and uric acid)
– Hormones (e.g. catecholamines, insulin, cortisol and thyroid
hormones)
2. Defense by WBCs
3- Homeostasis (maintenance of the constancy of the internal
environment, which is the ECF):
– Control of temperature (by distribution of heat by the blood)
– Control of pH (by buffers in the blood, e.g. HCO3-, proteins and
hemoglobin)
4- Hemostasis
– Prevention of blood loss & maintenance of blood in the fluid
state. Blood loss is prevented by arrest of bleeding (e.g. by
platelets and clotting factors) and maintenance of blood in the
fluid state occurs by the natural anticoagulants.

Formation of blood (hematopoiesis)
 Sites of hematopoiesis
 During pregnancy, blood is formed at the following sites:
Yolk sac:
- Forms blood during the intrauterine life, first trimester
Liver & spleen:
- Form blood during the intrauterine life, second trimester
- After delivery, the liver and spleen may resume their
hemopoietic activity in children suffering from chronic anemia
[this is known as extramedullary hematopoiesis]
Bone marrow):
- Forms blood during the intrauterine life, third trimester (and
then after delivery); called red marrow (active marrow)
- Found in almost all bones during pregnancy
 After delivery, blood is formed at the following sites:
The red bone marrow
- After delivery, the red bone marrow starts to be replaced
gradually by yellow marrow (inactive marrow)
- At about the age of 20y the red marrow is confined to:
o Flat bones
- Skull, sternum, ribs, scapula, vertebrae & iliac bone
o Ends of long bones “epiphyses” not the shaft “diaphysis”
o Small bones of hands & feet
- About 75% of the cells in the red bone marrow are WBC precursors
and only 25% are RBC precursors; inspite of the fact that RBC count
is over 500 times more than the WBC count. This indicates the
longer life span of RBCs.

THE RED BLOOD CELLS
Characteristics of RBCs
Shape: Biconcave disks
Diameter: 7.5 micrometer
Thickness: 1 micrometer (center), 2 micrometer (edges)
Fig 5.2:
Contents:
o No nucleus
- Therefore no reproduction
- Their life span is about 120 days
o No organelles
- e.g. no mitochondria and therefore no aerobic
glycolysis. However, they use anaerobic glycolysis to
generate small amount of energy for maintenance of
the integrity of the cell membrane
o Contain hemoglobin
- A red pigment found within RBCs
- Important for transport of oxygen
- The volume of a red blood cell is larger than its contents. This
allows it to squeeze itself through the narrow capillaries.

Count of RBCs
- In males: 4.8-5.8 million/mm3 & in females: 4.2-5.2 million/mm3
Functions of RBCs
 Transport oxygen (bound to iron in hemoglobin)
 Transport carbon dioxide (bound to globin in hemoglobin)
 Buffer (a function of hemoglobin)
 Contain antigens on its surface that determine the type of blood
group
Stages of erythropoiesis
Can be divided into:
 Replication phase
o The increase in number of RBCs
 Maturation phase
o The decrease in size of RBC precursors
o Loss of contents (nucleus and organelles)
o Acquisition of hemoglobin
Stages in the bone marrow:
 Pluripotent non-committed stem cells
- Nucleated cells that divide to form 2 major types of committed
stem cells: lymphoid and non-lymphoid (myeloid & erythroid) cells
 Committed stem cells (or progenitor cells)
- Nucleated cells that divide to form only one type of blood cells
(e.g. the lymphoid forms lymphocytes and the erythroid forms
RBCs, and the myeloid forms other WBCs “granulocytes,
monocytes” and precursors of platelets “megakaryocytes”).

 Proerythroblasts (or Normoblasts)
- The erythroid committed stem cells divide to form nucleated
cells known as proerythroblasts (or normoblasts).
- These divide many times and start to form hemoglobin; that’s
why they are described as early, intermediate & late or according
to the stain as basophilic and polychromatophilic.
- The normoblasts lose the nucleus & other organelles to become
reticulocytes.
Stages in the blood:
 Reticulocytes
- The first non-nucleated red blood cell precursors.
- They have no organelles except some ribosomes (so they are
still able to synthesize hemoglobin from ribosomal RNA).
- After their formation they stay in the bone marrow for 1-2 days;
then they enter the peripheral blood for the first time and stay for
another 1-2 days before they become mature erythrocytes.
- They constitute about 1% of total RBCs.
- High reticulocyte count (>2% = reticulocytosis) indicates
hyperactivity in the bone marrow (i.e. rapid synthesis of RBCs to
replace the lost ones) as occurs in:
o Hemolytic anemia (reticulocytosis indicates RBC hemolysis)
o Recent treatment of anemia (e.g. following vitamin B12
injections)
 Erythrocytes
- The mature red blood cells.

CONTROL OF ERYTHROPOIESIS
Normal erythropoiesis requires:
- Normal bone marrow
- Cytokines and colony stimulating factors
- Erythropoietin & other hormones (e.g. thyroid hormones)
- Certain nutrients (e.g. iron, vitamin B12 and folic acid)
 Normal bone marrow
- Normal bone marrow is essential for normal erythropoiesis.
- Diseases affecting the bone marrow usually results in abnormal
erythropoiesis (see anemia).
 Cytokines and colony stimulating factors
- Interleukins: IL-1, 1L-3, IL-6 and GM-CSF (Granulocyte- Monocyte
Colony Stimulating Factors) stimulate proliferation and conversion of
pluripotent stem cells into committed stem cells.
- These growth factors are produced by bone marrow stromal cells
such as fibroblasts, endothelial cells, activated T cells and
macrophages.
 Erythropoietin (= the principal regulator of erythropoiesis)
Characteristics:
- Glycoprotein (contains 24% carbohydrates and 76% protein).
- Have single chain with 165 amino acids.
- MWt: 34000.
Site of production:
- In adults: produced mainly in the kidneys (90%) & in the liver (10%).
- In fetal life: the liver is the main site of production.
Stimulus:
- Hypoxia (low oxygen at the tissue level).

Function
- Stimulates replication of stem cells and formation of erythroblasts.
- Erythropoietin dose not influence the maturation stages of RBCs.
Abnormalities
 Erythropoietin excess (= results in polycythemia)
- Caused by:
o High altitudes: people living at high altitudes have physiological
polycythemia due to the low oxygen tension at these sites.
o Renal problems (e.g. renal tumors or polycystic kidney disease):
these pathological problems are characterized by excessive
release of erythropoietin causing pathological polycythemia.
o Chronic respiratory problems: When these problems cause
hypoxia, patients develop polycythemia (e.g. lung fibrosis).
 - Erythropoietin deficiency (= results in anemia)
- Anemia caused by erythropoietin deficiency is characterized by low
count of RBCs but with normal shape and color “normocytic
normochromic anemia”. The chief cause is chronic renal failure.
 Other hormones needed for normal erythropoiesis:
o Androgens (= male hormones that increase bulk of muscles, e.g.
testosterone). Muscles are more active than fats, they consume
more oxygen. This stimulates erythropoietin production and
therefore RBC formation. That’s why RBC count is higher in
males than females of the same age (notice that this difference
between males and females is absent before puberty!).
o Growth hormone
o Cortisol
o Thyroid hormones

 Nutrients needed for erythropoiesis
o Amino acids: for formation of globin (Hb)
o Iron: for formation of heme (Hb). Its deficiency causes microcytic
hypochromic anemia
o Vitamin B12 & folic acid: for DNA synthesis (cell division).
Deficiency causes macrocytic normochromic anemia
o Vitamin C: for iron absorption (it is a reducing factor that
maintains iron in the ferrous state)
o Other B vitamins: Co factors in the metabolic reactions
o Vitamin E: for maintenance of RBC membrane (an anti-oxidant
that protects the cell membrane from oxygen radicals). Deficiency
causes hemolytic anemia.
o Trace elements:
- Copper: promotes iron absorption
- Cobalt: Needed for vitamin B12 synthesis in animals. It may
stimulate erythropoietin production.
Iron metabolism
 Distribution in the body
- Total amount in the body is about 3-5 grams. Distributed in:
o Heme of hemoglobin (65-75%)
o Cellular enzymes (catalase, cytochrome oxidase) (3%)
o Storage (ferritin, hemosiderin) (>20%)
o Plasma (transferrin) (< 1%)
 Dietary sources
- Animal products: e.g. liver, meat, egg
- Plant products: e.g. vegetables, beans
- The average diet provides 10-20 mg/day

 Daily requirements
- About 1 mg/day in an adult man, 2 mg/day in an adult woman
- The daily requirements are increased during:
o Pregnancy
o Lactation
o Infancy (the first year of life)
 Absorption
- Amount absorbed = 10-15% of ingested iron; however, it is highly
increased in patients suffering from iron deficiency anemia.
- Site of absorption: upper small intestine (duodenum).
- Mechanism of absorption: 2ndary active transport (Fe2+-H+ symport).
- Factors that increase absorption:
o Ferrous state (Fe2+)
o Gastric acidity (HCl), maintains iron in the ferrous state
o Vitamin C, also maintains iron in the ferrous state
o Iron in heme
- Factors that decrease absorption:
o Presence of phosphates, oxalates or phytates in diet
o Achlorohydria (low hydrochloric acid due to gastric atrophy)
o Diarrhea
o Clay
o Fever
o Tetracycline
 Iron in plasma
- Concentration= 100-130 microgram/dL
- Transported in plasma by a beta globulin known as transferrrin
- Transferrin is normally 30- 40% saturated with iron

 Storage
- Sites of storage: Intestinal mucosa, liver, spleen and bone marrow.
- Forms of storage: ferritin &hemosiderin.
- Ferritin is the main form of storage. It stores 65% of stored iron in a
soluble form that’s easily mobilized whereas hemosiderin stores 35%
of stored iron in an insoluble form that’s slowly mobilized.
 Function of iron: formation of heme in Hb
- Iron found in ferrous (Fe2+) form
- Each Hb molecule contains 4 (Fe2+)
- Each atom of iron binds 2 atoms of oxygen (Therefore each Hb
molecule carries 8 atoms of oxygen (or four molecules).
 Excretion
- Total daily loss of iron= 1 mg/day in adult men, 2mg/day in adult
women (i.e. daily intake = daily loss).
- Routes for iron loss: Feces, skin, urine and menstruation
 Abnormalities
o Iron deficiency anemia= (microcytic hypochromic anemia)
- Characterized by: Low Hb, small & pale RBCs (microcytic
hypochromic anemia), low concentration of iron in plasma, low
plasma ferritin and high total iron binding capacity (TIBC).
o Iron overload: 1о: Hemochromatosis & 2о: Hemosiderosis
- Hemochromatosis is a common hereditary condition characterized
by excessive iron absorption resulting in abnormal accumulation of
iron in many organs causing damage (e.g. liver cirrhosis, gonadal
atrophy, cardiomyopathy, skin pigmentation and diabetes mellitus).
- Hemosiderosis describes iron overload secondary to certain causes
(e.g. repeated blood transfusions and excessive iron therapy).

Vitamin B12
- Cyanocobalamin
- Water soluble vitamin
 Sources and requirement
- Found in food of animal origin (notice that vitamin B12 is formed by
micro-organisms that contaminate animal tissues, it is not found in
food of plant origin unless it is contaminated by these
microorganisms).
- Daily requirements are very low (about 1- 2 microgram/day)
 Site of absorption
- Terminal ileum
- Absorption is assisted by the intrinsic factor (produced by parietal
cells in the stomach). This binds iron in the stomach and travels with
it to the terminal ileum to be absorbed together by pinocytosis.
 Storage
- In the liver, the amount stored is enough for at least 3 years without
intake.
 Functions
o DNA synthesis: (needed for red blood cell replication)
o Myelination of nerves
 Abnormalities
o Deficiency causes:
- Macrocytic normochromic anemia (megaloblastic anemia)
- Sub-acute combined degeneration of the cord (demyelination)
o Causes of deficiency:
- Low intake (rare cause of deficiency except in strict vegetarians)
- Resection of the terminal ileum (decreases absorption)

- Gastrectomy (removal of the stomach decreases absorption
because there is no intrinsic factor).
- Gastric atrophy (caused by auto-antibodies that attack parietal
cells or the intrinsic factor); this is known as pernicious anemia.
Folic acid
- Water soluble vitamin
 Sources and requirement
- Found mainly in food of plant origin
- Daily requirement is about 100 microgram/day
- Requirements are increased during:
o Pregnancy
o Lactation
o Infancy
 Absorption
- In the small intestine (especially the jejunum)
 Function
- DNA synthesis (needed for red blood cell replication)
 Abnormalities
- Deficiency causes: macrocytic normochromic anemia
- Causes of deficiency:
o Decreased intake: malnutrition
o Decreased absorption: villous atrophy
o Increased requirements:
- Pregnancy
- Drugs (e.g. methotrexate)

HEMOGLOBIN
- The red pigment found in RBCs.
- Molecular weight is about 65000.
 Concentration
o 14-16 g/dL in adult males
o 13-15 g/dl in adult females
o 18-20 g/dl in neonates
 Structure
- Consists of 4 subunits. Each subunit consists of heme + a
polypeptide chain. [Hb = 4 heme + 4 polypeptide chains]
- Each heme is synthesized from glycine and succinyl- CoA. It has a
porphyrin ring containing iron in the reduced state (Fe2+).
- Each polypeptide chain is identical to another chain in Hb; therefore
the 4 polypeptide chains are 2 pairs; e.g. 2 alpha + 2 beta chains or 2
alpha + 2 gamma chains or 2 alpha + 2 delta chains. The 4 chains
are called collectively globin (i.e. Hb = 4 heme + globin).
Fig 5.3: The four subunits of hemoglobin

 Functions of Hb
o Carries 98% of oxygen in the blood
o Carries some carbon dioxide
o Buffer
 Normal types of Hb
 Hb A
- Adult Hb: constitutes about 98% of all Hb in adults
- Contains 2 alpha & 2 beta chains (α2β2)
- Each alpha chain contains 141 aa (formed by genes on
chromosome 16) whereas each beta chain contains 146 aa (formed
by genes on chromosome 11)
 Hb A2
- Adult Hb: constitutes about 2.5% of all Hb in adults
- Consists of 2 alpha & 2 delta chains (α2δ2)
- Delta chain is similar to beta chain, but differs in 10 aa. It is also
formed by genes on chromosome 11
 Hb F
- Fetal Hb
- Starts to be replaced Hb A before birth.
- At birth, it constitutes about 70% of total Hb. This decrease to less
than 2% (i.e. replacement is almost complete) by the age of 6 month.
- Hb F has higher affinity to oxygen than Hb A. This is because it
binds 2,3 DPG (di-phospho-glycerate) less avidly (in other words: 2,3
DPG does not occupy the sites available for oxygen binding as
occurs in Hb A.
- This facilitates delivery of oxygen from the mother to her fetus
through the placental membranes.

- Consists of 2 alpha & 2 gamma chains (α2γ2)
- Gamma chain is similar to beta chain except in 37 aa. It is also
formed by genes on chromosome 11.
 Hb A1c (Glycated Hb)
- Subtype of Hb A
- Its terminal amino acid (valine) can bind glucose
- Normally it constitutes about 5% of total Hb
- Higher percentage of Hb A1c indicates poorly controlled diabetes
mellitus
 Embryonic hemoglobins
- Types of hemoglobin during the first 8 weeks of pregnancy include:
 Gower 1 Hb: consists of 2 zeta and 2 epsilon chains (ξ2ε2)
 Gower 2 Hb: consists of 2 alpha and 2 epsilon chains (α2ε2)
 Portland Hb: consists of 2 zeta and 2 gamma chains (ξ2γ2)
 Abnormal types of Hb
 Hb S
- Sickle cell Hb
- It is Hb A but the amino acid number 6 in beta chains (glutamic
acid) is replaced by (valine)
- Hb S precipitates in cases of hypoxia. This changes the shape of
RBCs to a sickle shape
- Complications of the sickle shape:
o Hemolytic crisis: hemolytic anemia known as sickle cell
anemia
o Jaundice: pre-hepatic jaundice due to the excessive hemolysis
o Vaso-occlusive crisis: obstruction of small capillaries causing
atrophy of organs supplied with these blood vessels

- Symptoms appear after the age of 6 month when HbF is almost
totally replaced by Hb A (This is because Hb F prevents sickling of
RBCs since it does not contain beta chains)
- The disease is less severe in heterozygotes (who have one
chromosome affected and therefore 50% of their Hb is Hb S) than
homozygotes (who have defect in the two chromosomes that form
Hb A and therefore most of their Hb is Hb S).
Notes to remember about Hb S & sickle cell disease:
 In these patients, Hb F persists in high concentrations after the
age of 6 month and until adulthood as compensation.
 The disease in heterozygotes is known as sickle cell trait whereas
in homozygotes as sickle cell disease
 Sickle cell disease is a well known problem in certain tribes in
Western Sudan and Western Africa. It exists especially in malaria
endemic areas; this is explained by the fact that hemoglobin S
cannot be digested by malaria parasites (i.e. Hb S patients “the
sicklers” are rarely infected with malaria).
 Thalassemia
- Decreased production of globin chains; e.g. deficiency of alpha
chains (alpha thalassemia) or beta chains (beta thalassemia).
- Thalassemia is characterized by excessive hemolysis of RBCs
resulting in hemolytic anemia.
- The type of anemia is microcytic hypochromic anemia.
 Other abnormal types of hemoglobin
- Are numerous. They include Hb C, E, D and H.
- The abnormal types of Hb can be identified by electrophoresis (use
of an electrical current to separate normal and abnormal types of

hemoglobin in the blood, because they have different electrical
charges and different rates of movement).
Remember the following abnormal conditions of Hb:
 Methemoglobin
- Here iron is oxidized (from the ferrous state (Fe2+) to a ferric state
(Fe3+)) by some oxidizing agents (e.g. drugs). Normally this is
converted back by NADH- Methemoglobin Reductase System within
the RBCs. Congenital absence of this enzyme causes hereditary
methemoglonbinemia.
- The ferric state can not bind oxygen in a reversible reaction as the
ferrous state.
- Methemoglobin gives the skin a dark color resembling cyanosis.
 Carboxyhemoglobin
- Formed by reaction of hemoglobin with carbon monoxide.
- The affinity of Hb for CO is very high. That’s why it displaces
oxygen from its sites resulting in reduction of oxygen carrying
capacity of the blood (= anemic hypoxia).
RBC DESTRUCTION
Stages of destruction
- Every second, a large number of RBCs are broken down in the
tissue macrophage system (previously known as the
reticuloendothelial system); e.g. the spleen.
- At the same time the same number is replaced by new RBCs
produced in the bone marrow.
- Anemia occurs if breakdown is more than production whereas
polycythemia occurs if breakdown is less than production.

In the spleen (the main site of RBC destruction)
- Old and abnormally shaped RBCs that cannot pass through small
capillaries in the spleen are destroyed by macrophages and the main
product of destruction is hemoglobin which gives heme and globin.
- Globin is hydrolyzed into amino acids which are reutilized.
- Heme releases iron which is needed by the body for synthesis of
new RBCs. The remaining porphyrin ring is converted to biliverdin
and then to bilirubin.
- Bilirubin, a yellow pigment that’s water insoluble, is transported
towards the liver carried by albumin.
- Carriage of the insoluble bilirubin in the blood by plasma proteins
prevents its appearance in urine (can not be filtered).
In the liver and bile
- In the liver, bilirubin is conjugated to glucouronic acid to be water
soluble.
- Conjugation is catalyzed by the enzyme glucouronyl transferase.
- Conjugated bilirubin is then secreted in bile. It gives bile its
yellowish color.
- For this reason it is called bile pigment. However, some of it
escapes into the systemic circulation and appears normally in urine.
In the intestine
- When bile reaches the intestine, bilirubin is converted by bacteria to
stercobilinogen & urobilinogen (both called urobilinogens).
- Stercobilinogen is excreted in stool, giving it its characteristic color.
- Urobilinogen is absorbed to the entero-hepatic circulation. However,
some of it escapes into the systemic circulation and appears
normally in urine.

Fig 5.4: Excretion of bilirubin
Jaundice
- Yellowish coloration of the skin, sclera & mucus membranes.
- Occurs due to high level of bilirubin in the plasma (normal bilirubin
level is about 1mg/dL).
- Jaundice appears when the concentration is higher than 2mg/dL
Types of Jaundice
o Pre-hepatic (hemolytic)
o Hepatic
o Post-hepatic jaundice (obstructive)
 Pre-hepatic Jaundice
- Caused by excessive hemolysis of RBCs resulting in excessive
release of unconjugated bilirubin (gives indirect reaction in the van
den Bergh test).
- The high amount of unconjugated bilirubin exceeds the capacity of
the liver for conjugation and excretion into bile. For this reason the

unconjugated bilirubin appears in blood causing the yellowish color.
However, it does not appear in urine because it is bound to albumin
in the blood (acholuric jaundice).
- Conjugated bilirubin that’s secreted by the liver in bile is higher than
normal. Therefore production of urobilinogens in the intestine and
consequently its excretion in urine are also higher than normal.
- Prehepatic jaundice is usually associated with hemolytic anemia.
- Causes include:
 Abnormal RBC shape
o Sickle cell anemia (due to Hb S)
o Congenital spherocytosis (Due to lack of spectrin)
o Congenital elliptocytosis (due to lack of spectrin)
 Lack of RBC enzymes
o Glucose 6 phosphate dehydrogenase deficiency
o Pyruvate kinase deficiency
 Mechanical destruction of RBCs
o Malaria
o Hypersplenism
 Other causes like T
o Thalassemia
o Autoimmune hemolytic anemia …
 Hepatic Jaundice
- Caused by liver cell damage or lack of enzymes resulting in failure
of bilirubin conjugation in liver cells (thus increasing unconjugated
bilirubin in the blood) or failure of bilirubin secretion in bile after its
conjugation (thus increasing conjugated bilirubin in the blood).
- i.e. Bilirubin in hepatic jaundice may conjugated or unconjugated.

- Conjugated bilirubin appears in urine whereas unconjugated
bilirubin does not (because it is bound to albumin).
- Causes of hepatic jaundice include:
o Viral hepatitis (e.g. A, B, C, …) or alcoholic liver disease; cause
cell damage = failure of conjugation = unconjugated jaundice
o Dubin Johnson & Rotor syndromes: due congenital defect in the
mechanism of bilirubin secretion in bile = conjugated jaundice
o Crigler-Najjar syndrome (type I & II); due to congenital deficiency
of the conjugating enzyme = unconjugated jaundice
o Gilbert's syndrome; due to decreased activity of the conjugating
enzyme= one of the commonest causes of unconjugated jaundice
 Post-hepatic Jaundice
- Caused by obstruction of the biliary tracts. This prevents conjugated
bilirubin from reaching the intestine. Therefore it appears in blood
causing the characteristic yellowish color.
- The conjugated bilirubin, which is water soluble, appears in urine
(Choluric jaundice). It gives urine a characteristic dark yellowish
color. Urobilinogen is not produced in the intestine and so it is absent
from urine.
- Since bile does not reach the intestine, stool becomes pale (due to
absent bile pigments like bilirubin) and full of fat (due to absent bile
salts which are essential for fat digestion and absorption).
- Causes of obstructive jaundice include:
o Gall stones obstructing the common bile duct
o Parasites obstructing the common bile duct
o Tumors obstructing the common bile duct (e.g. carcinoma head of
the pancreas)

ANEMIA
Definition
- State of reduction in hemoglobin concentration below the normal
range (according to age and sex)
- This occurs because of:
o low Hb within each RBC (and/or)
o low total count of RBCs
Classification of anemia
o Decreased production of RBCs
o Increased destruction of RBCs
o Blood loss
1- Anemia due to decreased RBC production
 Diseases of the bone marrow
- Examples include:
o Bone marrow infiltration
- Tumors (primary tumors like leukemias or secondary
tumors from other sources like the bone or the thyroid)
- Myelofibrosis
o Bone marrow failure (Aplastic anemia)
- Congenital (Fanconi's anemia)
- Drugs (e.g. chloramphenicol)
 Lack of nutrients (Nutritional anemias)
- Examples include:
o Iron deficiency anemia
o Vitamin B12 deficiency anemia
o Folic acid deficiency anemia
o Deficiency of proteins

 Lack of hormones
- Examples include:
o Erythropoietin deficiency (e.g. chronic renal failure)
2- Anemia due to increased RBC destruction
- Causes include:
 Abnormal RBC shape
o Sickle cell anemia (due to Hb S)
o Congenital spherocytosis (Due to lack of spectrin)
o Congenital elliptocytosis (due to lack of spectrin)
 Lack of RBC enzymes
o Glucose 6 phosphate dehydrogenase deficiency
o Pyruvate kinase deficiency
 Mechanical destruction of RBCs
o Malaria
o Hypersplenism
 Other causes
o Thalassemia, Autoimmune hemolytic anemia …
3- Anemia of blood loss
 Acute blood loss
- Acute bleeding occurs following trauma
- The drop in Hb concentration does not occur immediately. It
occurs after about 3 days (i.e. after restoration of plasma
volume and before restoration of cells). The cells take about 4
weeks to be restored.
- Severity of anemia is best assessed by history (information
given by the patient or his relatives about the blood loss).
 Chronic blood loss

- Occurs due to daily loss of small amount of blood over long
period of time. This results in iron deficiency anemia (due to
loss of iron with blood; about 0.5 mg iron in each ml of blood).
- Examples include: Worms like ankylostoma (the hook worm),
chronic peptic ulcer and bleeding from a GIT tumor.
Diagnosis of anemia
Step 1 (symptoms):
- Anemia is suspected when patients complain of:
o Fatigability, palpitations, breathlessness and headache.
Remember that: Mild anemia and even severe anemia that’s
developed gradually over long time, may be asymptomatic due to
compensatory mechanisms.
Step 2 (signs):
- Doctors do clinical examination looking for:
o Pallor of mucus membranes
o Tachycardia
o High pulse pressure (increased systolic and decreased
diastolic pressure)
o Signs of the cause or signs of complications
- During clinical examination, doctors look for signs of a cause
that may be responsible for the anemia (e.g. jaundice
indicates hemolytic anemia and severe loss of weight
indicates malignancy). At the same time they look for a
possible complication of anemia, especially if it is severe. A
well known example is anemic heart failure presenting with
generalized edema.

Step 3 (investigations):
 Investigations are required to confirm the diagnosis of anemia.
These include: Hb estimation, PCV and RBC count
 Investigations are also needed to know the cause of anemia.
Examples include:
o Peripheral blood picture
- The shape and color of RBCs under the microscope may give
clue about the cause of anemia, look at this table:
Table 5.1:
Shape of RBCs Color of RBCs Possible causes
Microcytic Hypochromic Iron deficiency
Thalassemia
Macrocytic Normochromic Vitamin B12 deficiency
(Megaloblastic) Folic acid deficiency
Normocytic Normochromic Anemia of chronic illness
Chronic renal failure
- Direct microscopy may give additional information. For example

fragmented RBCs indicate hemolysis.
- High reticulocyte count and bilirubin level in plasma indicate
hemolytic anemia.
 RBC indices
- Can be calculated to give similar information as the microscopic
peripheral blood picture (i.e. information about the shape and color of
RBCs). - They include the following indices:
MCV (Mean corpuscular volume)
= PCV x 10/RBC; normally = 80 – 95 fL (may be up to 100 fL)

- RBCs with higher results are described as macrocytic, lower
results are microcytic and normal results are normocytic.
MCH (Mean corpuscular hemoglobin)
= Hb x 10/RBC
- Normally = 25-32 pg
- RBCs with lower results are described as hypochromic while
normal results are normochromic.
MCHC (Mean corpuscular hemoglobin concentration)
= Hb x 100/PCV
- Normally = 34% (or 34 g/dL) range: 32-36 g/dL
- RBCs with lower results are described as hypochromic while
normal results are normochromic.
 Investigations for specific causes
- For example:
o Investigations for iron deficiency like TIBC, iron concentration and
ferritin level in plasma (see iron metabolism).
o Investigations for chronic renal failure like serum creatinine, urea
and electrolytes.
o Investigations for leukemia like total WBC count and differential
count.
Treatment of anemia
1- Treatment of the cause (e.g. stop the site of bleeding)
2- Replacement of the deficient nutrient (e.g. iron and/or folic acid)
3- Correction of the low Hb by blood transfusion (if Hb is very low).
This is important to prevent anemic heart failure. However, if heart
failure has already developed, it is preferred to transfuse packed
cells rather than whole blood, to avoid additional fluid overload.

1. A male fetus during the second trimester of intra-uterine life has:

a. about 60% of his total body weight as water
b. red blood cells synthesized in the liver
c. “Gower” type of haemoglobin
d. anti A antibodies if he is blood group B
e. anti D antibodies if he is rhesus negative
2. All the following about haemoglobin s are correct except:
a. it consists of two alpha and two beta chains
b. its alpha chains are normal
c. it is absent in all neonates carrying the genes of sickle cell
disease
d. it precipitates due to hypoxia causing “sickling” of leucocytes
e. it results in sickle cell anemia
3. Iron:
a. is found in high amounts in mother’s milk
b. is absorbed mainly in the terminal ileum
c. is transported in plasma with albumin
d. is not stored in the liver
e. deficiency causes reduction in volume and color of red blood
cells
4. Which of the following is NOT a characteristic of obstructive
jaundice:
a. pale fatty stool
b. normal urine color
c. absent urobilinogen from urine
d. high conjugated bilirubin in blood
e. bleeding tendency
5. The principal hormone needed for red blood cell formation is:
a. cortisol
b. thyroxin
c. vitamin D
d. erythropoietin
e. parathyroid hormone
6. Iron deficiency anemia is characterized by:
a. high PCV
b. aplastic bone marrow
c. pale fatty stool
d. low ferritin level in the plasma
e. macrocytic normochromic RBCs

7. Concerning folic acid , it is:
a. a fat soluble vitamin
b. found in green leafy vegetable
c. absorbed better in presence of reducing factors
d. antagonized by vitamin B12
e. required for myelin formation
8. Hemolytic jaundice is characterized by:
a. high concentration of conjugated bilirubin in urine
b. high concentration of unconjugated bilirubin in plasma
c. absence of urobilinogen in urine
d. pale and fatty stool
e. abnormal function of the liver
9. The red bone marrow in an adult is found at all these sites except:
a. skull
b. ribs
c. pelvic bones
d. shaft of the femur
e. sternum
10. Reticulocytes are:
a. precursors of white blood cells
b. not present in normal blood
c. increased in bacterial infections
d. decreased in haemolytic anemia
e. increased following correction of nutritional anemia
11. The mature red blood cell in children:
a. is synthesized in the spleen
b. has few mitochondria
c. its volume increases in folic acid deficiency
d. of males has more hemoglobin than that of females
e. lives for about 8 hours
12. Concerning the packed cell volume (PCV), it is:
a. the percentage of RBCs out of total cells in the blood
b. higher in neonates than in infants
c. normally about 37% in the adult male
d. high in patients with haemolytic anemia
e. low in all subjects living at high altitude
13. Erythropoietin:
a. is stimulated by increased oxygen tension.
b. Is needed for Hb synthesis
c. reduces maturation time of red blood cells.
d. its level is always high in people living at high altitudes
e. its level is always low in patients with chronic kidney failure.

14. Hb S:
a. is similar to Hb F
b. is characterized by abnormal alpha chains
c. starts to appear in normal children after the age of 6 months
d. precipitates when there is hypoxia
e. is an important protective mechanism against malaria
15. Regarding iron absorption, it is:
a. hormonally controlled
b. decreased by HCL
c. Increased by intrinsic factor of the stomach
d. decreased by penicillin
e. about 10% of daily ingested iron
16. Hyperactivity in the bone marrow is indicated by:
a. jaundice
b. anaemia
c. leucocytosis
d. thrombocytosis
e. reticulocytosis
17. Microcytic hypochromic anemia occurs due to:
a. acute renal failure
b. hepatic cirrhosis
c. congestive heart failure
d. chronic peptic ulcer
e. filariasis
18. Vitamin B12:
a. is found in green vegetables
b. is absorbed in the stomach
c. is needed for haemoglobin synthesis
d. deficiency causes normocytic normochromic anemia
e. deficiency results in demyelination neuropathy
19. Hb concentration in a pregnant lady is 9 g/dL, PCV is 36% and
RBC count is 3 x 106 cell/mm3. Which of the following is not true:
a. mean corpuscular hemoglobin is normal
b. iron status is probably normal
c. volume of red blood cells is above normal
d. this lady most probably suffers from vit. B12 deficiency
e. folate deficiency is expected in this patient
Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Answer b d e b d d b b d e
Question 11. 12. 13. 14. 15. 16. 17. 18. 19.
Answer c b e d e e d e d

LEUCOCYTES
Definition
- The motile units in the blood that protect the body against invaders.
Count
- 4000-11000/mm3
- Higher count (leucocytosis) is caused by leukemia, infections,
inflammation...
- Lower count (leucopenia) is caused by certain diseases of the bone
marrow and certain infections (e.g. typhoid fever).
Formation of WBCs
 Site: bone marrow
 Stages: (Proliferation & Maturation)
- Like other types of cells, formation starts by differentiation of
pluripotent stem cells into committed stem cells (progenitor cells).
- There are separate committed stem cells for lymphocytes,
basophils and eosinophils, whereas neutrophils and monocytes have
a common precursor.
 Regulation: by certain colony stimulating factors (GM-CSF) and
cytokines (IL3, IL4 and IL5).
Classification
- According to presence or absence of cytoplasmic granules, they are
classified into two major types:
o Granulocytes
o Agranulocytes
 The granulocytes:
- Have granulated cytoplasm
- Have polysegmented nucleus

- known as poly-morpho-nuclear leucocytes [PMNL]).
- Have very short life span (Hours)
- Have 3 types (according to reaction of the cytoplasmic granules
with acidic or basic dyes):
1- Neutrophils: the granules react with basic and acidic dyes
2- Eosinophils (Acidophils):the granules react with acidic dyes (e.g.
eosin dye)
3- Basophils:the granules react with basic dyes (e.g. mythelene blue
dye)
 Neutrophils
- Constitute 50-70% of total WBCs (the most abundant type)
- Nucleus: segmented (3-5 lobes)
- Cytoplasm: granulated
- Granules: react with acidic and basic dyes, purple in color
Fig 5.5: Neutrophil
- Can phagocytose bacteria and then perform intracellular killing (see

below).
- Increased in:
o Bacterial infections
o Stressful stimuli
o Hormones (adrenaline/cortisol)

 Eosinophils (Acidophils)
- Constitute 1-4% of total WBCs
- Nucleus: segmented (2-3 lobes)
- Cytoplasm: granulated
- Granules: bright red in color. React with acidic dyes (like eosin).
Fig 5.6: Eosinophil
- Increased in:
o Parasitic infections (attack parasites that are too large
to be phagocytosed).
o Allergic reactions (e.g. asthma).
- They release proteins, cytokines and chemokines that can induce
inflammation and kill microorganisms (e.g. Major basic protein and
Leukotriene C4)
 Basophils
- Constitute (0-0.4%) of total WBCs (i.e. they are the least abundant
WBCs)
- Nucleus: may be segmented but hidden by the granules
- Cytoplasm: granulated. The granules: rough, dense and dark blue
in color. They obscure the nucleus behind them.

Fig 5.7: Basophil
- The granules contain heparin and histamine (similar to mast cells).

They react with basic dyes like methylene blue dye.
- They release their contents in response to stimulation from T
lymphocytes.
- They are essential in immediate hypersensitivity reactions
- Generally increased in allergic reactions (e.g. allergic rhinitis and
allergic dermatitis).
 Agranulocytes
- Generally have non-granulated cytoplasm (they may have few fine
granules).
- Have one nucleus (not segmented)
- Have longer life span (days, months or years)
- Two types: Monocytes and lymphocytes
 Monocytes
- Have larger diameter than other types of WBCs
- Nucleus: kidney shaped
- Cytoplasm: not granulated
- They can phagocytose bacteria and kill it intracellularly

Fig 5.8: Monocyte
- They stay in the circulation for (2-3 days) and then enter the tissues
where they transform into tissue macrophages. However, the life
span of tissue macrophages is uncertain; may be 3 months or more.
- Tissue macrophages include: Kupffer cells in the liver, Langerhans
cells in the skin, Microglia in the brain, Osteoclasts in bone and
Alveolar macrophages in the lung (= members of the mononuclear
phagocyte system, used to be known as reticulo-endothelial system).
- Functions of the tissue macrophages (or the phagocyte system):
 Phagocytosis (activated of phagocytes by T lymphocytes)
 Presentation of antigens to lymphocytes
 Release of cytokines and other substances (see immunity).
 Lymphocytes
- Size: may be small or large
- Nucleus: rounded
- Cytoplasm: scanty and not granulated.

Fig 5.9: Lymphocyte
- Before birth, they are produced in the bone marrow as lymphocyte

precursor cells.
- Then after birth, some still arise from bone marrow. However, most
lymphocytes are formed in the lymph nodes, thymus or spleen, from
the original precursor cells that developed in the bone marrow and
processed in one of the following sites: Thymus gland or Burza of
Fabricius (in birds) /or burza equivalent tissues like the fetal liver and
the bone marrow (in humans)
- Accordingly there are 2 types of lymphocytes:
- T-Lymphocytes (processed in the thymus gland) &
- B-Lymphocytes (processed in the Burza equivalent tissues).
The two types circulate between blood and lymph.
 T-Lymphocytes:
- Constitute about 80% of total lymphocytes
- Mature in the thymus gland
- Types: Helper T cells (CD4 cells) & cytotoxic T cells (CD8 cells).
- When activated, the T lymphocyte form memory T cells; for future
recognition of the invader (= the secondary immune response)
- They are responsible for cell mediated immunity (see below)

 B-Lymphocytes:
- Constitute about 20% of total lymphocytes.
- Maturate in the bone marrow
- When activated, they differentiate into plasma cells (for production
of antibodies) and memory B cells (for future recognition of the
invader, = the secondary immune response)
- Responsible for humoral immunity; i.e. secretion of antibodies that
are mixed with body fluids (see below)
How can white blood cells perform their functions?

 Chemotaxis
- Attraction of neutrophils to the site of infection by certain
substances including components of the complement system (C5a),
leukotrienes and products of damaged tissues, bacteria or
leucocytes.
 Diapedisis
- Passage of white blood cells from the blood to the tissues through
the wall of capillaries (e.g. neutrophils, basophils, eosinophils and
monocytes).
 Opsonization
- Preparation for eating or making the foreign cell palatable or tasty
for phagocytosis. Opsonins that coat foreign cells include IgG and
some proteins of the complement system.
 Phagocytosis
- The process of ingestion of bacteria or any abnormal cell by a
phagocytic cell (e.g. neutrophils, Monocytes or macrophages).
- Preceded by recognition and followed by intracellular killing.

 Intracellular killing
- Fusion of cytoplasmic granules in the phagocytic cell with the
phagocytic vacuole, then release of the antimicrobial agents found
within these granules into the vacuole.
- The antimicrobial agents found within the granules of neutrophils
include:
o Defensins
o Proteases (elastase, metalloproteinases)
- Other antimicrobial agents released by neutrophils:
o Toxic oxygen metabolites (O2- , H2O2)
o Oxidants (HOCl, HOBr, …)
- The toxic oxygen metabolites (O2- , H2O2) are oxidants formed
following activation of a cell membrane bound enzyme (NADPH
oxidase).
- It is associated with a process known as the respiratory burst,
characterized by marked increase in oxygen uptake and metabolism
in the neutrophil.
- Steps of formation:
NADPH + H+ + 2O2 = NADP+ + 2H+ + 2O2-
O2- + O2- + H+ + H+ = H2O2 + O2
(The second step is catalyzed by the enzyme superoxide dismutase
(SOD))
- Formation of the other oxidants (HOCl, HOBr) is catalyzed by the
enzyme myeloperoxidase.
- Notice that certain types of bacteria can resist intracellular killing
and remain viable within the WBCs.

IMMUNITY
- The physiological process by which the body destroys or
neutralizes foreign particles. Includes two types:
o Non specific immunity (Innate immunity)
(Does not depend on recognition of the invader (i.e. non specific))
o Specific immunity
(Depends on recognition of the invader)
Non specific immunity (Innate immunity)
- The first line of defense against invaders. It includes:
 Natural barriers
 Inflammation
 Natural killer cells
 Complement system
 Natural barriers:
- Prevent invasion of tissues by microorganism. They include:
o Anatomical barriers (e.g. skin and mucus membranes)
o Biochemical barriers (e.g. saliva, tears and gastric acid)
o Mechanical barriers (e.g. cough and vomiting)
 Inflammation:
= The response of the body to infection. It acts to localize infection. It
involves:
o Attraction of WBCs to the site of infection
o Release of active substances by WBCs
o The active substances destroy the microorganisms. However,
they also damage tissues and result in changes in blood vessels
(e.g. vasodilatation and increased permeability).
- Signs of inflammation: redness, swelling, pain & loss of function.
 Natural killer cells (= NK cells)
- A small fraction of circulating lymphocytes is neither T nor B
lymphocytes; most of these are natural killer cells (NK cells).
- They resemble cytotoxic lymphocytes in killing their targets by
releasing granules containing cytolytic enzymes (perforins).
However, they differ from them in that:
o They kill naturally (generally they do not need activation,
however, they may become activated by interferons α and β.
o They attack cells which lack class I MHC antigens on their
membranes; these include some virus infected cells (because
some viruses inhibit expression of MHC-I antigens) & tumor
cells (because these have low or no class I MHC expression).
 The complement system
- Group of proteins (30 or more), activated to produce a cell killing
effect.
- They include: (C1 (has 3 subunits: q, r and s), C2, C3a, C3b, C4,
C5, C6, C7, C8, C9, factor B, factor D, factor H, factor I …).
- Most of these proteins are inactive beta globulins (= 5% of all
globulins).
- They are activated by:
 Classic pathway
- Triggered by antigen-antibody complexes.
- The first factor to be activated is C1 (see fig 5.10).
 Alternative pathway
- Triggered by the surface of pathogens like bacteria or viruses.
- The first factor to be activated is C3 (see fig 5.10).
 Lectin pathway

- Triggered by contact of lectin with certain carbohydrate groups
(mannose) in bacterial wall (mannose-binding lectin (MBL)).
- MBL acts like C1q it activates C2 & C4, then other steps follow.
Fig 5.10: Activation of the complement ystem
Mechanism of action:
- The cell killing effect of the complement proteins is achieved by:
 Opsonization (e.g. by C1q and C3b)
 Chemotaxis (e.g. by C5a)
 Cell lysis (by the perforating complex C5b6789)
 Degranulation of mast cells to release histamine (e.g. by C3a)

Remember that:
- Complement proteins are tightly regulated by complement control
proteins that inhibit their damaging effects on the normal cells.
- Deficiency of some of the complement proteins may predispose to
repeated infections (e.g. meningitis).
Specific immunity
- Depends on the action of lymphocytes which, in addition to their
immediate defensive role, form memory cells for future recognition of
the invaders.
- This explains the fact that a secondary immune response (induced
by subsequent exposure to an antigen) is always more rapid and
stronger than a primary immune response (induced by first exposure
to the antigen).
- Antigens are presented to lymphocytes by antigen presenting cells
which, after phagocytosis, present some of the invader antigens on
their surface; to be recognized by the lymphocytes.
- The antigen presenting cells are:
o Dendritic cells (found in lymph nodes spleen and skin)
o Macrophages (in different tissues)
o Native B lymphocytes (can bind antigen directly through
IgM antibodies expressed on their surface. However, they
need T helper cells for full activation (see below)).
- After recognition of the antigen, the lymphocytes proliferate and
mediate two types of specific immunity:
o Cell mediated immunity (mediated through activation and
proliferation of T lymphocytes).

o Humoral immunity (mediated through activation and
proliferation of B lymphocytes).
Cell mediated immunity
- T helper lymphocytes recognize antigens presented by the antigen
presenting cells when these antigens are linked with the major
histocompatibility proteins type II (MHC-II).
- Certain markers on the surface of T helper cells (known as cluster
of differentiation 4 or CD4) facilitate this recognition.
Fig 5.11: Proliferation of T helper cells
- The activated T helper cells release cytokines for activation of T

cytotoxic lymphocytes, natural killer cells and macrophages. These
attack primarily virus infected cells, intracellular bacteria, fungi,
protozoa and cancer cells. In addition they play an important role in
rejection of transplanted organs. The cytokines also activate the B
lymphocytes.

- The Cytotoxic T cells can recognize antigens presented by the virus
infected cells when these antigens are linked with the major
histocompatibility proteins type I (MHC-I).
- Certain markers on the surface of cytotoxic T cells (known as
cluster of differentiation 8 (CD8)) facilitate this recognition. They kill
their targets by releasing proteins known as “perforins” into them.
These make pores into the virus infected cells and initiate apoptosis.
Fig 5.12: Proliferation of cytotoxic T cells
- It is important to notice that T helper lymphocytes are two types:

o T helper 1 (TH1): the principal cells activated in cellular
immunity
o T helper 2 (TH2): interacts with B lymphocytes in relation to
humeral immunity
- Examples of the cytokines released By T H1:
o IL-2 (activates lymphocyte proliferation (autocrine effect),
natural killer (NK) cells and macrophages)
o  Interferon (IFNγ activates macrophages and inhibits TH2)

- Examples of the cytokines released by TH2:
o IL 4 (activates B lymphocytes to produce IgE antibodies)
o IL-5 (stimulates differentiation of eosinophils)
- Human immuno-deficiency virus (HIV) attacks CD4 cells (T helper
cells); resulting in failure of cytokine production and therefore failure
of activation and proliferation lymphocytes and macrophages. This
causes acquired immune-deficiency syndrome (AIDS) and renders
the body susceptible for infection (with even the nonpathogenic
bacteria) and cancer.
Humoral Immunity
- Activated B-lymphocytes transform into plasma cells and produce
large number of antibodies
- The antibodies attack the invaders in different ways (see below).
- Unlike cell mediated immunity, humoral immunity is directed mainly
against extracellular organisms like bacteria).
 Note:
- Proteins of the major histocompatibility complex (MHC) are
encoded by genes located on the short arm of chromosome 6. These
proteins are found on the outer surface of body cells and they are
unique for each person. In humans they are known as human
leukocyte antigens (HLA).
- The MHC genes are classified into 3 classes:
 Class I
o Encodes for MHC-I proteins, which are coupled with antigens
formed within the cell (e.g. formed by intracellular virus).
These proteins are found on all nucleated cells. They are
recognized by CD8 cells.

 Class II
o Encodes for MHC-II proteins, which are coupled with antigens
of extracellular organisms like bacteria. The antigens are
selected after phagocytosis of bacteria and then presented in
association with MHC-II proteins. Therefore these proteins are
found on antigen presenting cells. They are recognized by
CD4 cells.
 Class III
o Encodes for some immunological proteins (e.g. some
cytokines and complement proteins).
The cytokines
- Cytokines are proteins produced by a wide variety of immune and
non-immune cell types.
- They are involved in regulation of growth, development, and
activation of immunity and in the mediation of inflammation.
- A single cytokine can be released by different cells and different
cytokines may have similar functions and can act on different cells.
- Actions of cytokines may be:
o Autocrine: the cytokine acts on the same cell that secretes it
o Paracrine: the cytokine acts on a nearby cell
o Endocrine: the cytokine circulates in blood and acts on distant
cells
- Cytokines have names that describe their targets or their functions.
For example, cytokines acting on leucocytes are interleukins (IL-1, 2,
3, 4 …); whereas cytokines stimulating hematopoiesis are colony
stimulating factors (granulocyte-monocyte colony-stimulating factor).

- Chemokines are cytokines that regulate cell movement (e.g.
Chemotaxis which is regulated by the chemokines IL-8 & RANTES).
Table 5.2: Examples of some cytokines and their functions

Cytokine Cell source Function
IL-1 Macrophages Hematopoiesis
Epithelial cells Fever & hepatic acute phase proteins
Fibroblasts Activation of WBCs
IL-2 T cells Activation & proliferation of T cells
Activation of B cells, NK cells and
macrophages
IL-3 T cells Hematopoiesis
NK cells
IL-4 T cells Stimulation of B cells to secrete anti-
Mast cells bodies
Stimulation of TH2 proliferation
IL-5 T cells, mast cells Activation of eosinophils
& eosinophils
IL-6 B cells Fever & induction of acute phase
Epithelial cells proteins from the liver
Fibroblasts T & B cell differentiation
IL-8 Macrophages, Chemotaxis
WBCs, fibroblasts Release of histamine from basophils
& endothelial cells
IL-12 Macrophages Induces TH1 cell formation
Neutrophils
IFN α & β All cells Anti-viral activity. Stimulate T cell,
macrophage, and NK cell activity.
Direct anti-tumor effects
IFN γ T cells Regulates macrophage and NK cell

(interferon NK cells activations. Stimulates immunoglobulin
- γ) secretion by B cells
TNFα Macrophages Fever, anorexia, shock, capillary leak
(tumor Most WBCs Leukocyte cytotoxicity, enhanced NK cell
necrosis Epithelial cells function, acute phase protein synthesis,
factor α) Fibroblasts pro-inflammatory cytokine production
RANTES Macrophages, T Chemotaxis
cells, fibroblasts & Induces release of histamine from
basophils basophils

The antibodies
- Gamma globulins, called immuno-globulins or (Ig); produced by
activated B-lymphocytes (known as plasma cells).
Structure of the basic unit of antibodies:
- 2 heavy chains & 2 light chains connected by disulfide bridges.
- Each chain consists of both variable (V) and constant (C) regions.
- The C regions form the “Fc portion” for cell binding whereas the V
regions form the “Fab portion” for antigen binding.
- The variable regions have variable sequences of amino-acids; this
makes the Fab portion in each immunoglobulin molecule differs from
Fab portions in other molecules. That’s why antibodies secreted
against specific antigen do not attack other antigens.
 Remember that: Each antibody attacks only one specific antigen
by its antigen binding site (Fab portion).
Fig 5.13: The basic structure of antibodies

- The immunoglobulins (Ig) are classified according to the types of
heavy chains into 5 types: G, M, A, E and D; therefore they are
described as IgG, IgM, IgA, IgE and IgD.
 IgG:
- The most abundant (constitutes more than 75% of total
immunoglobulins in plasma).
- The smallest type (monomer: has two sites for binding antigens)
- The only type that can cross the placenta from the mother to the
fetus to protect him from micro-organisms (= passive immunity)
- IgG is the main antibody in the secondary immune response (i.e.
the immune response following exposure to an antigen for the
second time or more)
 IgM:
- The largest type
- Pentamer (5 of the basic units connected together)
- It is the main antibody in the primary immune response (i.e. the
immune response following exposure to an antigen for the first
time).
 The secondary immune response is more faster and stronger
than the primary immune response due to presence of memory
cells formed during the primary response. They immediately react
with the antigen and result in secretion of adequate amounts of
IgG antibodies against the antigen
 IgA:
- Monomer, dimer or trimer
- In addition to plasma, it is also found on the mucosal surfaces
(e.g. mucosa of the GIT, genitor-urinary and respiratory systems),

and in body secretions like saliva, milk and tears. For this reason
it is called the secretory immunoglobulin.
- Plays an important defensive role at these sites against
colonization of mucosa by pathogens.
 IgE:
- After its formation during a primary immune response induced
by certain allergens, it becomes attached to membranes of mast
cells & basophils through the Fc portion. Then during a
subsequent exposure to the same allergen, it binds the allergen
through the Fab portion. This induces release of histamine from
these cells causing symptoms and signs of immediate
hypersensitivity reaction and sometimes a severe anaphylactic
shock due to profound vasodilatation.
- In addition to its role in allergic reactions, it also offers protection
against parasites (e.g. worms).
 IgD:
- Has unknown function; may be antigen antibody recognition
(may act as antigen binding receptor on B lymphocytes).
Mechanisms of action of the immunoglobulins
 Opsonization of bacteria to facilitate phagocytosis (e.g. IgG)
 Neutralization of some toxins
 Blocking attachment of some viruses and bacteria to cells
 Activation of the complement system (IgG and IgM antibodies)
 Agglutination of group of cells or substances together to prevent
their spread; to be captured by phagocytes in one action
 Precipitation of some antigen-antibody complexes
 Degranulation of mast cells and basophils (release of histamine)

1. Concerning the white blood cells, which of the following is true:
a. neutrophils are increased in viral infections
b. basophils are increased in parasitic infections
c. eosinophils have kidney shaped nuclei
d. monocytes phagocytose bacteria
e. lymphocytes release histamine
2. B- Lymphocytes are:
a. phagocytic cells produced by the bone marrow
b. premature cells activated in the thymus gland
c. the dominant type of lymphocytes
d. responsible for humeral immunity
e. increased in bacterial infections
3. The major basic protein is:
a. found in the granules of eosinophils
b. involved in allergic reactions
c. an anti-parasitic substance
d. a cause of bronchospasm in asthmatic patients
e. all the above statements are true
4. Which of the following antibodies is found in mother’s milk:
a. IgA
b. IgM
c. IgG
d. IgD
e. IgE
5. A stained blood film of a patient with hypersplenism shows:
a. neutropenia with reticulocytosis
b. thrombocytopenia with erythroblastosis
c. anemia with neutrophilia
d. anemia with agranulocytosis
e. pancytopenia with reticulocytosis
6. Concerning natural killer cells, which of the following is not true:
a. they are non T, non B lymphocytes
b. they attack tumor cells
c. they attack antigens presented with class I MHC proteins
d. they kill virus infected cells by releasing perforins
e. they are similar to T-cytotoxic lymphocytes
7. B lymphocytes differ from T lymphocytes in that they:
a. have large oval nuclei
b. may act as antigen presenting cells
c. form memory cells
d. populate lymph nodes
e. play an important role in immunity

8. Regarding T-Lymphocytes, which of the following is correct:
a. helper cells recognize antigens when presented in association with
MHC class I
b. cytotoxic cells expose CD4 molecules on their membranes
c. major cytokines are released by the CD8 cells
d. TNFα is immediately released by T helper cells after their activation
e. T lymphocytes constitute the majority of lymphocytes in circulation
9. Acute bacterial infections are characterized by high count of:
a. neutrophils
b. basophils
c. monocytes
d. lymphocytes
e. both a & c
10. A stained normal blood film shows:
a. 20% nuetrophils.
b. 4% basophils.
c. 8% lymphocytes.
d. 4% monocytes.
e. 11% eosinophils.
11. "T Lymphocytes" differ from "neutrophils" in all the following
except:
a. their cytoplasm is not granulated
b. they are not markedly increased in bacterial infections
c. they are attacked by the Human Immunodeficiency Virus (HIV)
d. they cannot produce antibodies
e. their nuclei are not segmented
12. Neutrophils:
a. have granules containing heparin
b. are produced in the thymus gland
c. can leave the blood and enter tissues
d. live up to three days
e. are increased in viral infections
13. Immunogloblin:
a. D has the largest size
b. E is found in milk
c. G is found mainly in primary immune response
d. M is the only type that activates complement proteins
e. A is found in the mucosa of the respiratory tract
14. Immunoglobulin M (IgM) is:
a. described as the secretory immunoglobulin
b. most abundant in the secondary immune response
c. the dominant type of immunoglobulin in plasma
d. the antibody type directed against antigens of the ABO system
e. found on surface of mast cells

15. The following cytokine is not released by T lymphocytes:
a. IL-1
b. IL-2
c. IL-3
d. IL-4
e. IFNγ
16. Attraction of neutrophils to the site of infection occurs by:
a. phagocytosis
b. coagulation
c. diapedesis
d. agglutination
e. Chemotaxis
17. Phagocytosis is the major function of:
a. B lymphocytes
b. neutrophils
c. endothelial cells
d. basophils
e. eosinophils
18. Development of acquired immunity requires all the following
except:
a. B lymphocytes
b. T lymphocytes
c. Macrophages
d. Major histocompatibility complex
e. Basophils
19. This cell presents antigens to T helper with MHC class II proteins:
a. virus infected cell
b. tumor cell
c. dendritic cell
d. mast cell
e. NK cell
20. Which of the following factors is not a chemotactic agent:
a. IL-8
b. C5b
c. RANTES
d. C3a
e. Leukotrienes
Question o o o o o o o o o o
Answer d d e a e c b e a d
Question o o o o o o o o o o
Answer d c e d a e b e c d

BLOOD GROUPS AND BLOOD TRANSFUSION
BLOOD GROUPS
= Antigens found on the surface of red blood cells
 Importance
- Blood transfusion
- Exclusion of paternity (paternity can be excluded by blood groups;
however, its confirmation requires DNA fingerprinting).
 Types
- There is large number of these antigens.
- The most important are: ABO system & rhesus system.
- Others (of less importance): MNS, Lutheran, Kell, Kidd, Duffy …
The ABO System
 Antigens (Agglutinogens): A & B
- Two antigens on surface of RBCs: A & B.
- Accordingly there are 4 blood groups:
 Blood group A has antigen A
 Blood group B has antigen B
 Blood group AB has both antigens A & B
 Blood group O has neither antigen A nor B.
-These antigens are also found in other tissues (salivary glands,
kidney, liver, lung, pancreas, testes and amniotic fluid).
- They are glycosphingolipids in RBCs but glycoproteins in the other
tissues.
- Basically, all groups have H antigens. In individuals with blood
group O, all the H antigens persist without conversion into antigen A
or B. In individuals with blood group A or B, the H antigens are
converted into antigens A or B respectively. This is achieved by

adding N-acetylgalactosamine to H antigens in blood group A, or
adding galactose to H antigens in blood group B.
- A and B glycoproteins are secreted by tissue cells into the
circulation. Some individuals are “non-secretors”. They are
susceptible to a variety of infections because the glycoproteins may
bind to polysaccharides on cells and block attachment of bacteria to
these polysaccharides.
 Antibodies (Agglutinins): anti A & anti B
- Anti A and anti B antibodies (of IgM type) are acquired naturally
after birth by unknown mechanism.
- Suggested mechanisms for their formation in neonates after birth:
 Food contains antigens similar to A & B antigens. Ingestion and
absorption of these antigens induce the immune system to attack
them by antibodies that circulate in the blood as anti A & anti B
antibodies.
 Certain intestinal bacteria contain antigens similar to A & B
antigens. If these bacteria infect the neonate, the immune system
will form antibodies against the bacterial antigens. These
antibodies circulate as anti A and anti B antibodies.
- The most interesting fact is that: The body forms antibodies against
the ABO antigens not present on surface of red blood cells. For
example a subject with group A has antigen A on RBC membranes,
so his body forms antibodies against B antigen (anti B antibodies).
- Accordingly, plasma contains the following types of antibodies:
 Anti A antibodies in subjects with blood group B
 Anti B antibodies in subjects with blood group A
 Anti A & anti B antibodies in subjects with blood group O

 No antibodies in subjects with blood group AB
 Donors (In blood transfusion)
- Selection of a donor depends on absence of antigens on RBCs of
the donor that may react with antibodies in plasma of the recipient
(i.e. reactions between donor’s cells & recipient’s plasma “or serum”).
- On the other hand, reaction between the donor’s plasma and
recipient’s cells is neglected. This is because the volume of blood
collected from the donor is about 500 ml and therefore the amount of
antibodies in the plasma of this blood is very small. In addition to
that, it will become diluted in the plasma of the recipient.
- Accordingly, donors are selected for each blood group as follows:
 Donors for blood group (A) are those with blood groups A & O
 Donors for blood group (B) are those with blood groups B & O
 Donors for group (AB) are those with blood groups A, B, AB, O
 Donors for blood group (O) are those with blood group O
Notes to remember about the donors:
 Subjects with blood group AB can receive blood from every
blood group (they are described universal recipients)
 Subjects with blood group O can give blood to every blood
group (they are described as universal donors).
 Inheritance: Autosomal dominant
- Blood group antigens are inherited from each parent as autosomal
dominant characters in chromosome 9p (i.e. A & B antigens are
inherited in the two copies of chr 9, from the father and the mother).
- Therefore, the genotype for each blood group will be as follows:
 Blood group A: the genotype is [AA] or [AO]
 Blood group B: the genotype is [BB] or [BO]

 Blood group AB: the genotype is [AB]
 Blood group O: the genotype is [OO]
- If a father and his wife have blood groups A and B respectively,
their children may have any type of blood groups (A, B, AB or O).
But, if they are A and A, their children may have either A or O only.
 Distribution (%)
- The ABO blood groups are distributed as follows:
 Blood group A is found in about 42% of population
 Blood group B is found in about 8% of population
 Blood group AB is found in about 3% of population
 Blood group O is found in about 47% of population
Notes to remember about distribution of blood groups:
 The most dominant blood group is O (blood group of the
universal donors) and the least dominant is AB (blood group of
the universal recipients).
The Rhesus System

- First studied in the rhesus monkeys.
 Antigens: D
- Include antigens C, c, D, E, e.
- Unlike the ABO antigens, these proteins are only found on RBCs
(not found in other tissues).
- The most important of these antigens is antigen D (has the highest
antigenisty).
- Accordingly, there are (2) types of rhesus groups:
 Rh +ve (antigen D is present on RBC surface)
 Rh -ve (antigen D is absent from RBC surface)

 Antibodies: anti D
- Unlike the anti A & anti B antibodies, antibodies of the rhesus
system (anti D antibodies) are of the IgG type (i.e. the smallest type
that can cross the placenta from maternal blood to fetal blood).
- Also unlike anti A and anti B antibodies, anti D antibodies are not
naturally acquired after birth.
- They develop only in (Rh -ve) subjects (never in Rh +ve subjects).
- Causes of their development in rhesus –ve subjects:
 Blood transfusion of Rh +ve blood to Rh –ve subjects
 Delivery of (Rh +ve) baby by Rh –ve mothers (During labor, the
placenta separates from the uterus resulting in bleeding and
entrance of some fetal blood in maternal circulation
 Donors
- Rh +ve subjects do not have anti D antibodies. They can receive
blood from Rh +ve & Rh –ve subjects.
- Rh -ve subjects do not have anti D antibodies unless they receive
Rh +ve blood. Therefore, they should receive Rh -ve blood only.
- During emergencies, Rh –ve blood is not always available; that’s
why rhesus –ve subjects may receive Rh +ve blood for the first time.
This induces formation of anti D antibodies in his plasma within 3
days after the transfusion.
- Therefore, any future transfusion of Rh +ve blood is contra-
indicated because it will be associated with severe reaction.
 Inheritance
- Autosomal dominant character in chromosome 1.
- Chrmosome 1 carries E or e plus D or without D (absence of D is
indicated as d) plus C or c. For example: Cde or cDe or CdE …

- Since antigen D determines the rhesus group, genotype for each
group (chromosomes from father and mother) will be as follows:
 Rh +ve genotypes: DD or Dd
 Rh –ve genotype: dd
Remember that:
 A child of a rhesus +ve father & rhesus +ve mother can be
either Rh +ve or a Rh –ve (if the genotype of both father and
mother is “Dd”).
 A child of a rhesus -ve father & rhesus -ve mother should be
Rh –ve.
 Distribution (%)
- Percentage of subjects with Rh +ve blood group, in all populations,
is far higher than that of Rh –ve subjects.
- For example: 99% are Rh +ve & only 1% are Rh –ve in Europe. In
other communities, the percentage of rhesus positive subjects is
about 85% and 15% for Rh –ve subjects.
Remember that:
 In the ABO system of blood grouping, transfusion of a
mismatched blood (e.g. group A subject receiving blood group
B) is always associated with severe reaction.
 In the Rhesus system, blood transfusion reactions are:
- Never expected for Rh +ve subject receiving Rh –ve blood
- Not expected in the first blood transfusion for Rh -ve subject
receiving Rh +ve blood
- Always expected in subsequent transfusions for Rh –ve
subject receiving Rh +ve blood

Hemolytic disease of the newborn
- Also known as erythroblastosis fetalis because the early stages of
RBCs (erythroblasts) appear in fetal blood together with reticulocytes
as compensation to the excessive hemolysis.
- It occurs in Rh +ve neonates of Rh –ve mothers.
- During delivery of the first Rh +ve neonate, some of his blood
enters maternal circulation. The delivered neonate is normal; but the
mother forms anti D antibodies of IgG type to get rid of the baby’s
RBCs (i.e. she becomes immunized).
- When she becomes pregnant again with a Rh +ve fetus, these
antibodies cross the placenta, enter the fetal circulation and attack
RBCs of the fetus who develops hemolytic anemia and jaundice.
- The hemolytic anemia is associated with hyperactive bone marrow
to replace the lost RBCs. This results in appearance of the early
stages of RBC in fetal blood (erythroblastosis & reticulocytosis).
- Anemia may become complicated by heart failure associated with
generalized edema (hydrops fetalis) and the fetus may die in utero.
- The jaundice is caused by unconjugated bilirubin which is insoluble
in water. It may precipitate in the basal ganglia in the brain causing
Kernicterus (characterized by motor problems and may be
associated with mental retardation).
- If the newborn is delivered with jaundice, he can be treated with:
 Phototherapy: converts the insoluble bilirubin to a water
soluble substance, lumirubin, that’s soluble (do not precipitate
in the brain) and can be excreted easily in urine
 Exchange transfusion: taking Rh +ve blood from the neonate
and giving him Rh –ve blood

 Plasmapheresis: usage of a machine that extracts the
antibodies from blood of the neonate
- Prevention is better than cure. Here an injection of anti D antibodies
given to the mother immediately following labor and not more than 72
hours after it will attack fetal RBCs that carry the rhesus antigen and
therefore prevent formation of anti D antibodies by the mother
herself.
Remember that:
 Antibodies injected to a subject stay in the circulation for short
time and then disappears completely.
 Antibodies formed by a subject himself stay in the circulation
for very long time because memory cells continue to secrete
the antibodies for life.
- Sometimes, ABO incompatibility between the mother and the

neonate offers some natural protection against the hemolytic
disease. For example when the mother is blood group A and the
neonate is blood group B, here the naturally occurring anti B
antibodies in maternal blood attack RBCs of the neonate as soon as
they enter maternal circulation and therefore prevent formation of anti
D antibodies.

Blood transfusion
 Precautions
- When blood is infused intravenously into patients, plasma of the
patients should not contain antibodies that may react with blood
group antigens on RBCs of the donor.
- To achieve this, suitable donors should be selected for each blood
group, and this is further confirmed by cross matching test.
- In cross matching test the plasma of the recipient (containing
antibodies) is mixed with the donor's blood and then examined under
the microscope for evidence of agglutination of the RBCs.
Agglutination indicates that the blood of the donor is not suitable for
the recipient.
- In spite of this, errors may occur and unfortunate patients may
receive mismatched blood by accident. For this reason, blood
transfusion should always be taken seriously, with certain
precautions, including release of a few drops at first to make sure
that there is no reaction and close follow up of the process, putting
life saving drugs at reach beside the patient.
 Complications of mismatched blood transfusion
 Agglutination of RBCs, followed by hemolysis:
o In mild cases, agglutination of RBCs may be complicated by post-
transfusion jaundice.
o In severe reaction, a few ml of blood are sufficient to cause
severe pain in the back or in other sites and tightness in the chest
(due to block of capillaries by the agglutinated RBCs). This is also
followed by hemolysis of the RBCs and release of hemoglobin in
plasma.

 Acute renal failure:
o Some of the intravascular hemoglobin is filtered at the glomeruli
and excreted in urine (hemoglobinuria).
o Some precipitates in the renal tubule resulting, in addition to the
low blood pressure, in acute renal failure.
o Acute renal failure is characterized by low urine output, high urea
and high potassium ions. Death may occur in few days.
 Disseminated intravascular coagulation (DIC):
o In severe cases, antigen-antibody reactions may result in
activation of coagulation causing DIC and therefore fatal bleeding
due consumption of the clotting factors.
 Complications of compatible blood transfusion
o Hyperkalemia due to potassium released from hemolysed RBCs
during storage of blood
o Hypocalcemia due to excess anticoagulant (e.g. citrate, which is a
calcium chelating agent)
o Fever (febrile reaction) due to pyrogens and/or cytokines in the
donor’s blood
o Allergy (allergic reaction) due to allergens in the donor’s blood;
sometimes severe anaphylaxis may occur.
o Transmission of infection due to transfusion of infected blood (e.g.
HIV, Hepatitis B, malaria …)
o Air embolism
o Thrombophlebitis at the injection site
o Fluid overload especially in patients with heart failure
o Iron overload due to repeated blood transfusions (hemosiderosis)

HEMOSTASIS
 Definition
- Prevention of blood loss by arrest of bleeding and maintenance of
blood in the fluid state.
 Mechanisms (or steps) of hemostasis following injury
o Vasospasm
o Formation of platelet plug
o Formation of blood clot (Coagulation)
o Fibrinolysis or fibrous tissue formation
 Vasospasm
- Occurs immediately following injury due to:
o Myogenic response (the vascular smooth muscle responds to
trauma by spasm)
o Humoral factors (serotonin & catecholamines like epinephrine
and norepinephrine cause vasoconstriction)
o Neural factors (neural reflex involving the sympathetic
neurons)
- The vasospasm is expected to be weak in cases of:
o Hypoxia
o Metabolic acidosis
o Small surface area (spasm caused by a knife is weaker than
that caused by a stone; because the surface area of blood
vessels injured by the knife is smaller than by the stone)
 Formation of platelet plug
- Aggregation of platelets to close a hole in the blood vessel
- Enough to close small holes in blood vessels
- Large holes need the third step: blood coagulation

 Platelets (Thrombocytes)
- Small cells (2- 4µm in diameter)
- Count: (200,000 – 400,000/mm3)
- Life span: about 5 days (up to 10 days)
- Arise from stem cells & then megakaryocytes in the bone marrow.
- The cytoplasm of each megakaryocyte breaks down into large
number of platelets (i.e. they are non-nucleated).
- Formation is regulated by colony stimulating factors and a hormone
known as thrombopoietin, a protein released by the liver and kidneys.
- About one third are stored in the spleen. That’s why splenectomy
(removal of the spleen) is sometimes used for treatment of
thrombocytopenia to increase platelet count.
- Their membranes contain receptors for collagen and von Willebrand
factor (vWF); both are important for attachment of platelets to
collagen at sites of blood vessel injury. Also they have receptors for
ADP and fibrinogen.
- Platelets contain two types of granules:
o Alpha granules (contain protein substances like the clotting
factor number 13, platelet derived growth factor (PDGF) which
is a potent stimulus for wound healing & vWF which is
synthesized by megakaryocytes and also by endothelial cells)
o Dense granules (contain non-protein substances like serotonin
and ADP)
- Functions of platelets:
 Participates in the various mechanisms of hemostasis as follows:
o Vasospasm: they release a vasoconstrictor (serotonin)
o Platelet plug formation: major function of platelets (see below)

o Blood coagulation (platelets release some clotting factors (e.g.
factor 13 and platelet factor 3 “phospholipids”)
 Clot retraction: after formation of a blood clot and incubation of
blood for half an hour or so, platelets contract because they
contain actin and myosin fibers in their cytoplasm. This decreases
the size of the clot (to about 10% of its original size), and
expresses serum (read table 5.2).
- Platelet deficiency (thrombocytopenia) results in increased bleeding
tendency. A count less than 50,000 cell/µL is associated with
hemorrhage after minor injuries and possibly multiple petechial
hemorrhages under the skin and mucus membranes
“thrombocytopenic purpura”; however, purpura is very common when
the platelet count is less than 20,000 cell/µL.
- On the other hand, high count of platelets (thrombocytosis)
predisposes to thrombotic problems.
Mechanism of platelet plug formation:
1. Platelets attach to collagen fibers (this step is facilitated by
collagen receptors on platelets & vWF)
2. Activation of platelets (attachment to collagen fibers activates
platelets to swell, become irregular in surface and become sticky)
3. Release of contents (serotonin, thromboxane A2 “TXA2”, ADP ...)
4. Aggregation of platelets (serotonin causes vasospasm whereas
TXA2 & ADP activate nearby platelets to swell and stick to the
previous ones and release the same contents, then TXA 2 & ADP
activate other platelets and the cycle repeats itself in a form of
“positive feedback mechanism” until the small hole in the blood
vessel is sealed by the plug (large holes need coagulation).

Table 5.2: Comparison between serum and plasma
Difference Plasma Serum
Formation By centrifugation By incubating a clotted
of blood sample for sometime
Clotting proteins Present Absent (consumed)
(e.g. fibrinogen)
Serotonin Low High (released by

activated platelets)
 Blood coagulation
- Biochemical reactions that involve activation of clotting factors
(present in blood in inactive form) in a cascade way to form a blood
clot.
- The clotting factors are indicated by roman numbers from I to XIII or
by names; for example:
o Fibrinogen Factor I
o Prothrombin Factor II
o Tissue factor Factor III or tissue thromboplastin
o Calcium Factor IV
o Factor V Proaccelerin or labile factor
o Factor VII Serum prothrombin conversion accelerator
(SPCA) or stable factor
o Factor VIII Anti-hemophilic factor A
o Factor IX Christmas factor or antihemophilic factor B
o Factor X Stuart factor
o Factor XI Antihemophilic factor C

o Factor XII Hageman factor
o Factor XIII Fibrin-stabilizing factor
- Most of these factors are produced by the liver (exceptions include
factors: III, IV and XIII).
- Remember that: there is no clotting factor known as factor VI.
- Activation of the clotting factors occurs through two pathways:
o Intrinsic pathway
o Extrinsic pathway
 The intrinsic pathway
- All factors involved are present in the blood (i.e. there is no need for
an extrinsic factor from the tissues).
- Factors activated through this pathway include: XII, XI, IX, VIII, X,
V, II and I; plus calcium ions (factor IV) & phospholipids (provided by
platelets as platelet factor 3).
- The first factor to be activated is factor XII; it is activated when
blood comes in contact with collagen or wettable negative surface
like glass. See the other steps in figure 5.14:
 The extrinsic pathway
- It is called extrinsic because a tissue factor (known as
thromboplastin or factor III) is needed for its activation. This factor
consists of phospholipids and protein.
- Factors activated through this pathway include: VII, X, V, II and I;
plus calcium ions (factor IV) & phospholipids (provided by the tissue
factor).
- This pathway is faster than the intrinsic pathway.
- The first factor to be activated is factor VII; it is activated by the
tissue factor. See the other steps in figure 5.14.

- Factor X, II, I and V are activated through both intrinsic and extrinsic
pathways; that’s why they are described as factors of the common
pathway.
Fig 5.14: The pathways of coagulation

Important notes about coagulation
 Calcium ions are needed in all steps of coagulation except the
first two steps of the intrinsic pathway which need high molecular
weight kininogen (HMWK) and Prekallikrein (PK).
 Phospholipids are needed in many steps (e.g. activation of factor
X and II).
 Phospholipids in the intrinsic pathway are provided by platelets
and in the extrinsic pathway are provided by the tissue factor.
 Factor V and VIII are cofactors, their activation by thrombin
results in amplification and repetition of the reactions through a
positive feedback mechanism.
 Thrombin, the active form of factor II, is an alpha globulin
synthesized in the liver as prothrombin. Its activation requires
many factors: aX, aV, calcium and phosplolipids. All these factors
are known collectively as prothrombin activator complex or
thrombokinase.
 Activation of prothrombin to thrombin is the most important step in
coagulation. Actions of thrombin include:
o Activation of fibrinogen (factor I)
o Activation of factor V
o Activation of factor VIII
o Activation of plasminogen (see below)
o Activation of platelets
o Activation of protein C (through thrombomodulin, see below)
 Thrombin activates fibrinogen to form fibrin strands. These
combine together to form a net at the site of injury. The net
catches cells and protein until it is completely sealed as clot.

 The blood clot is stabilized by factor XIII (fibrin stabilizing factor)
and Ca++. Factor XIII is released by platelets. It forms covalent
bonds between fibrin strands.
Fig 5.15: The blood clot
 Fibrinolysis
- After formation of the blood clot, bleeding stops; but the clot causes
partial obstruction within the blood vessel. Therefore, it should be
removed by the process of fibrinolysis; however, some clots may
become invaded by fibroblasts (invited by platelet derived growth
factors). These cells convert the clot into a permanent fibrous tissue.
- Fibrinolysis involves enzymatic degradation of fibrin by the enzyme
plasminn resulting in formation of fibrin degradation products.
- Plasmin is produced by the liver as an inactive protein
(Plasminogen).
- Plasminogen is activated by factors called (Plasminogen activators)
- These factors can be obtained from:
o Blood
o Tissues
o Urine
o Bacteria

 Plasminogen activators in blood
- These are: aXII and thrombin.
- Although they are responsible for formation of the blood clot, they
participate in its lysis by activating plasminogen into plasmin.
However, lysis does not occur immediately following blood clot
formation because plasmin is inhibited by a plasma protein known as
α2 anti-plasmin. The level of plasmin has to increase gradually until it
becomes sufficient to cause lysis of the clot, this usually occurs after
48 hours. During this time regeneration occurs and the hole in the
blood vessel is closed.
 Plasminogen activator in the tissues
- This is the tPA (tissue Plasminogen activator). It is released by the
tissues, e.g. vascular endothelium, to cause lysis of the clot.
- It can be synthesized by recombinant DNA from melanoma cells for
medical purposes (to be used for treatment of acute myocardial
infarction). However, it is very expensive to be used in the developing
countries.
 Plasminogen activator in urine
- This is urokinase which is synthesized by the transitional epithelium
of the urinary tract and released in urine.
- Its physiological significance in urine is unknown, may be to cause
immediate lysis for clots that may obstruct the renal tubules.
 Plasminogen activator from bacteria
- This is streptokinase, a toxin produced and released by streptococci
to break clots formed by the body to limit its spread.
- The bacteria are cultured and streptokinase is extracted for
treatment of acute myocardial infarction. It is rather cheaper than

tPA. However, since it is extracted from bacteria, its IV infusion
induces formation of antibodies against it. Therefore, its future use in
the same patient requires certain precautions.
 The normal endothelium can activate plasminogen
- The endothelial cells have Plasminogen receptors on their surface.
These activate Plasminogen when it binds them.
ANTICOAGULANTS
 Natural anticoagulants
- These are present naturally within the body. They prevent clotting
within the circulation.
- Abnormalities associated with a defect or absence of one or more
of these factors are usually associated with intravascular clotting.
- They include:
 The normal endothelium
- Prevents clotting by the following:
o Smooth surface prevents activation of the clotting factors
o Release of prostacycline & nitric oxide (these cause
vasodilatation and inhibit platelet aggregation)
o Have plasminogen receptors on their surface that activates
plasmin when it binds them
o Thrombomodulin (see below)
 The blood flow
- Rapid blood flow inhibits coagulation whereas stasis of blood favors
coagulation. Stasis may occur due to:
o Mechanical obstruction of a blood vessel
o Prolonged sitting (e.g. during prolonged flight or bus journey)

o Prolonged lying down (e.g. comatose patients or those with
fractures)
 Anti-thrombin III
- An alpha globulin synthesized by the liver.
- Inactivates IX, X, XI and XII.
- Its activity is increased about 1000 times by heparin. For this
reason it is called the heparin cofactor
- Hemoglobin may also facilitate the activity of antithrombin III.
 Heparin
- Sulfated polysaccharide (MWt: 15,000-18,000)
- Found in the granules of mast cells and basophils
- Acts through activation of antithrombin III
- Its low level in plasma indicates that it is not very important as a
natural anticoagulant at normal conditions.
- It is very important for prevention of coagulation in containers used
for blood collection and when given intravenously in therapeutic
doses (e.g. in cases of deep vein thrombosis (DVT)).
- When given accidentally in toxic doses, protamine sulphate is used
to neutralize it (= antidote).
 Alpha II macroglobulin
- Similar to anti-thrombin III
- Inactivates some clotting factors.
 Thrombomodulin
- A protein expressed on surface of most endothelial cells (except
those in cerebral capillaries)
- Binds thrombin to form a complex that activates protein C.


 Protein C and its cofactor: protein S
- Produced by the liver
- Require vitamin K for their synthesis.
- Inactivate the following:
o Factor V
o Factor VIII
o Inhibitor of tissue Plasminogen activator (i.e. activates tPA
and therefore increases plasmin)
 Fibrin, plasmin and FDPs
- Fibrin adsorbs some clotting factors and this prevents propagation
of the clot within the blood vessel.
- Plasmin breaks down fibrin resulting in dissolution of clots.
- Fibrin degradation products (FDPs) also inhibit coagulation (by
inhibiting thrombin).
 Synthetic anticoagulants
 Vitamin K antagonists
- For example warfarin (Coumarin derivative)
- This interferes with the action of vitamin K that’s needed for
synthesis of the following clotting factors in the liver (1972):
o Factor II (prothrombin) (2)
o Factor VII (7)
o Factor IX (9)
o Factor X (10)
- Warfarin is the only anticoagulant that can be taken orally. It is used
for prevention of thrombosis and embolism.
- Warfarin interacts with many drugs that may potentiate or inhibit its
effects (e.g. aspirin); that’s why drugs taken with it should be revised.

- Warfarin therapy should be monitored by testing the INR
(International Normalized Ratio). This is calculated from prothrombin
time (PT) as follows: INR = (PT test/PT control)ISO Where ISO is the
international sensitivity index.
Very important notes to remember:
 Effects of warfarin start to appear 3 days after initiating therapy.
That’s because warfarin acts through inhibiting synthesis of
vitamin K dependent clotting factors in the liver, but factors
already present in blood continue to act during the first few days.
 In addition to that, coagulation tendency is sometimes increased
when starting warfarin therapy, rather than decreased! That’s
because warfarin inhibits activity of the anticoagulants protein C &
S which are also vitamin K dependent factors.
 Therefore, the best way to anti-coagulate the patient during this
period is to give heparin together with warfarin when starting
treatment and to monitor warfarin effects with INR; then stop
heparin and continue with warfarin.
 Calcium chelating agents
- These include: oxalate, citrate and EDTA.
- They bind calcium and make it unavailable for coagulation
- Not used in vivo because they may decrease calcium concentration
in the plasma and cause tetany.
Remember that:
 Anticoagulants used only in vitro: Calcium chelating agents
 Anticoagulants used only in vivo: Vitamin k antagonists
 Anticoagulants used in vitro and in vivo: Heparin
-
TESTS FOR HEMOSTATSIS
 Bleeding time (BT)
- A test for platelets because it is done by causing small hole in a
blood vessel (a pinprick at the lobe of the ear or the anterior surface
of the forearm, using a lancet)
- Normally takes 1-7 minutes.
- It is prolonged in the following conditions:
o Thrombocytopenia
o Thromboasthenia
o Von Willebrand disease
o Vitamin C deficiency
 Clotting time
- A test for the clotting factors of the intrinsic pathway or common
pathway (because it involves collection of blood in a test tube and
then initiation of coagulation by contact of blood with glass).
- Normally takes less than 10 minutes.
o Hemophilia
o von Willebrand disease
o Vitamin K deficiency
o Chronic liver disease
o Afibrinogenaemia
o Obstructive jaundice
 Prothrombin time (PT)
- A test for the clotting factors of the extrinsic pathway because blood
is collected in a tube containing citrate to remove Ca++; then Ca++ &
thromboplastin are added to allow blood to clot (= extrinsic pathway).

- Normally takes 12-15 seconds.
o Vitamin K deficiency
o Chronic liver disease
o Afibrinogenaemia
o Obstructive jaundice
- As mentioned above, it is used for calculation of the international
normalized ratio (INR).
 Activated partial thromboplastin time (aPTT)
- A test for the clotting factors of the intrinsic pathway.
- It is activated to shorten the time of coagulation by adding certain
substances like kaolin and it is called partial because thromboplastin
is not added.
- It normally takes 25-39 seconds.
- It is prolonged by the same causes that prolong the clotting time.
EXAMPLES OF BLEEDING TENDENCIES

 Hemophilia
- Occurs due to deficiency of:
o Factor VIII (hemophilia A, classical, 85% of cases).
o Factor IX (hemophilia B, less common, 15% of cases, also
known as Christmas disease).
- Inherited as X- linked recessive (therefore it is more common in
males).
- Characterized by normal BT and prolonged clotting time and aPTT.
- Treatment: factor VIII injections or fresh frozen plasma or blood.


 Von Willebrand disease
- vWF is a glycoprotein produced by endothelial cells and
megakaryocytes.
- It is needed for stabilization of factor VIII and for attachment of
platelets to collagen.
- Congenital deficiency of this factor causes bleeding tendency with
prolonged bleeding time and clotting time.
 Afibrinogenaemia
- Deficiency of fibrinogen may be congenital (since birth), or acquired
later in life by a disease (e.g. placental abruption during pregnancy
results in clotting of blood behind the placenta. This consumes
fibrinogen and causes its deficiency).
- Characterized by prolonged clotting time and prothrombin time;
however, the best test is thrombin time (TT) which gives information
about availability of fibrinogen.
 Chronic liver diseases
- Impairs synthesis of the clotting factors which are synthesized in the
liver.
 Obstructive jaundice
- Impairs absorption of vitamin K. which is a fat soluble vitamin that
needs bile for its absorption from the intestine.
- Vitamin k is needed for synthesis of clotting factors the II, VII, IX
and X (1972). Therefore obstructive jaundice causes deficiency of
these factors. For this reason, patients with obstructive jaundice
should receive vitamin K injections daily for 5 days before surgery.



Examples of clotting tendencies (thrombosis):
 Due to congenital problems
- Deficiency of protein C, protein S or antithrombin III
 Due to atherosclerotic blood vessels
- Atherosclerosis may be complicated by complete occlusion of a
blood vessel.
- It is predisposed by systemic diseases like diabetes and
hypertension.
- Most dangerous at the coronary, renal and cerebral arteries
 Due to sluggish blood flow
- Follows prolonged periods of bed ridden (e.g. due to operations,
delivery or fractures).
- May be complicated by detachment of the clots (embolization).
- A large embolus detached from a lower limb vein that obstructs the
pulmonary artery usually causes immediate death.
- This is known as pulmonary embolism.
 Due to wide spread deposition of fibrin in the circulation
- This is known as disseminated intravascular coagulations (DIC).
- It is caused by septicemia, disseminated cancers or massive tissue
injuries. These stimulate formation of multiple clots within the
intravascular space.
- The clots consume the clotting factors and therefore patients bleed
from the skin, GIT and respiratory tract … (usually fatal).

PLASMA
- The fluid part of the blood
 Volume
- About 5% of total body weight in a 70 kg adult male (= 3.5 L)
 Contents
 Water (= 90%)
 Inorganic substances (minerals, electrolytes …)
 Organic substances (proteins, glucose, fats, bilirubin, urea …)
 Plasma proteins
- Types:
 Albumin
 Globulins (,  and )
 Fibrinogen
- Synthesis
 The liver (synthesizes most plasma proteins)
 Plasma cells (Synthesizes gamma globulins which are not
synthesized by the liver (also known as immunoglobulins or
antibodies)
- Concentration:
 Total = 6-8 g/dL
 Albumin: 3.5-5 g/dL
 Globulins (,  and ): 2.3 g/dL
 Fibrinogen: 0.3 g/dL
- Functions:
 Oncotic pressure (albumin because its particles are smaller
and larger in number than other types of plasma proteins)

 Viscosity of blood (globulins and fibrinogens because of the
asymmetrical shape and large size of their particles)
 Clotting (fibrinogen and some globulins- most clotting factors
are beta globulins but prothrombin is an alpha globulin)
 Transport of hormone like thyroid, adrenocortical and gonadal
hormones (albumin and globulins)
 Carriage of ions, metals, bilirubin … (e.g. albumin carries
bilirubin and the beta globulin transferrin carries iron)
 Protection by antibodies (gamma globulins)
 Buffer (= 15% of the buffering capacity of the blood, by the
COOH and NH2 groups in all proteins)

1. The intrinsic pathway of blood coagulation:
a. is triggered by contact of factor X with collagen
b. is faster than the extrinsic pathway
c. utilizes 50% of the clotting factors present in the blood
d. requires tissue thromboplastin for its activation
e. is never completed in the absence of Ca++
2. Platelets:
a. are non nucleated biconcave cells
b. arise from megakaryocytes in the bone marrow
c. always stop bleeding
d. their count is higher than red blood cells
e. their size is larger than white blood cells
3. A child whose both father & mother are group B-positive may be:
a. blood group A positive
b. blood group A negative
c. blood group AB positive
d. blood group O-negative
e. blood group AB negative
4. Vitamin K deficiency causes low production of factor:
a. I
b. VII
c. VIII

d. XI
e. XII
5. Prolonged clotting time is found in all the following except:
a- heparin therapy
b- obstructive jaundice
c- congenital afibrinogenaemia
d- thrombocytopenia
e- chronic liver disease
6. The following is not a function of thrombin:
a- breakdown of fibrinogen
b- activation of protein C
c- activation of factor VIII
d- activation of plasminogen
e- activation of factor XI
7. The following is not a primary function of globulins:
a- blood coagulation
b- transport of iron
c- immunity
d- colloid osmotic pressure
e- blood viscosity
8. A woman who is blood group O Rh -ve:
a- has no any antigens on surface of RBCs
b- has anti-A, anti-B and anti D antibodies in plasma
c- acts as a universal donor
d- can never have a rhesus +ve child
e- usually gives birth to a jaundiced baby
9. The following statement about the extrinsic pathway is not true:
a- it is triggered by tissue trauma
b- it involves factor II
c- it requires calcium ions
d- it is prolonged in haemophilia
e- it is normal in von Willebrand disease
10. The following anticoagulant acts “in vitro” and “in vivo”:
a- heparin
b- warfarin
c- thrombomodulin
d- EDTA
e- citrate
11. Bleeding tendency commonly occurs due to all the following
except:
a- warfarin therapy
b- obstructive jaundice
c- hypocalcaemia
d- thromocytopenia

e- chronic liver disease
12. The following is not transported by plasma proteins
a. iron
b. oxygen
c. carbon dioxide
d. bilirubin
e. thyroxine
13. This factor is not activated through the intrinsic pathway?
a. I
b. II
c. V
d. VII
e. VIII
14. Plasminogen is activated by all of the following except:
a. Urokinase
b. Streptokinase
c. Tissue plasminogen activator (tPA)
d. thromboplastin
e. thrombin
15. All the following are natural anticoaguans except:
a. thromboxane A2
b. prostacycline
c. protein C
d. antithrombin III
e. plasminogen
16. Hemophilia is:
a. more common in males than females
b. due to congenital deficiency of Hageman factor
c. characterized by normal bleeding time
d. characterized by low level of vWF
e. diagnosed when the INR is higher than normal
17. Anti-thrombin III:
a. is a beta globulin
b. activity is inhibited by heparin
c. is similar in structure to alpha 2 macroglobulin
d. deficiency causes bleeding tendency
e. level in plasma is decreased by warfarin
Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Answer e b d b d e d c d a
Question 11. 12. 13. 14. 15. 16. 17.
Answer c b d d a c c

CHAPTER 6
THE CARDIOVASCULAR SYSTEM
THE CARDIAC MUSCLE
Fig 6.1: The heart
 Human heart consists of:

o 4 chambers
• 2 atria (thin walled, receive blood from major veins and allow
it to fill the ventricles)
•2 ventricles (thick walled, pump blood to pulmonary and

systemic circulation)
o 4 valves
• 2 Atrio-ventricular valves (AV valves):

- Mitral (left) and Tricuspid (right)
• 2 Semilunar valves:
- Aortic (left) and Pulmonary (right)

Properties of the cardiac muscle
- The cardiac muscle contains two types of muscle fiber:
• Cardiac muscle proper
• Conductive system
- It has special properties that characterize it from other types of
muscles, these properties include:
1- The histology of the cardiac muscle
- Unlike skeletal muscle, there are anatomical connections between
the myocardial fibers (intercalated discs and gap junctions); and
unlike smooth muscle, the cardiac muscle is striated.
Fig 6.2: The muscle differences in histology
2- Functional syncytium
- Stimulation of one cardiac muscle cell results in stimulation of all
the cells. This occurs due to presence of gap junctions & intercalated
discs between the fibers (which are areas of low electrical resistance
that allow movement of ions and therefore transmission of action
potential easily between cells).
- Therefore, the heart contracts as one unit (as a syncytium which is
multiple cells grouped together as one unit within a common cell
membrane forming a single multi-nucleated cell).
- Remember that the heart is not an anatomical syncytium but it is a
functional syncytium.

Fig 6.3: The cardiac muscle histology
3- The main source of energy

- The cardiac muscle consumes fat as the main source of energy.
Under basal conditions, 60% of the caloric needs are provided by
free fatty acids, 35% by carbohydrates and 5% by ketones and
amino acids.
- On the other hand, skeletal muscles utilize carbohydrates as the
main source of energy, especially during exercise.
4- Blood flow (supply)
- The cardiac muscle receives its blood supply mainly during diastole
(unlike skeletal muscles which receive their blood supply mainly
during systole).
- The left ventricle receives its blood supply during the diastolic
phase only whereas the right ventricle receives its blood supply
during both systole & diastole.
- This is explained by many physiological & anatomical mechanisms:
 Physiological explanation: During systole, aortic pressure= 120
mmHg, left ventricular pressure= 120 mmHg and right
ventricular pressure= 25 mmHg; therefore blood flows from the
aorta through the right coronary artery but not the left one. On

the other hand, during diastole, aortic pressure= 80 mmHg, left
ventricular pressure= 0 mmHg and right ventricular pressure= 0
mmHg; therefore blood flows from the aorta through both right
and left coronary arteries.
 Anatomical explanation: during systole, leaflets of the aortic
valve obstruct openings (sinuses) of coronary arteries.
5- Oxygen extraction
- At basal conditions, the cardiac muscle extracts higher amount of
oxygen than skeletal muscle. It consumes about 9 mL O2/ 100 g
tissue/minute. This is approximately about 70-80% of the oxygen
delivered by each unit of blood.
6- Metabolism
- The cardiac muscle depends on aerobic metabolism for generation
of energy. Anaerobic metabolism provides less than 1% of the total
energy. This figure may increase slightly during hypoxic states;
however, there is no oxygen debt mechanism (obstruction of the
coronary artery reduces oxygen delivery to the cardiac muscle and
results in its necrosis and death). On the other hand, skeletal muscle
depends on both aerobic & anaerobic metabolism for generation of
energy, and there is oxygen debt mechanism (oxygen debt is the
extra amount of oxygen consumed after exercise to repay oxygen
taken from myoglobin & to get rid of lactate accumulating in muscle.
7- Electrical activity (action potential)
- Action potential of the cardiac muscle proper is characterized by the
plateau phase (due to calcium influx), and that of the conductive
system is characterized by the prepotential (see below). Theses
phases are not found in action potentials of other types of muscles.

Fig 6.4: Actions potentials in the cardiac muscle
8- The refractory period

- Is prolonged in cardiac muscle (200-400 ms) due to presence of the
plateau phase. This protects the heart from tetanus (summation of
contractions during successive stimulation) and therefore allows the
cardiac muscle to relax; because relaxation is essential for
ventricular filling. The refractory period in skeletal muscles is about 5-
20 ms.
Fig 6.5: the refractory periods in muscles
9- ECF calcium:
- Contraction of the cardiac muscle depends on both ICF & ECF
calcium, whereas contraction of skeletal muscle depends on ICF
calcium only. The T tubules in the cardiac muscle allow influx of
calcium during action potentials to stimulate contraction. Therefore,

increasing ECF calcium increases contractility in cardiac muscle and
may stop the heart in systole.
10- No Recruitment in cardiac muscle
- Increasing strength of stimulation in skeletal muscles results in
recruitment (i.e. it increases number of stimulated fibers) whereas in
the cardiac muscle there is no recruitment (no increase in the
number of stimulated fibers). That’s because stimulation of one fiber
in cardiac muscle results in stimulation of all the fibers.
11- Automaticity
- The various parts of the conductive system can discharge action
potential spontaneously. This is explained by the prepotential phases
that characterize action potentials of the different structures of the
conductive system (the conductive system has no resting membrane
potential but gradual elevation of prepotential towards the threshold,
see below). This results in spontaneous generation of action
potentials by the conductive system (especially the sino-atrial node).
However, the cardiac muscle proper, which has no prepotential, can
discharge action potentials spontaneously, but in abnormal
conditions (e.g. ischemia). This is known as idio-ventricular rhythm.
12- Rhythmicity
- The cardiac muscle undergoes regular rhythmic contractions due to
presence of the conductive system, which controls these rhythmic
contractions whereas skeletal muscle cannot contract rhythmically.
13- Conductivity
- This is again a characteristic of the conductive system, which
generates rhythmic action potentials and conducts it to the whole
parts of the cardiac muscle (see below).

The conductive system
- The conductive system is formed of cardiac muscle fibers that are
less striated and lack definitive boundaries.
- It consists of the following structures:
 Sino-atrial node (SA node)
 Atrio-ventricular node (AV node)
 Internodal atrial pathways
 Bundle of His
 2 Bundle branches (BB):
o Rt Bundle branch (RBB)
o Lt Bundle branch (LBB).
- The left BB is divided into anterior & posterior fascicles
o Purkinje fibers
Fig 6.6: the conductive system

The sino-atrial node (SA Node)
- The SA node is found in the right atrium, at the opening of the SVC.
- It can discharge action potential spontaneously (the discharge
probably originates from small rounded cells in the SA node called P
cells).
- It is supplied by sympathetic neurons from the right side (because it
is developed from structures in the right side of the embryo). The
sympathetic neurons increase its rate of discharge.
- Similarly, it is supplied by parasympathetic neurons from the right
vagus. The parasympathetic neurons decrease its rate of discharge.
- Without innervation, its rate of discharge = 100/min, with innervation
(symp & parasymp) = 70/min. This indicates that the parasympathetic
effect is more dominant than the sympathetic effect on the SA node.
- The rate of discharge of the SA node is faster than other parts in
the heart, e.g.: AV node [45 /min] and Ventricles [15-35 /min]. That’s
why the SA node determines the heart rate (because it is the fastest).
For this reason it is regarded as the cardiac pacemaker.
- Its action potential is characterized by the prepotential (gradual
elevation of the membrane potential towards the threshold) due to
low K+ efflux through the K+ leak channels (remember that potassium
efflux generates the resting membrane potential). In addition to that,
the prepotential is completed by some Ca++ influx (through transient
Ca++ channels (T channels).
- The depolarization phase is due to Ca++ influx (through long lasting
calcium channels (L channels)); with some sodium influx; whereas
the repolarization phase is due to potassium efflux through the K+
voltage gated channels.

- The sympathetic makes the prepotential more vertical and therefore
increases heart rate whereas the parasympathetic makes the
prepotential more horizontal and therefore decreases the heart rate.
Fig 6.7: Effects of neurons on the prepotential
The AV Node
- The AV node is found in the Rt atrium on the right side of inter-atrial
septum, above the fibrous ring that separates atria from ventricles.
- It delays conduction from atria to ventricles (because its muscle
fibers have lower number of gap junctions and smaller diameter than
the SA node).
- This delay allows atrial contraction to precede ventricular
contraction and therefore completes ventricular filling with blood.
- When the SA node is diseased as in fibrosis of the SA node in old
subjects (known as sick sinus syndrome), the AV node becomes the
cardiac pacemaker. Here the heart rate decreases to about 45 beats/
min).
- When the AV node is damaged, ventricular rate becomes 15-35/min

THE ELECTROCARDIOGRAM (ECG)
- It is a record of the electrical activity of the heart from the surface of
the body using electrodes.
- The record represents the sum of all action potentials of myocardial
fibers at the time of recording as follows:
o The sum of all atrial depolarizations
o The sum of all atrial repolarizations
o The sum of all ventricular depolarizations
o The sum of all ventricular repolarizations
- All these events appear in the ECG as waves and intervals. The
waves are indicated by the letters p, q, r, s, t and sometimes u.
 Methods of Recording
- The ECG is recorded by two types of recording:
o One active electrode + an inactive electrode (= unipolar
recording)
o Two active electrodes + an inactive electrode (= bipolar
recording)
- The inactive electrode is the reference electrode that gives the iso-
electric line in the ECG; it is usually attached to the right foot.
- The isoelectric line determines whether a wave is positive or
negative. A positive wave is that recorded above the isoelectric line
whereas a negative wave is that recorded below it.
- A current of depolarization or repolarization coming towards an
active electrode produces a positive ECG wave whereas a current
passing a way from an active electrode produces a negative wave.
- The active electrodes are placed on the forearms, legs and chest;
at different locations to detect abnormalities in different sites of the

heart. Abnormalities appear as changes in the normal configuration
of the different waves and intervals in the ECG.
o The unipolar leads
- These are readings obtained by unipolar recording (i.e. each
reading is recorded by one active electrode). They include:
Limb leads (recorded by electrodes placed on the limbs):
o aVR (augmented vector of the right arm)
o aVL (augmented vector of the left arm)
o aVF (augmented vector of the left foot, remember that the
reference electrode is placed on the right foot)
Chest leads (recorded by electrodes placed on the chest):
o V1 (Vector of electrode placed on the 4th intercostal space to
the right of the sternum)
o V2 (Vector of electrode placed on the 4th intercostal space to
the left of the sternum)
o V3 (Vector of electrode placed midway between V2 & V4)
o V4 (Vector of electrode placed on the 5th intercostal space at
the mid-clavicular line)
the anterior axillary line)
the mid-axillary line)
o The bipolar leads
- Readings obtained by bipolar recording (2 active electrodes)
- Include three limb leads (I, II & III):
o Lead “I” is recorded by two active electrodes placed on the
right and left arms.

o Lead “II” is recorded by two active electrodes placed on the
right arm & the left foot.
o Lead “III” is recorded by two active electrodes placed on the
left arm & the left foot.
Einthoven’s triangle
- An imaginary equilateral triangle formed by the three bipolar
electrodes (I, II and III). The heads of the triangle are the points of
attachment of the unipolar leads aVR, aVL and aVF; with the
assumption that the heart lies in the center of this triangle.
- It is well known in electricity that: "In an equilateral triangle, with a
source of electricity in the center, the summation of potentials at the
heads of the triangle = zero".
- Taking Einthoven's triangle: (aVR+ aVL + aVF = zero) or (I + III = II)
- Einthoven’s triangle is used to determine the cardiac axis (i.e. the
orientation of the heart relative to the horizontal plane), which lies
normally between the angles -30 & +90 degrees (or up to + 110).
- Left ventricular hypertrophy deviates the axis to the left of -30
whereas right ventricular hypertrophy deviates the heart to the right
of 110 degrees.
Fig 6.8: Einthoven’s triangle

 Importance of the ECG
 The ECG is used to:
o Calculate the heart rate
o Assess the size of the heart
o Diagnose diseases of the heart (e.g. ischemic heart disease
(IHD), myocardial infarction, pericardial effusion …),
o Diagnose arrhythmias
o Diagnose electrolyte disturbances (e.g. hyper or hypokalaemia)
Remember that:
 The ECG does not detect the mechanical events in the heart (i.e.
it does not show contraction or relaxation of the cardiac muscle);
it only detects the electrical activity (i.e. depolarization and
repolarization).
 The standard ECG

Fig 6.9
The normal waves

o P wave due to atrial depolarization
o QRS complex due to ventricular depolarization
o T wave due to ventricular repolarization
o U wave due to papillary muscle repolarization; however, in
sometimes, it may be absent from the ECG or may be present
with other abnormal ECG signs indicating hypokalemia.

o Atrial repolarization is not shown in the ECG; it is obscured by
the QRS complex.
The Intervals
o PR interval
- From beginning of P wave to the beginning of QRS complex.
- Its duration (0.12-0.2 s) represents time taken for spreading of
depolarization from the SA node to the ventricular septum
(through AV node and bundle of His).
- Short PR interval indicates tachycardia (e.g. due to Wolf
Parkinson White syndrome “WPW”) whereas prolonged PR
interval indicates 1st degree heart block (e.g. due to hypokalemia).
o QRS duration
- From beginning of “Q“ wave to the end of “S” wave.
- Its duration (< 0.1 s) represents time taken for spreading of
depolarization throughout both ventricles.
- Prolonged QRS duration (described as broad complexes)
indicates ventricular ischemia (ischemic heart disease “IHD”).
o QT interval
- From beginning of “q” wave to the end of “T” wave.
- Its duration (about 0.43 s) represents time of depolarization &
then repolarization of both ventricles.
- Prolonged QT interval predisposes to ventricular arrhythmias.
o ST segment
- From the end of S wave to the beginning of T wave.
- Equivalent to the plateau phase in action potential of the
ventricular muscle; that’s why it is affected by changes in Ca++
ions (prolonged in hypocalcaemia short in hypercalcaemia).

 Calculation of the heart rate
- The heart rate from the ECG =
Paper speed (in mm/s) / duration of one ECG cycle (in mm)
- The paper speed = 25 mm/s (unless the other value “50 mm/s” is
used) whereas the duration of one ECG cycle is best taken as RR
interval (in mm). This gives heart rate in beats per second.
- To calculate the heart rate in beats “per minute” rather than “per
second”, the “second” should be divided by 60; therefore the formula
becomes:
Heart rate (beat/min) = 25 x 60 /RR interval (in mm)
- Remember dimensions of the ECG paper:
Fig 6.10
ABNORMAL ECG
 Normal sinus rhythm
- The normal cardiac rhythm is a sinus rhythm (i.e. the pacemaker is
the SA node).
- Abnormal rhythms like nodal rhythm (pacemaker is AV node) or
idioventricular rhythm (pacemaker is the ventricle) occur when the
SA node is diseased or when there is complete block of conduction
between atria and ventricles (3rd degree heart block).
- Presence of normal P wave in the ECG indicates normal rhythm.


 Sinus arrhythmia
- This is a normal physiological condition in healthy children & young
adults. It depends on intact autonomic nervous system.
- It is defined as change in heart rate with respiration (heart rate
increases with inspiration & decreases with expiration). This variation
in the heart rate is lost in patients with autonomic neuropathy.
Possible explanations for the sinus arrhythmia:
1- Inspiration = decreased intra-thoracic pressure = increased
venous return = Bainbridge reflex or effect (see below) = increased
heart rate.
2- Inspiration = discharge of inspiratory impulses from the respiratory
center in the medulla = radiation of these impulses to the nearby
cardiac center = increased sympathetic discharge from this center to
the heart = increased heart rate.
3- Inspiration = inflation of the lung = stimulation of stretch receptors
in smooth muscle of bronchioles = inhibitory impulses pass through
the vagus to the cardio-inhibitory center in the medulla = decreased
parasympathetic supply to the heart = increased heart rate.
4- Inspiration = increased venous return to the right side of the heart
but decreased venous return to the left side = decreased cardiac
output from the left side = decreased blood pressure = less
stimulation of baroreceptors = increased heart rate (read below).
Fig 6.13: variation in heart rate with respiration (sinus arrhthmia)

 Abnormal sinus rhythm
Sinus tachycardia
o The heart rate is fast (> 100/min) while the pacemaker is still
the SA node.
o Causes may be physiological (e.g. motions, pain, hypoglycemia
and exercise) or pathological (e.g. hyperthyroidism and drugs
like beta adrenergic agonists and muscarinic blockers).
Fig 6.11
Sinus bradycardia
o The heart rate is slow (< 60 /min) while the pacemaker is still
the SA node.
o Causes may be physiological (e.g. sleep and athletes) or
pathological (e.g. hypothyroidism, hypothermia and drugs like
beta blockers and muscarinic stimulators).
Fig 6.12

Arrhythmias
- Abnormal rhythm of the heart that may be determined by a new
pacemaker.
Causes include:
o Damage to the normal pacemaker
o Appearance of a new, abnormal pacemaker, with a faster
discharge (this occurs in atria or ventricles due to ischemia)
o Block in the transmission through the conductive system
o Abnormal pathways for transmission (e.g. the bundle of Kent
in Wolf Parkinson White Syndrome).
 Types of arrhythmias
 Atrial arrhythmias:
 Atrial extrasystole
- Premature discharge from an atrial focus (an ECG cycle that
appears before completion of a previous one).
- Characterized by abnormally shaped P wave (because atrial
depolarization is initiated in an abnormal site, not the SA node).
- The premature beat occurs once and it is followed by a delay in the
new discharge from the SA node (known as compensatory pause).
Fig 6.14: Atrial extrasystole showing the abnormal P wave

 Atrail tachycardia
- Regular rapid discharge with narrow QRS complexes (the narrow
complexes generally indicate that there is no problem in ventricles).
- The heart rate from the ECG= the radial pulse and may reach about
200 beat/min.
Fig 6.15: Atrial tachycardia
 Atrial flutter
- Regular rapid discharge with narrow complexes.
- The rate of atrial discharge (rate of P waves in the ECG) is about
(200-350/min) whereas the radial pulse (= rate of QRS complexes) is
less than that.
- This is because of the delay in the AV node (every discharge from
the SA node is not necessarily conducted to the ventricles; therefore
number of P waves is higher than number of QRS complexes).
- P waves give a characteristic appearance in atrial flutter (the saw-
toothed appearance).
Fig 6.16: Atrial flutter showing the saw-toothed appearance

 Atrial fibrillation
- Irregular rapid discharge with narrow complexes.
- The rate of discharge in atria is expected to be (300-500/min);
however, its calculation from the ECG is impossible because P
waves are completely absent.
- The ventricular rate (i.e. rate of QRS complexes) is slower because
of the delay in the AV node.
Fig 6.17: Atrial fibrillation
Consequences of atrial arrhythmias:

- Occasional extrasystoles have no ill effects and do not need
treatment; however, other atrial arrhythmias decrease time of the
cardiac cycle (because of the tachycardia); this decreases the
diastolic time which is necessary for ventricular filling and therefore
decreases the stroke volume and the cardiac output. The reduction in
cardiac output may cause heart failure.
Treatment of atrial arrhythmias:
- According to severity of arrhythmia and patient condition, atrial
arrhythmias may be treated with simple maneuvers that increase
vagal discharge (like carotid sinus massage at the angle of the jaw,
eyeball pressure or induction of vomiting); or by anti-arrhythmic drugs
(like digitalis, beta blockers …); or by using the defibrillator.

 Ventricular arrhythmias
 Ventricular extrasystole
- Premature discharge from a ventricular focus (an ECG cycle that
appears before completion of a previous one).
- Characterized by abnormally shaped QRS complex (because
ventricular depolarization is initiated in an abnormal site, not the
normal site which is the septum).
Fig 6.18
 Ventricular tachycardia
- Regular rapid discharge with broad QRS complexes (the broad
complexes indicate that there is a problem in ventricles).
- Other ECG waves may be hidden by the broad complexes.
- The heart rate is very fast.
- The commonest cause is ischemic heart disease.
Fig 6.19

 Ventricular fibrillation
- Very rapid discharge of multiple ventricular foci.
- Results in appearance of an abnormal bizarre shaped ECG).
- ECG waves are not clear.
- It is a cause of death in patients with myocardial infarction.
Fig 6.20
Consequences of ventricular arrhythmias:

- Occasional extrasystoles have no serous effects and do not need
treatment.
- Ventricular tachycardia decreases cardiac output because the time
available for ventricular filling is decreased and therefore the stroke
volume and cardiac output are decreased. This causes heart failure.
- In addition to that, ventricular tachycardia may be complicated by
ventricular fibrillation.
- Ventricular fibrillation is the most dangerous type of arrhythmia. It
causes death in minutes because the heart fibrillates without ejecting
blood to supply the brain.
Treatment:
- According to severity of arrhythmia & patient condition, ventricular
arrhythmias can be treated with anti-arrhythmic drugs or defibrillators
(= electric shock).

Heart Block
- Block of conduction from atria to ventricles.
- May be: 1- Incomplete heart block: first or second degree
2- Complete heart block: third degree
 First degree:
- Prolonged PR interval (> 0.2s)
- Causes include: IHD & hypokalaemia.
Fig 6.21
 Second degree
- Conduction from atria to the ventricles is blocked (e.g. due to IHD).
- This results in generation of P wave two or three times before
appearance of the QRS complex (2:1 or 3:1 conduction).
Fig 6.22
 Third degree
- Complete block of conduction from atria to ventricles (due to IHD).
- Atria continue to contract by the SA node whereas ventricles
continue to contract by a ventricular focus (idioventricular rhythm).

- P waves appear at regular intervals with a normal rate (60-100/min)
- QRS complexes are not related to the P waves. They appear
independently with an abnormal shape and a slow rate (15-35/min).
Fig 6.23
- Patients with complete heart block develop Stokes Adams attacks

(become immediately unconscious and collapse with a minimal
degree of exercise). That’s because the low cerebral blood flow is
further decreased with exercise due to shifting of blood towards
muscles.
Myocardial infarction (MI)

- Death of myocardial fibers due to interruption of the blood supply
(block in the coronary artery or some of its branches).
- This produces characteristic changes in the ECG. The changes are
explained by the findings that the infarcted area develops rapid
repolarization (due to accelerated opening of K+ channels) followed
by reduction in the resting membrane potential (RMP) and then
delayed depolarization. The reduction in the RMP makes the normal
area more negative relative to the infarcted area (in the extracellular
surface of cells not the intracellular). Therefore the electrical currents

flow from inside the infarcted area to the normal area (from positive
to negative). This means that the currents are flowing towards the
ECG electrodes overlying the infarcted area. The electrodes develop
upward deflection. This appears as ST elevation in the ECG (Note:
the currents are flowing away from the electrodes opposite to the
infarcted area. This appears as ST depression in other ECG leads).
Fig 6.24
- Some days later, the dead muscle becomes electrically silent (after
development of scar tissue). Here the infarcted area becomes more
negative relative to the normal area (extracellularly). This results in
disappearance of the ST elevation and appearance of abnormal Q
waves).
Fig 6.25

- The ECG does not only diagnose MI but also localizes its site
(according to which lead develops ECG changes). For example:
 ST elevation in II, III and aVF indicates inferior MI
 ST elevation in V1, V2, V3 and V4 indicates anteroseptal MI
 ST elevation in V4, V5, V6, I and aVL indicates anterolateral MI
 Tall R wave and ST depression in V1 and V2 indicates
posterior MI
Remember that:
 Acute MI is a life threatening problem. It may cause immediate
death due to:
- Arrhythmia (e.g. ventricular fibrillation)
- Severe heart failure
- Rupture of the infarcted area.
 The risk of these complications is highest during the first week
following the infarction. That’s why these patients should be
treated appropriately (e.g. by thrombolytic therapy) in special
wards (Coronary Care Units “CCU”) for close follow up and
monitoring during the acute phase.

ECG changes during electrolyte disturbances
 Hyperkalemia
o Tall, slender peaked T wave
o Absent P wave
o Wide, slurred QRS
Fig 6.26
 Hypokalemia
o ST segment depression
o Appearance of U wave
o Prolonged PR interval
o T wave inversion.
Fig 6.27

 Hypercalcemia:
o Short QT interval
 Hypocalcemia:
o Long QT interval
Fig 6.28
Important notes
 Hyponatremia causes low voltage ECG.
 Hyperkalemia decreases the resting membrane potential (RMP)
towards the threshold, making the cells more excitable (causing
arrhythmias) and eventually the RMP reaches the threshold,
making the cells non excitable. Here the heart stops in diastole.
 Hypercalcemia increases contractility in the heart because ECF
calcium enters the cells to cause contraction.
 Severe hypercalcemia stops the heart in systole. For this reason
IV injection of calcium in patients with hypocalcemia should be
slow to avoid injection of large amount of calcium.

THE CARDIAC CYCLE
Duration
• The normal heart rate is about 75 beat/min (i.e. 75 beats in 60

seconds); therefore, each beat takes 60/75 = 0.8 second.
• Each beat is regarded as one cardiac cycle that involves phases of

contraction & relaxation for both atria and ventricles.
• Therefore, each cardiac cycle (0.8s) can be studied in 3 phases:

o Atrial systole (takes 0.1 s)
o Ventricular systole (takes 0.3 s)
o Atrial diastole (takes 0.7 s) & ventricular diastole (takes 0.5 s)
Atrial Systole
• During the phase of atrial systole, the ventricles are in state of

diastole. Therefore, atrial contraction ejects blood to fill the
ventricles through the atrio-ventricular (AV) valves.
• Ventricular filling occurs by two ways: Passive filling (blood flows

passively from atria to ventricles) & active filling (BY atrial systole).
• About 70% of ventricular filling occurs passively. Then atrial

systole completes ventricular filling (provides the 30%).
• Atrial contraction increases atrial pressure and causes reflux of

blood through the superior vena cava, causing a characteristic “a”
wave (“a” for atrial systole) in both atrial pressure curve and
internal jugular venous pressure “JVP” curve (see figure 6.29).
Ventricular Systole
• Occurs immediately after atrial systole because of the delay in the

AV node (i.e. ventricles contract while atria relax).

• When the ventricles start to contract, the pressures inside them
start to rise, then contraction continues until ventricular pressure
exceeds atrial pressure, here the AV valves close to prevent reflux
of blood back to the atria.
• Closure of the AV valves results in the first heart sound “S1” (the
sound is caused by turbulence of blood due to closure of valves).
• Then the ventricles continue to contract & their pressures continue

to rise, while all valves are closed. This is the isovolumetric
contraction phase. It occurs immediately after S1.
• When pressure in the left ventricle reaches 80 mmHg and in the

right ventricle reaches 10 mmHg, the semilunar valves open &
blood starts to be ejected into the aorta and pulmonary artery
(remember that inspite of the difference in pressure, the two valves
open almost in the same time).
• The ventricles continue to contract & the pressures continue to rise

to maintain ejection which starts rapidly at first (rapid ejection
phase) and then slows down (slow ejection phase).
• The maximum pressure reached in the left ventricle is 120 mmHg

& in the right ventricle = 25 mmHg (= systolic pressure).
• About 70 ml of blood is ejected from each ventricle. It is known as

stroke volume “SV” and it is defined as volume of blood ejected
from each ventricle per beat.
• About 50 ml of blood remains in each ventricle at the end of

systole. It is known as end systolic volume “ESV”.
• About 120 ml of blood is found in each ventricle before ejection.

• This 120 ml is known as the end diastolic volume “EDV”. It is
defined as volume of blood that remains in each ventricle at the
end of diastole.
• Remember that: contraction of ventricles pushes cusps of the AV

valves backwards towards the atria. This causes a characteristic
wave in atrial pressure curve & JVP curve known as “C” wave (“C”
for cusp shooting). Look at the following figure.
Fig 6.29: The cardiac cycle
Atrial & Ventricular Diastole

Atrial diastole
• Precedes ventricular diastole and continues throughout most of

the cycle (because it takes 0.7 s and the whole cycle is 0.8 s).
• During this phase blood enters the atria (venous return).

• Accumulation of blood in atria raises atrial & jugular venous
pressures and produces “V” wave in atrial pressure curve and JVP
curve (“V” for venous return).
Ventricular diastole:
• Ventricular diastole starts during atrial diastole and filling of atria

with blood.
• When the ventricles start to relax, the pressures inside them start
to drop. When the ventricular pressures become lower than the
pressures in aortic & pulmonary arteries, the semilunar valves are
closed to prevent return of blood back to the ventricles.
• Closure of the semilunar valves results in the second heart sound

“S2” (the sound is caused by turbulence of blood due to closure of
the valves).
• Then the ventricles continue to relax & the pressures inside them
continue to drop, while all valves are closed. This is the
isovolumetric relaxation phase. It occurs immediately after S2.
• When the pressures inside the ventricles become lower than the
pressures in atria, the AV valves open. This allows passive filling
of ventricles with blood that already filled atria during this period.
• Then the atria contract to complete ventricular filling and to start a

new cycle.

THE HEART SOUNDS
- Heart sounds are 4 sounds that result from turbulence of blood flow
within the heart during closure of the valves or rapid filling of the
ventricles.
- The first two sounds are normal sounds, the third is normal in
children and young adults and abnormal in older ages (indicates
heart failure). The fourth sound is always abnormal (hypertension).
The first heart sound (S1)
- Caused by closure of the AV valves.
- Occurs at the beginning of ventricular systole (i.e. at start of the
isovolumetric contraction phase).
- It is low pitched and more prolonged than S2.
The second heart sound (S2)
- Caused by closure of the semilunar valves
- Occurs at the start of ventricular diastole (i.e. at the start of the
isovolumetric relaxation phase).
- It is high pitched and takes less time than S1.
- It may split into two components (aortic S2 and pulmonary S2).
- In normal states, closure of aortic valve precedes closure of the
pulmonary valve (i.e. aortic S2 precedes pulmonary S2).
- Wide splitting of S2 occurs during deep inspiration, when closure of
the pulmonary valve is delayed because the stroke volume is
increased by the extra volume of blood delivered to the heart during
deep inspiration (inspiration causes chest expansion, this decreases
intra-thoracic pressure and increases venous return and therefore
stroke volume).
- Splitting of S2 decreases in expiration and pulmonary hypertension.

The third heart sound (S3)
- Caused by rapid ventricular filling (turbulence of blood during
passive filling of ventricles).
- It is normal in children and young adults (filling causes turbulence
because the size of ventricles is small).
- It indicates heart failure in adults because blood volume of passive
filling is added to high end systolic volume in patients with heart
failure (the end systolic volume is high in heart failure because of the
weak ventricular contractions).
- On auscultation, presence of S3 plus S1 & S2 gives a characteristic
sound described as “Galloping rhythm”.
- Galloping rhythm is an important sign of heart failure in adults.
The fourth heart sound (S4)
- S4 is an abnormal sound; it is also known as atrial sound.
- It is caused by atrial systole in patients suffering from hypertension.
- In normal states, atrial systole does not cause a sound because
ventricles expand to receive blood ejected by atrial systole; however,
in a hypertensive patient, ventricular wall becomes stiff due to
hypertrophy (because they act against resistance). That’s why atrial
systole results in turbulence of blood and generation of S4.
Abnormal sounds
- Abnormal musical sounds heard over the heart are known as
murmurs. They are generated by turbulence of blood flow within the
heart due to valvular lesions.
- Abnormal sound heard over arteries is known as bruit (e.g. renal
bruit due to renal artery stenosis (narrowing).
- Abnormal sound heard over veins is known as venous hum.

- Murmurs are either systolic or diastolic.
- Systolic murmurs are caused by:
 Stenosis (narrowing) of semilunar valves
 Regurgitation (reflux or dilatation) of atrio-ventricular valves
- Diastolic murmurs are caused by:
 Stenosis (narrowing) of atrio-ventricular valves
 Regurgitation (reflux or dilatation) of semilunar valves
- For example mitral (or tricuspid) stenosis causes mid diastolic
murmur and aortic (or pulmonary) regurgitation causes early diastolic
murmur whereas mitral (or tricuspid) regurgitation causes pan-
systolic murmur and aortic (or pulmonary) stenosis causes ejection
systolic murmur.
Pressure volume curves of the ventricles
- This curve summarizes various events in the cardiac cycle. The Y
axis represents pressure whereas X axis represents volume. The
following figure describes the curve of the left ventricle.
Fig 6.30: The pressure volume curve of the left ventricle

- In the above curve:
 A represents: passive ventricular filling
 B represents: atrial systole
 C represents: isovolumetric contraction
 D represents: rapid ejection phase
 E represents: isovolumetric relaxation
 Op1 represents: opening of AV valves
 Op2 represents: opening of semilunar valves
 S1-4 represents: sites of heart sounds
 50 ml = End systolic volume
 120 ml = End diastolic volume
THE CARDIAC OUTPUT

Definition
- Volume of blood ejected by each ventricle each minute (not both
ventricles). It is about 5 L/min in an average adult male, at rest (less
in females and more during exercise).
- The cardiac index (CI) is sometimes calculated to compare between
subjects. It equals (COP/surface area) e.g. CI in adults = 5 /1.6 = 3.1
L/m2. CI in children is higher because surface area is smaller.
Measurement
- Many methods can be used for measurement of the cardiac output.
- These include:
 Indirect methods (like indicator dilution technique, Fick
principle and thermodilution method)
 Direct methods (using electromagnetic or ultrasonic flow-
meter devices).

Indicator dilution technique or Hamilton dye method
- In this method, Q amount of a dye is injected in an arm vein; then
serial arterial samples are obtained from a peripheral artery to
measure the concentration of the dye as it is ejected from the heart
to the systemic arteries.
- The concentrations are plotted in a graph paper against time.
- The resulting curve shows that the concentrations increase to a
maximum, and then they start to decrease and then increase again
because of recirculation of the dye (look at figure 6.31).
- The descending limb at point (x) is extrapolated to the X axis to
obtain the time of one circulation (t). The area under the curve is
used to calculate the average concentration (C).
- Then the COP can be obtained in (L/min) as follows:
COP = (Q x 60) / (C x t)
Fig 6.31: Hamilton dye dilution method

Fick principle
- Fick principle is commonly used for measurement of blood flow to
organs (e.g. renal blood flow, cerebral blood flow, liver blood flow …).
- It states that “the amount of a substance consumed (or added) by
an organ in a given time equals the arterial-venous difference in
concentration times the blood flow to the organ.
- In summary: Q = [A] - [V] x Blood flow to the organ (where Q= the
quantity of a substance consumed by the organ, [A] and [V] are the
concentrations of the substance in the artery supplying and the vein
draining the organ respectively and [A] - [V] is the arterial-venous
difference in concentration.
- From the above principle the blood flow can be calculated as
follows: Blood flow = Q / [A] – [V]
- If the lungs are taken as an organ, their blood flow = the cardiac
output from the right ventricle = the cardiac output (revise definition of
COP). Therefore COP = Q / [A] – [V]
- The substance consumed (actually added) by the lungs is oxygen.
- Oxygen added by the lungs = 250 ml oxygen/min, measured by
spirometer.
- Oxygen concentration in the pulmonary artery (carrying
deoxygenated blood) = 150 ml oxygen/L blood (measured using a
catheter introduced into the pulmonary artery).
- Oxygen concentration in the pulmonary vein (carrying oxygenated
blood) = 200 ml oxygen/L blood (measured from any peripheral
artery because all arteries have the same concentration of oxygen).
- Remember that oxygen concentration in the deoxygenated blood of
the pulmonary artery is not taken from peripheral veins.

- By applying the above values to the formula:
COP = Q / [A] – [V]
COP = 250 ml oxygen/min / [50 ml oxygen/L]
(Where 50 is the arterial-venous difference between 150 and 200 ml
oxygen/L); therefore the COP = 5 L/min.
Thermo-dilution technique
- This is similar to the dilution method.
- A cold saline is injected as an indicator in the right atrium and the
change in blood temperature within the pulmonary artery is used for
calculation of the COP.
Direct methods
- Used mainly in experimental animals.
- Here surgery is needed to enter the heart through great arteries or
veins and measure the cardiac output directly using a flow-meter
device (electromagnetic or ultrasonic flow-meter device).
Control of the COP

- The COP = heart rate x stroke volume.
- 5 L/min = 72 beat/min x 70 ml/beat.
- Therefore, the two factors that control the COP are the heart rate &
stroke volume.
Control of the heart rate (HR)
- The heart rate is the number of cardiac beats per minute.
- It ranges between 60 & 100 beats per min; the average is about 72
beat/min at rest; however, normal heart rate differs according to age
(in neonates>infants>children>adults).

- In normal adults, a value less than 60 beat/min is described as
bradycardia whereas a value more than 100 beat/min is described as
tachycardia.
- The term positive chronotropic effect is used to describe increase in
heart rate whereas negative chronotropic effect describes the
reverse.
- Remember that: when the heart rate is increased, the time for
ventricular filling is decreased and therefore the stroke volume is
decreased, this occurs if contractility of the heart is not affected;
however, when contractility is also increased, the stroke volume is
increased (i.e. factors that increase the heart rate & contractility:
increase the stroke volume; whereas factors that increase the heart
rate alone: decrease the stroke volume).
 Factors affecting the HR are:
Neural factors
o Sympathetic neurons
- Release noradrenaline to act on beta 1 receptors
- Activated by stress (fear, pain, emotions …)
- Increase heart rate (positive chronotropic effect)
o Chemoreceptors
- Chemical receptors found in aortic bodies (in aortic arch) & carotid
bodies (in carotid bifurcation).
- Stimulated by hypoxia, hypercapnia and acidosis
- Increase heart rate (positive chronotropic effect)
o Bainbridge effect or reflex
- Increase in heart rate (positive chronotropic effect) due to
increase in venous return that initiates a reflex or effect as follows:

- The reflex is initiated in receptors in the right atrium and integrated
in the medulla. It results in stimulation of the SA node to increase
its rate of discharge (Bainbridge reflex)
- The effect is a direct mechanical effect of the blood on the SA
node to increase its rate of discharge (Bainbridge effect)
o Parasympathetic neurons
- Release acetylcholine to act on muscarinic receptors.
- Activated by rest and sleep
- Decrease heart rate (negative chronotropic effect)
o Baroreceptor reflexes
- Stretch receptors found in aortic sinus (in aortic arch) & carotid
sinus (in carotid bifurcation).
- Stimulated by elevation in blood pressure.
- Decrease heart rate (negative chronotropic effect).
Hormonal factors:
- Many hormones have positive chronotropic effect.
- Examples include catecholamines & thyroid hormones.
- Thyroid hormones act indirectly by increasing number and affinity
of beta1 receptors in the heart to catecholamines.
Physiological factors
- HR is increased by exercise (which is associated with sympathetic
stimulation due to physical stress or excitement “emotions”).
- It low during sleep (which is associated with parasympathetic
stimulation).
Physical factors
- Changes in body temperature (due to hot or cold environment or
due to fever or hypothermia) affect heart rate.

- Elevation in body temperature by one degree centigrade
increases heart rate by about 15 beat/min whereas reduction in
body temperature does the reverse.
Drugs
o Atropine (muscarinic blocker):
- Blocks the parasympathetic; that’s why it increases the heart rate.
- It is used in cases of cardiac asystole.
o Atenolol & propranolol (beta blockers):
- Both drugs decrease HR by blocking beta 1 receptors in SA node.
- Atenolol is selective beta blocker (blocks beta1) whereas
propranolol is non-selective beta blocker (blocks both beta 1&2).
- Salbutamol is a commonly used drug for treatment of asthma. It
is a beta 2 agonist. Therefore, it should not increase the heart rate;
however, the drug has some effect on beta1 receptors, that’s why it
increases the heart rate as a side effect.
o Digitalis (anti arrhythmic drug that slows conduction):
- Decreases the heart rate because it slows the conductive system.
- It increases entry of calcium in cardiac muscle (through a
mechanism that involves inhibition of the Na+-K+ pump). That’s why it
increases contractility of the heart.
Control of the stroke volume (SV)

- Defined as the volume of blood ejected by each ventricle each beat.
- Normal value is about 70 ml (in an average adult male, at rest);
however, it differs according to age, sex and physiological state.
- It is smaller in neonates < infants < older children < adults due to
gradual increase in the size of the heart with normal development.

- The stroke volume is larger in males compared to equivalent female
of the same age and body size because the heart is adapted to eject
more blood to more active tissues in males (muscles) compared to
more inactive tissues in females (fats).
- During stress (emotions, pain, hypoglycemia & exercise), the
sympathetic nervous system is activated resulting in increased
contractility of the heart, this increases stroke volume. At rest, the
stroke volume returns to its normal value “70 ml”.
- The term positive inotropic effect is used to describe increase in
contractility of the heart whereas negative inotropic effect describes
the reverse.
- When contractility of the heart is increased, subjects become aware
of the heart beating, this is described as “palpitation”.
- Remember that: when contractility of the heart is increased, the
stroke volume is increased whereas the end systolic volume is
decreased.
Factors affecting SV are:
Neural factors
o Sympathetic neurons
- Increase the stroke volume (positive inotropic effect).
o Chemoreceptors
- Increase the stroke volume (positive inotropic effect).
o Parasympathetic neurons
- Do not supply ventricles of the heart. Therefore they have no
direct effect on contractility of the heart or stroke volume.
o Baroreceptor reflexes
- Decrease the stroke volume (negative inotropic effect).

Hormonal factors:
- Many hormones have positive inotropic effect.
- Examples include catecholamines & thyroid hormones.
- Thyroid hormones act indirectly by increasing number and affinity
of beta1 receptors in the ventricles to catecholamines.
Physiological factors
- SV is increased by exercise (positive inotropic effect).
Physical factors
- Changes in body temperature (due to hot or cold environment or
due to fever or hypothermia) have direct effect on contractility.
- High temperature increases the stroke volume (positive inotropic
effect); whereas low temperature does the reverse.
Drugs
o Atropine (muscarinic blocker):
- Blocks the parasympathetic; that’s why it has no direct effect on
contractility and stroke volume.
o Atenolol & propranolol (beta blockers):
- Both drugs decrease SV by blocking beta 1 receptors in
ventricles. They are commonly prescribed for patients with IHD
because they decrease cardiac contractility and therefore decrease
the need for oxygen by cardiac muscle.
o Digitalis (anti arrhythmic drug that slows conduction):
- Increases entry of calcium in cardiac muscle (it inhibits the Na/K
ATPase pump resulting in accumulation of sodium in cells. This
inactivates a sodium-calcium antiport pump which takes calcium to
outside in exchange to sodium. Calcium increases contractility and
therefore SV.

- Digitalis also decreases heart rate and gives ventricles extra time
for filling. This increases the end diastolic volume and therefore the
SV is increased (by Frank-Starling law described below).
Calcium ions
- SV is increased by calcium ions (positive inotropic effect)
-Severe hypercalcemia is fatal. It stops the heart in systole.
Preload & after load
Preload
- It is the load on a ventricle before contraction (or the degree of
stretch before contraction).
- It is equivalent to the end diastolic volume (EDV), which depends
on venous return. Therefore, when the preload is increased, the SV
is increased (direct relationship). The increase in SV occurs
according to the Frank-starling Law (see below).
After load
- It is the resistance in arteries against ejection.
- When increased, the stroke volume is decreased (inverse
relationship).
- After load is increased by: aortic stenosis, pulmonary stenosis,
systemic hypertension, pulmonary hypertension or vasoconstriction.
Frank-Starling Law
- Described first by Frank and confirmed experimentally later by
Starling. It states that: “Within certain limits, the energy of contraction
is directly proportional to the initial length of muscle fibers”.
- The length of cardiac muscle fibers depends on the EDV, which
also depends on venous return. Therefore, higher venous return
increases EDV, this increases contractility & so increases the SV.

THE VENOUS RETURN
- It is the blood that returns back to the heart through veins.
- It equals the cardiac output (= 5 L/min in a resting adult male.
- It is affected by the following factors:
Pressure gradient
- Pressure in arteries is higher than vein, higher than right atrium.
- Therefore, blood passes down the pressure gradient from arteries
to veins to right atrium in the heart.
Respiratory pump
- Inspiration increases venous return (inspiration increases chest
volume and therefore decreases intra-thoracic pressure; that’s why
venous return is increased). Expiration decreases venous return
especially expiration against closed glottis (valsalva maneuvre) which
is done during defecation, labor or lifting heavy weights.
Muscle pump
- Contraction of the lower limb muscles squeezes blood in the veins
upwards towards the heart (the venous blood does not pass down
during muscle contraction because of the one way valves in veins.
Gravity
- Standing decreases venous return due to gravity whereas lying
down increases venous return.
Blood volume
- Bleeding decreases venous return by decreasing the total blood
volume whereas fluid overload increases venous return.
Venodilation & venoconstriction
- Venodilation decreases venous return because it increases
diameters of these capacitance vessels to store blood.

- Venoconstriction increases venous return (by adding some of the
stored blood to the circulation). This is very important in shock.
State of heart valves
- Stenosis or regurgitation of any of the heart valves decreases the
venous return and results in heart failure.
Pericardial pressure
- Pericardial effusion increases pressure within the pericardial sac
and therefore decreases venous return.
- It is caused by inflammation (pericarditis) due to viral or bacterial
infection or due to hypothyroidism or connective tissue diseases.
CONTROL OF ARTERIAL BLOOD PRESSURE

Definitions
Blood pressure
- The pressure of blood on walls of blood vessels.
- Remember that: hydrostatic pressure is the pressure of water (i.e.
plasma) on walls of blood vessels.
Systolic pressure
- The maximum pressure in a vessel during systole of the heart.
- Normal value is less than 120 mmHg in adults. Values of 120
mmHg or more and less than 140 have been regarded as normal;
however, according to recent studies, these values indicate pre-
hypertension state. Systolic blood pressure of 140 mmHg or more is
hypertension.
Diastolic pressure
- The minimum pressure in a vessel during diastole of the heart.

- Normal value is less than 80 mmHg in adults. Values of 80 mmHg
or more and less than 90 have been regarded as normal; however,
according to recent studies, these values indicate pre-hypertension
state. Diastolic blood pressure of 90 mmHg or more is hypertension.
Pulse pressure
- The difference between the systolic and the diastolic pressures.
- Normal pulse pressure is less than 60 mmHg.
- When the systolic pressure is increased and the diastolic is
decreased, the pulse pressure becomes “wide”.
- Causes of wide pulse pressure include:
o Hyperthyroidism
o Aortic regurgitation
o High body temperature
o Hard exercise
o Severe anemia
o Pregnancy
o Arterio-venous fistula
Mean arterial pressure
- The mean pressure during the cardiac cycle.
- It is calculated as follows:
The mean arterial pressure= The diastolic + 1/3 pulse pressure
- Its value is more near to the diastolic than the systolic because the
diastolic phase takes longer time than the systolic in the cardiac
cycle).
- Example: If a blood pressure of a subject = 120/80
o The systolic = 120 mmHg
o The diastolic = 80 mmHg

o The pulse pressure = 120 – 80 = 40 mmHg
o The mean arterial pressure = 80 + (1/3 x 40) = 93 mmHg
Control of the arterial blood pressure

- Blood pressure = Cardiac output  Peripheral resistance.
- Therefore the blood pressure is controlled by controlling the cardiac
output and the peripheral resistance.
- The cardiac output is controlled by controlling both the heart rate
and the stroke volume (see above). It determines the systolic
pressure (i.e. the increase in COP increases systolic pressure).
- The peripheral resistance is determined by blood viscosity, length of
arteries and radius of arteries as follows:
PR = 8VL/ r4
- Where V is the blood viscosity, L is the length of arteries and r is the
radius of blood vessels.
- The peripheral resistance determines the diastolic blood pressure.
Viscosity of the blood
- Depends on:
o The packed cell volume (PCV)
o Plasma proteins especially globulins and fibrinogen (because
of the large size of their particles)
o Body temperature (this is quite constant in the normal
physiological conditions)
Length of blood vessels
- Constant in adults.
Radius of blood vessels
- The most important factor in determining the peripheral resistance.

- Inversely proportional with the peripheral resistance. For example:
vasoconstriction decreases radius of arteries & increases the
peripheral resistance and therefore increases the blood pressure
whereas vasodilatation increases the radius & decreases the
peripheral resistance and therefore decreases the blood pressure.
Remember that:
 Blood pressure in children is less than that in adults.
 The systolic is less because the COP in children is less (child’s
heart is small= stroke volume is smaller= COP is lower; in spite of
the faster heart rate).
 The diastolic is less because the length of arteries is less;
therefore, peripheral resistance is less (in spite of other factors).
The mechanisms that control the blood pressure

 Very rapid mechanism (act in seconds)
• Baroreceptors
• Chemoreceptors
• CNS ischemic response
 Less rapid mechanisms (act in minutes to hours)
• Hormonal vasoconstriction by
o Renin- Angiotensin system
o Antidiuretic hormone (ADH)
o Catecholamines
• Stress relaxation and inverse stress relaxation
• Capillary fluid shift
 Long term mechanisms (act in days)
• Renin-Angiotensin-Aldosterone system

• ADH
• Atrial natriuretic peptide (ANP)
• Thirst mechanism
•Other hormones that may affect the blood pressure
 Local regulation of blood pressure
VERY RAPID MECHANISMS

Baroreceptors
- Stretch receptors found in high pressure areas of the circulation
(aortic sinus in aortic arch and carotid sinus in carotid bifurcation).
- They are stimulated by stretch caused by high blood pressure.
- They send impulses through the vagus & glossopharyngeal nerves
to the medulla oblongata.
- The impulses reach the nucleus of tractus solitarius (NTS) and from
there inhibitory impulses pass to the vaso-motor center (VMC) &
cardiac center (CC) in the medulla causing reduction in sympathetic
discharge from these centers to the heart and blood vessels.
- Excitatory impulses pass to the cardio-inhibitory center in the
medulla causing increased parasympathetic discharge from this
center to the heart.
- The decreased sympathetic & increased parasympathetic result in:
o Reduction in heart rate & stroke volume (i.e. lower COP and
therefore lower systolic blood pressure)
o Vasodilatation (i.e. decreased peripheral resistance and therefore
lower diastolic blood pressure)
- Consequently the B.P is reduced back to normal within a second.
- The opposite occurs when there is reduction in B.P: hypotension=
less stretch= less stimulation of baroreceptors= less inhibitory
discharge to the medulla= more sympathetic and less
parasympathetic= increased HR & SV= higher COP= Increased
blood pressure back to normal within a second (systolic & diastolic).
Important notes:
 When the blood pressure is normal, the baroreceptors send tonic
discharge through the buffer nerves (9 and 10) causing
continuous reduction in activity of the VMC and the CC.
 Denervation of the baroreceptors (cutting the buffer nerves)
causes elevation in blood pressure.
 Baroreceptors adapt to new pressures (this is known as
resetting). For example when the BP is chronically elevated, the
baroreceptors increase the rate of their tonic discharge to correct
the pressure; however, if the BP remains elevated, the rate of
discharge will decrease gradually over time until it reaches the
earlier rate. The resetting phenomenon is reversible.
- There are other types of baroreceptors found at the venous side
(low pressure areas). These include:
o Type A atrial baroreceptors: discharge during systole
o Type B atrial baroreceptors: discharge during diastole
- Stimulation of these venous barorecptors results in reflex
vasodilatation like the arterial baroreceptors; however, the heart rate
increases.

Chemoreceptors
- The peripheral chemoreceptors are found in the carotid body in
carotid bifurcation and aortic body in aortic arch.
- They are stimulated by hypoxia (low O2 in tissues), hypercapnia
(high CO2) and acidosis (high H+). These stimuli are associated with
hypotension because of the low tissue perfusion.
- They send excitatory impulses through the vagus and
glossopharyngeal nerves to the respiratory center to increase
respiration.
- The impulses also stimulate the vasomotor and the cardiac centers
(due to radiation of impulses in the medulla).
- This increases the blood pressure by increasing sympathetic
discharge from these centers to the heart and blood vessels causing
increased heart rate, higher stroke volume and vasoconstriction.
CNS ischemic response
- Reduction of the blood supply to the brain (ischemia), is caused by
hypotension. This results in accumulation of CO2.
- The vasomotor center is very sensitive to CO2. It is stimulated to
release its sympathetic discharge to the blood vessels. This
increases the blood pressure and therefore improves the blood
supply to the brain.
- A high intracranial pressure (e.g. caused by a brain tumor) impairs
cerebral circulation and results in brain ischemia. This induces similar
CNS ischemic response resulting in elevation of the blood pressure
to high levels (hypertension).
- The high blood pressure stimulates the baroreceptors to inhibit the
heart through the cardiac center and the cardioinhibitory center, but

they can not inhibit the vasomotor center which is stimulated by the
CO2; this results in bradycardia.
- This sign (hypertension with bradycardia) is an important sign of
raised intracranial pressure (known as Cushing's sign).
LESS RAPID MECHANISMS
Hormonal vasoconstriction
ADH
- Release of this nona-peptide hormone from the posterior pituitary
gland is stimulated, among other stimuli, by hypotension.
- It acts on V1 receptors in the blood vessels causing
vasoconstriction. This elevates the blood pressure.
- It also elevates the B.P. by acing on V2 receptors in the kidney;
however, this action is grouped with the long term mechanisms.
Catecholamines
- Adrenaline and noradrenaline are released in response to
hypotension (which is a form of stress).
- They act on  receptors in blood vessels causing vasoconstriction.
This elevates the blood pressure.
- Remember that: noradrenaline acts on alpha receptors better than
beta whereas adrenaline acts on beta receptors better than alpha.
- That’s why noradrenaline increases the diastolic (by increasing the
peripheral resistance) whereas adrenaline increases the systolic (by
increasing the cardiac output).
Renin-Angiotensin II
- Renin enzyme is released by the Juxtaglomerular cells in the
kidney. It is stimulated by renal ischemia, hyponatremia &
sympathetic stimulation (all these are associated with hypotension).

- It acts on angiotensinogen (plasma protein from the liver)
converting it to angiotensin I.
- Angiotensin I is converted to angiotensin II by angiotensin
converting enzyme (ACE) which is poduced by endothelial cells
(especially of pulmonary capillaries).
- Angiotensin II causes vasoconstriction.
- It also activates the sympathetic to release renin, then renin
converts angiotensinogen to angiotensin I and the cycle repeats itself
(positive feedback mechanism).
- Other actions of angiotensin II are long term effects (see below).
Stress relaxation and inverse stress relaxation
- The stress on walls of blood vessels, caused by high blood
pressure, leads to relaxation of smooth muscles in the walls and
reduction in the blood pressure in minutes (stress relaxation).
- Conversely, reduction in the blood pressure leads to less stress on
the walls of blood vessels and therefore constriction of the blood
vessels leading to elevation in the blood pressure (inverse stress
relaxation).
Capillary fluid shift
- Occurs due to hypotension because there is reduction in the
hydrostatic pressure (which is responsible for filtration).
- It becomes lower than the oncotic pressure in capillaries (which is
responsible for absorption).
- This shifts fluid from the interstitium to the intravascular space. The
blood volume is increased and therefore the blood pressure is slightly
increased.

LONG TERM MECHANISMS
Renin-Angiotensin Aldosterone system
- As mentioned above, angiotensin II rapidly elevates the blood
pressure by causing vasoconstriction.
- In addition it has other long term effects. These include stimulation
of aldosterone, stimulation of ADH and stimulation of the thirst
center.
- There are many stimuli of aldosterone. However its stimulation by
angiotensin II completes activation of the renin angiotensin
aldosterone system.
- Aldosterone Acts on the distal convoluted tubules and collecting
ducts in kidney causing reabsorption of sodium and secretion of
potassium. Water follows sodium to the intravascular space.
- This increases blood volume & therefore the blood pressure.
ADH
- As mentioned above, in addition to vasoconstriction, ADH has
another long term effect to elevate the blood pressure. It acts on V2
receptors in the collecting ducts of the kidney causing reabsorption of
water to the intravascular space.
- This increases blood volume & therefore the blood pressure.
Thirst
- Controlled by a thirst center in the hypothalamus.
- It is stimulated by hypotension and other stimuli (hypovolemia,
hyperosmolarity & angiotensin II). The subject drinks water in
response to thirst.
- This increases the blood volume & therefore the blood pressure.

Atrial natriuretic peptide (ANP)
- Atrial natriuretic peptide is a hormone released by atria in response
to stretch by hypervolemia (hypervolemia is associated with higher
blood pressure).
- ANP acts in the kidney to decrease sodium reabsorption in the
proximal convoluted tubules and antagonizes aldosterone in the
distal convoluted tubules and collecting ducts of the kidney. Sodium
is lost in urine followed by water.
- This decreases the blood volume & therefore the blood pressure.
Other hormones that may affect the blood pressure:
o Kinins: (vasodilators- decreases the B.P.)
o Adrenomedullin & pro-adrenomedullin (vasodilators- decrease it)
o VIP (vasodilator- decreases the B.P.)
o Urotensin II (vasoconstrictor- increases the B.P.)
LOCAL REGULATION
- Aim of Local regulation of blood pressure:
o To maintain adequate perfusion and therefore adequate supply
of O2 and nutrients to the tissues.
o To adjust the perfusion to tissues according to their needs;
which vary from time to time according to variation in activities.
- Local regulation occurs by the following:
1- Autoregulation:
- It is the intrinsic capacity of tissues to regulate their own blood flow.
- Found in many tissues like skeletal muscles, cardiac muscle, brain,
liver,...

- Can be explained by:
 The myogenic theory of autoregulation
- High perfusion pressure results in local vasoconstriction (in organs)
to prevent their rupture (according to Law of Laplace, see below) and
to adjust blood flow to organs. This mechanism is not expected to
occur in response to very low or very high perfusion pressures.
 Metabolic theory of autoregulation
- Active tissues produce metabolites that can cause vasodilatation.
When the blood flow decreases, they accumulate and when the
blood flow increases, they are washed away.
- Metabolites that can cause vasodilatation include: CO2, H+ and K+,
ATP, ADP, adenosine, pyruvate, lactate …
- Localized vasoconstriction can be caused by serotonin and cold.
2- Substances secreted by the endothelium:
• Prostacyclin:
- Cause vasodilatation & inhibits platelet aggregation
- Prostacyclin is balanced by throboxane A2 (TXA2) which is
released from platelets (TXA2 causes vasoconstriction and
stimulates platelet aggregation). The balance is shifted towards
prostacyclin by low dose aspirin; that’s why low dose of aspirin is
commonly prescribed to patients at risk of thrombosis (e.g. diabetic
and hypertensive patients).
• Nitric oxide (NO):

- It is the endothelial derived relaxation factor (EDRF).
- It is synthesized from arginine by the enzyme “NO synthase”
- It is an important vasodilator in many organs (e.g. causes erection
in males); however, it has many other functions in other organs.

• Endothelins
- Polypeptides (21 aa)
- They are potent vasoconstrictors
- They have many other functions.
IMPORTANT NOTES ABOUT BLOOD VESSELS

Arteries and arterioles
- The walls of large arteries contain high amount of elastic fibers
whereas the walls of the arterioles contain less amount of elastic
fibers, but more smooth muscle.
- The arterioles are the major site of resistance to blood flow
(resistance vessels).
Capillaries
- These are the major site of fluid exchange between plasma and
interstitium (exchange vessels).
- The junctions between endothelial cells in capillaries may be very
tight (e.g. in brain capillaries and to a lesser extent in muscles); or
fenestrated (e.g. in liver sinusoids and to a lesser extent in
glomerular capillaries).
- Blood capillaries have the highest surface area (surface area
exceeds 6300 m2 in adults) and the lowest velocity of blood flow.
- In spite of the thin wall of capillaries, they do not rupture because of
their small diameter. Similarly, arterioles constrict to resist rupture
when the perfusion pressure is high (explained by “Law of Laplace”).

- The law states that: the tension (T) in the wall of a cylinder is equal
to the product of the transmural pressure (P) and the radius (r),
divided by the wall thickness (w).
Fig 6.32
- As mentioned above: T = Pr/w

- The transmural pressure (P) = pressure inside the cylinder –
pressure in tissue which is negligible. Therefore (P) = the pressure
inside the cylinder (= the distending pressure)
- The wall thickness of capillaries (w) is negligible
- Therefore the equation becomes: T = Pr
P = T/r (in blood vessels)
or P = 2T/r (in spheres)
- From the above law, the smaller the radius of a blood vessel, the
lower the tension that’s needed to balance the distending pressure;
that’s why vessels with smaller radius resist rupture.
- On the other hand, the pressure needed to inflate a sphere should
be higher than the pressure inside (i.e. higher than P). Since P is
inversely related to the radius, the smaller the radius, the higher the
distending pressure needed for inflation.

Venules and veins
- Their walls are relatively thin and easily distended. Therefore they
can accommodate large volume of blood (capacitance vessels); for
example they accommodate 50% of circulating blood at rest.
- Venoconstriction occurring during hypotension (e.g. shock) adds
large amount of this stored blood into the circulation.
- The inner layer (intima) of the limb veins is folded into valves.
These are absent from the veins in the abdomen, chest, head and
neck.
Lymphatics
- The excess interstitial fluid is collected by diffusion into lymphatic
capillaries.
- These start in the interstitium of the whole body, joined
progressively together and traverse lympn nodes to drain eventually
in the right and left subclavian veins, at the neck.
- Once within the lymphatics, the fluid is called lymph. The lymph is
similar to interstitial fluid; however, it circulates lymphocytes and
transports lipids (chylomicrons) absorbed in the small intestine. It
also carries small amount of protein filtered from capillaries.
- Lymphatic vessels contain valves, and there are no visible
fenestrations in their walls.
The pulse wave
- Is a pressure wave that travels along the blood vessels and
expands them on its way. The expansion is palpable as pulse.
- In the arteries it is known as the arterial pulse. The pulse wave
moves faster than the blood flow, especially with increased age (i.e.
when the arteries lose their elastic fibers and become rigid).

The blood flow
- The blood flow through a blood vessel = pressure/ resistance.
- It is calculated directly by the Fick principle using special
substances consumed by the organs to which the blood flow is being
measured (revise measurement of the cardiac output). Examples
include: or example:
o N2O for cerebral blood flow (N2O = nitrous oxide)
o PAH for renal blood flow (PAH= Para-amino-hippuric acid)
o Oxygen for blood flow to the lung (i.e. the cardiac output)
- The aorta has the highest velocity of blood flow, then the velocity
decreases gradually to be lowest in the capillaries and then it
increases slightly in veins.
- The blood flow through straight blood vessels is laminar. However,
there is certain critical velocity, above which the blood flow becomes
turbulent.
- This critical velocity may be exceeded at sites of constriction within
a blood vessel, producing turbulence beyond the constriction, or in
the heart due to rapid blood flow or closure of the valves.
- Turbulent blood flow produces noise that’s heard as bruit over
arteries or a murmur over the heart whereas laminar blood flow is
silent.
CIRCULATION THROUGH SPECIAL ORGANS

THE CORONARY CIRCULATION
- The cardiac muscle is supplied by the right and left coronary
arteries that originate from coronary sinuses at the root of the aorta,
behind two cusps of the aortic valves.

- The venous blood is drained to the right atrium through the
coronary sinus and anterior cardiac veins; however, small cardiac
veins (e.g. thebesian veins) drain into other chambers, resulting in
reduction of the PO2 in arterial blood (physiological shunt).
- Coronary blood flow to the left ventricle occurs during diastole and
to the atria and the right ventricle occurs during both systole and
diastole. This is explained by the pressure gradient between the
aorta and theses chambers during the cardiac cycle (see above).
- The coronary blood flow = 250 mL/min (= 5% of the cardiac output).
It is controlled by:
- Metabolites (high CO2, H+, lactate, K+, prostaglandins and
adenosine): These are the primary dilators of the coronary artery.
Among these metabolites adenosine is the most important dilator.
- Sympathetic stimulation: Both alpha and beta 2 receptors are found
in the coronary artery but the direct sympathetic effect is
vasoconstriction through alpha receptors; however, the sympathetic
increases contractility and therefore increases metabolites. Through
metabolites it causes vasodilatation and increases the coronary
blood flow (i.e. the indirect effect is more dominant).
- Parasympathetic stimulation: causes dilatation of the coronaries.
•Factors affecting the coronary blood flow (CBF) include:

- Tachycardia (decreases diastole and therefore decreases coronary
blood flow “CBF”).
- Aortic stenosis (associated with severe compression of the
coronary artery during systole of the left ventricle= decreases CBF).
- Hypotension (= decreases pressure in aorta and therefore
decreases CBF).

- Reduction in the coronary blood flow (ischemia) decreases oxygen
supply to the cardiac muscle. This produces severe chest pain that’s
aggravated by exercise and relieved by rest (angina pectoris).
- Prolonged or severe ischemia (due to complete obstruction of the
coronary artery) results in necrosis and death of the cardiac muscle
(Myocardial infarction). Here the pain is not relieved by rest.
CEREBRAL CIRCULATION
= 0.75 L/min (measured by the Fick principle using inhaled N2O).
- In addition to the sympathetic and parasympathetic innervation,
cerebral blood vessels are supplied by sensory nerves. These nerves
carry pain sensation triggered by traction or injury of these vessels.
- The brain is very sensitive to hypoxia; occlusion of its blood supply
causes unconsciousness in about 10 seconds.
- Chronic hypoxia produces intellectual deficits and affects the basal
ganglia, the thalamus and the inferior colliculus; however, the
vegetative structures in the brain stem are more resistant to hypoxia.
SPLANCHNIC CIRCULATION
= The liver receives 1.5 L/min of blood (0.5L /min by the hepatic
artery and 1.0 L/min by the portal vein).
- Other abdominal viscera receive about 1.0 L of blood per minute.
- This indicates that the liver and viscera receive about 1.5 L of
arterial blood per minute (= about 30% of the cardiac output).
- However, the blood flow to the small intestine increases after a
meal for up to 3 hours and therefore shifts some of the blood supply
to the brain. That’s why subjects become sleepy after a meal.

- The pressure in the portal vein has a clinical importance (= 10
mmHg). It is high in patients with portal hypertension (e.g. due to
bilharziasis).
CUTANEOUS CIRCULATION
= less than 0.5 L/min but varies with environmental temperature. It is
controlled by sympathetic neurons (no parasympathetic supply).
- Skin blood vessels develop the following reactions:
White reaction
- Follows light skin trauma by a pointed object. The reaction is
caused by reduction in capillary blood flow following contraction of
the precapillary sphincter.
Triple response
- Follows firm skin trauma by a pointed object. It involves three
changes in the skin:
o Red reaction: (due to capillary dilatation by the pressure)
o Local swelling (wheal): (due to increased capillary permeability)
o Diffuse reddening (flare): (due to arteriolar dilatation)
- The capillary changes appear to be due to local release of
substance P.
- The triple response is an example of axon reflex (in which afferent
impulses travel antidromically through axons of sensory nerves).
Reactive hyperemia
- Increased blood flow to an area after a transient occlusion of its
blood supply; due to vasodilatation caused by hypoxia and
metabolites.

CARDIOVASCULAR RESPONSES TO EXERCISE
- The cardiovascular responses to exercise differ according to the
type and level of exercise and according to the age and degree of
training. Most of the responses involve changes in the cardiovascular
and reparatory systems. The following is a brief account about some
of the cardiovascular responses:
Increased heart rate due to:
o Increased sympathetic stimulation (due to stress)
o Withdrawal of the parasympathetic effect on the heart (more
important than the increased sympathetic)
o Circulating catecholamines (from adrenal medulla & sympathetic)
o Proprioceptors (send excitatory impulses to the medullary
centers)
o Temperature (stimulates the SA node directly)
o Bainbridge effect (due to increased venous return by the muscle
pump & respiratory pump)
o Stimulation of chemoreceptors (due to hypoxia and acidosis)
o Stretch receptors in the lung (when the lung is inflated, impulses
pass through the vagus to inhibit the cardio-inhibitory center)
- The maximum heart rate (MHR) achieved during exercise
decreases with age.
- The easiest method to calculate it is by the formula:
MHR = 220 - age
However, there are many alternative formulas suggested by
researchers (e.g. MHR= 206.9 - (0.67 x age)).
- Trained athletes start with lower heart rate because their resting
heart rate is low (they have physiological bradycardia).
Increased stroke volume due to:
o Increased sympathetic stimulation (due to stress)
o Circulating catecholamines (from adrenal medulla & sympathetic)
o Temperature (stimulates the SA node directly)
o Stimulation of chemoreceptors (due to hypoxia and acidosis)
o Increased venous return = increases EDV (Frank-Starling’s law)
- Exercise with isotonic contractions produce marked increase in
stroke volume whereas exercise with isometric contraction produces
little change in it.
Increased venous return due to:
o Muscle pump
o Respiratory pump (hyperventilation)
o Venoconstriction (by the sympathetic and catecholamines)
Increased cardiac output due to:
o Increased HR & SV
o Depends on degree of training and level of exercise
o May reach more than 35L/min in athletes
Increased or decreased peripheral resistance (PR) due to:
o Compression of blood vessels during isometric contractions (=
increased peripheral resistance “PR”)
o Dilatation of skeletal muscle arterioles during isotonic contractions
(= decreased peripheral resistance). This dilatation occurs due to:
- Sympathetic cholinergic discharge acting on M receptors
- Circulating catecholamines acting on B2 receptors
- Metabolites
- Remember that: the level of exercise determines the net effect on
peripheral resistance. Hard exercise decreases PR.

Blood pressure changes:
- Changes in systolic blood pressure are determined by the cardiac
output whereas changes in the diastolic blood pressure are
determined by the peripheral resistance.
- Generally, isometric contraction increases both systolic and
diastolic pressures whereas isotonic contraction increases the
systolic and decreases the diastolic; however, these effects depend,
to a large extent, on the level of exercise.
- In strenuous exercise the systolic is increased, the diastolic is
decreased and therefore the pulse pressure is increased.
HEART FAILURE & SHOCK

HEART FAILURE
- Defined as failure of the heart to meet the metabolic demands of
tissues.
- Causes include: Severe anemia, severe hypertension, arrhythmia,
myocardial infarction, valvular disease and thyrotoxicosis.
- Heart failure can be classified as:
o Left sided HF (LHF): failure of the left side of the heart
o Right sided HF (RHF): failure of the right side of the heart
o Congestive HF (CHF): failure of the left & right sides of the heart
- Other terms may be used: for example “high output heart failure”
Here the cardiac output is increased; however, the high COP is still
not enough to meet the metabolic demands of tissues which are
highly increased (e.g. in thyrotoxicosis).

Physiological mechanisms in heart failure
= All the mechanisms in heart failure are stimulated by hypotension
and tissue hypoxia.
- These include activation of the renin-angiotensin-aldosteone
system because of the low blood supply to the kidney. This results in
retention of sodium and water and therefore contributes to edema
formation (see control of blood pressure).
- When the left ventricle fails to eject blood (LHF), blood accumulates
in the lung causing pulmonary edema whereas when the right
ventricle fails (RHF), blood accumulates in the venous side causing
raised JVP, hepatomegaly, ascites and lower limb edema.
- When the two ventricles fail (CHF), blood accumulates in the lung
and the venous side; therefore, all symptoms and signs of LHF and
RHF are found in CHF.
Symptoms of heart failure include:
- Due to blood accumulation in the lung & pulmonary edema:
o Breathlessness: occurs in LHF & CHF
o Cough: occurs in LHF & CHF
o Sputum with blood: occurs in LHF & CHF
- Due to blood accumulation in venous side:
o LL swelling: occurs in RHF & CHF
o Venous pulsations in the neck: occur in RHF & CHF
- Due to low blood supply to muscles:
o Fatigability & weakness: may occur in all types of HF
- Other symptoms:
o Palpitation: may occur in all types of HF
o Cyanosis: may occur in all types of HF (especially LHF & CHF)

Signs of LHF include:
o Third heart sound (galloping rhythm)
o Signs of pulmonary edema (basal crepitations)
Signs of RHF include:
o Third heart sound (galloping rhythm)
o Generalized edema
o Engorged neck veins (raised JVP)
o Hepatomegaly and sometimes splenomegaly
o Ascites
Signs of CHF include:
o Signs of both LHF & RHF
Signs that may give clue to the possible cause of HF include:
o Displaced apex beat: Lt ventricular hypertrophy (hypertension)
o Pale mucus membranes: Anemia (or vasoconstriction)
o Murmur: Valvular lesion
o Irregular pulse: Arrhythmia (atrial fibrillation)
o Goiter (thyroid enlargement): Thyrotoxicosis
Investigations:
o To assess the heart: ECG, chest X ray and echocardiography.
o For a possible cause: Hb and PCV, level of thyroid hormones
in the plasma …
Treatment
o Correction of the cause (e.g. blood transfusion for anemia)
o Diuretics like “Lasix” (for the fluid overload)
o Angiotensin converting enzyme inhibitors (ACEI) (to inhibit
formation of angiotensin II and to decrease aldosterone)
o Others (e.g. oxygen, morphine …)

SHOCK
- Defined as state of the circulation in which there is inadequate
tissue perfusion resulting in disturbance of functions.
Types
 Hypovolemic shock (due to decreased blood volume)
 Distributive or low resistance shock (due to vasodilatation)
 Cardiogenic shock (due to cardiac lesion causing low COP)
 Obstructive shock (due to obstruction of blood flow in the chest)
Symptoms
o Irritability (due to low blood supply to the brain)
o Thirst (due to hypovolemia)
o Palpitation (due to increased contractility of the heart for
compensation)
Signs (Not in all types of shock)
o Pallor and cold clammy skin (due to vasoconstriction)
o Sweating (due to sympathetic activation)
o Tachycardia (due to sympathetic activation)
o Hypotension (due to hypovolemia, vasodilatation, cardiac
lesion or kinking of the aorta …)
o Low urine output (due to low renal blood flow and high
release of ADH)
o Hyperventilation (due to chemoreceptor stimulation by hypoxia
or acidosis)
Body responses to shock
o Revise the mechanisms that control the blood pressure (very
rapid, less rapid and long term mechanisms).

Complications of shock
- Failure to treat shock leads to refractory or irreversible state. Here a
positive feedback mechanism is initiated (low COP= low blood
pressure= low venous return= low COP= low blood pressure and so
on) which leads eventually to death.
Hypovolemic shock
- Subdivided according to the cause of hypovolemia into:
o Hemorrhagic shock
o Surgical shock
o Traumatic shock
o Burn shock
o Shock of fluid loss (e.g. by vomiting or diarrhea)
- The compensatory reactions to shock are rapid and long term (see
control of blood pressure).
- In hemorrhagic shock, plasma is restored in about 3 days whereas
red blood cells are restored in 4-8 weeks.
Distributive shock
- Subdivided according to the cause of vasodilatation into:
o Anaphylactic shock (caused by histamine released by allergic
reactions)
o Septic shock (caused by endotoxins released by bacteria)
o Neurogenic shock (caused by vasovagal attacks caused by
severe traumatic pain in certain sites; e,g. testicular trauma)
- Due to the vasodilatation, the skin is usually warm (this
differentiates hypovolemic shock, in which the skin is cold, from
distributive shock (like septic shock), in which the skin is warm.

Cardiogenic shock
- Caused by diseases of the heart which impair the cardiac output.
- Examples include:
o Myocardial infarction
o Arrhythmias
o Congestive heart failure
- In addition to the symptoms and signs of shock, there are usually
symptoms and signs of pulmonary congestion.
Obstructive shock
- Occurs due to obstruction of blood flow within the chest (kinking of
the aorta or interruption of pulmonary blood flow).
- Examples include:
o Tension pneumothorax
o Cardiac tamponade
o Cardiac tumor
o Pulmonary embolism

1. The cardiac muscle differs from skeletal muscle because it is:
a. Striated muscle
b. Supplied by the autonomic nervous system
c. Inactive in the absence of external stimulation
d. Tetanized after repeated stimulation
e. Active in the absence of oxygen
2. The stroke volume is directly proportional to:
a. Parasympathetic simulation
b. The chronotropic effect of sympathetic stimulation
c. Starling’s forces
d. The initial length of muscle fibers
e. All of the above
3. During the cardiac cycle, closure of the aortic valve occurs at the:
a. End of isometric contraction
b. Beginning of rapid ejection phase
c. Beginning of ventricular relaxation
d. End of ventricular contraction
e. End of rapid filling phase
4. Normal P wave in the ECG indicates:
a. Increased size of atria
b. Normal atrial contraction
c. Ventricular depolarization
d. Normal cardiac pacemaker
e. Papillary muscle repolarization
5. Which of the following about the ECG is not true:
a. Can detect the size of the heart
b. Is useful in detecting reduction in the coronary blood flow
c. It is recorded from limb leads and chest leads
d. It can detect some electrolyte disturbances
e. Is used for measurement of the cardiac output
6. Measurement of cardiac output using Fick principle depends on:
a. Measurement of circulation time
b. Frequent arterial blood sampling
c. Use of a dye injected into an arm vein
d. Calculation of blood flow using the formula (blood flow= Q x 60/Ct)
e. None of the above
7. Left ventricular heart failure leads to:
a. Increased pulmonary capillary hydrostatic pressure
b. Engorged neck veins
c. Bradycardia
d. Increased myocardial contractility
e. Ascites

8. Coronary blood flow:
a. Is mainly regulated by sympathetic supply
b. Increases due to beta blockers
c. Is highest during systole because of myocardial activity
d. Increases when myocardial metabolism increases
e. Is regulated by myogenic autoregulation
9. If the radius of an artery is halved (divided by 2) its resistance will
increase:
a. 2 times
b. 4 times
c. 8 times
d. 16 times
e. 32 times
10. End diastolic volume may not increase in which of the following:
a. An increase in preload
b. Sympathetic stimulation
c. Reduction in the ejection fraction
d. An increase in venous return
e. An increase in afterload
11. The pressure in the left ventricle:
a. Varies between 0 am 120 mmhg
b. Rises rapidly during ventricular filling
c. Shows a maximum of 80 mmHg
d. Falls rapidly during the initial phase of diastole
e. Remains constant during the rapid ejection phase
12. Venous return:
a. Is increased on standing
b. Increases during inspiration
c. Is decreased by venoconstriction
d. When decreased, it activates bainbridge reflex
e. When increased, it increases both heart rate & stroke volume
13. Which of the following is a vasodilator:
a. Serotonin
b. Endothelin
c. Nitric oxide (NO)
d. Thromboxane A2
e. Norepinephrine
14. When viscosity of blood is increased, which of the following is
increased:
a. Systolic blood pressure
b. Diastolic blood pressure
c. Central venous pressure
d. Venous return
e. PCV

15. Activity in the carotid sinus results in:
a. Tachycardia
b. Hyperventilation
c. Increased peripheral resistance
d. Edema
e. Sweating
16. “Lead II” in the ECG is:
a. Unipolar lead
b. Normally characterized by absent Q wave
c. Characterized by tall peaked T wave in hypokalemia
d. Characterized by absent P wave in fast atrial fibrillation
e. Not characterized by ST elevation in anterior myocardial infarction
17. The heart rate is increased by:
a- Parasympathetic stimulation
b- Beta blockers
c- Cervical sympathectomy
d- Denervation of the SA node
18. Concerning the ECG:
a- P wave follows atrial systole
b- ORS complex is due to ventricular repolarization
c- ST segment represents conduction in all the conductive system
d- the first heart sound follows the P wave
e- the third heart sound occurs at the same time as the P wave
19. The cardiac muscle proper:
a- Consumes protein as the main source of energy
b- Depends on anaerobic metabolism for generation of energy
c- Characterized by prepotential phase on its action potential
d- Undergoes rhythmic contractions
e- Is not protected from tetanus
20. The ECG is most important in detecting a major reduction in:
a- Ventricular contractility
b- Mean blood pressure
c- Total peripheral resistance
d- Cardiac output
e- Coronary blood flow
21. Propagation of Action Potential through the heart is fastest in:
a- SA node
b- AV node
c- Atrial muscle
d- Purkinge fibres
e- Ventricular muscle
22. The cardiac output:
a. Is about 2 L/min at rest in adults
b. Is always increased by increasing the heart rate

c. Is decreased by increasing the stroke volume
d. Is not changed during exercise
e. Is higher in males than females
23. If a blood pressure is 130/70, which of the following is not true:
a. Systolic pressure equals 130 mmHg
b. Diastolic pressure equals 70 mmHg
c. Pulse pressure equals 60 mmHg
d. Mean arterial pressure equals 120 mmHg
e. The blood pressure is normal
24. The sino-atrial node (SA node):
a. Is an un-myelinated neural structure
b. Is found in the left atrium
c. Is supplied by the sympathetic but not the parasympathetic
d. Delays conduction from atria to ventricles
e. Responsible for the normal cardiac rhythm
25. The stroke volume is decreased by:
a. Stimulation of the parasympathetic
b. Calcium ions
c. Stimulation of the baroreceptors
d. Exercise
e. Digitalis
26. A drug that has a positive inotropic effect on the heart will:
a. Increase the heart rate
b. Increase the force of contraction
c. Decrease the force of contraction
d. Decrease the heart rate
e. Increase the end diastolic volume
27. The peripheral resistance in adults is mainly determined by:
a. Radius of arterioles
b. Radius of great arteries
c. Viscosity of the blood
d. Length of blood vessels
e. Radius of veins
28. Baroreceptors:
a. Are located in the carotid and aortic bodies
b. Their activity is increased on standing
c. Result in tachycardia when stimulated
d. Afferents from them terminate directly on the vasomotor centre
e. Send tonic discharge in response to normal blood pressure
29. Hypovolemic shock is characterized by all the following except:
a. Tachycardia
b. Sweating
c. Thirst
d. Vasodilatation

e. Low urine output
30. Bradycardia may be produced by stimulation of
a.  1 adrenergic receptors
b.  2 adrenergic receptors
c.  adrenergic receptors
d. Muscarinic receptors
e. Nicotinic receptors
31. The stroke volume is proportional to:
a. Parasympathetic simulation
b. The chronotropic effect of sympathetic stimulation
c. Starling’s hypothesis
d. The initial length of muscle fibers
e. End systolic volume
32. The pacemaker prepotential:
a. Is a slow depolarization due to opening of Ca++ channels
b. Is a slow inecrease in the RMP
c. Maitained by opening of long acting Ca channels
d. Is due to a decrease in K+ efflux
e. Occurs only in the SA node
33. The following is true regarding action potential of cardiac muscle:
a. Increased extracellular K+ causes immediate depolarization
b. Repolaristion is due to Na+ current
c. Exrtacellular Na+ affects the pacemaker potential
d. Plateau phase of action potential is due to Ca++ influx
e. Repolarisation is due to delayed K+ efflux
34. Clinical examination of a patient shows pale mucous membranes,
a pulse rate of 110/min and blood pressure of 150/ 40 mmHg.
Which of the following is a possible diagnosis:
a. Heart failure
b. Hypertension
c. Aortic regurgitation
d. Hypothyroidism
e. High grade fever
Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Answer b d c d e e a d d b a e
Question 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
Answer c b c d d d d e d e d e
Question 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.
Answer c b a e d d d d d c

CHAPTER 7
THE RESPIRATORY SYSTEM
STRUCTURE AND FUNCTION
Divisions
- The respiratory system is divided anatomically into:
Upper respiratory tract (URT)
- includes all structures outside the thoracic cavity (the chest). These
are the nasal cavity, pharynx, larynx and upper part of the trachea.
Lower respiratory tract (LRT)
- includes all structures inside the thoracic cavity. These are the
lower part of the trachea, bronchi, bronchioles, alveolar sacs
(including alveolar ducts and alveoli).
Fig 7.1: The respiratory system

- The URT is characterized by presence of hair (within the nose),
ciliated epithelium, mucus secreting cells and rich blood supply.
- Evaporation of water from surface of the respiratory mucosa
moistens and equilibrates temperature of inspired air with that of the
body; thus making the inspired air suitable for gas exchange in the
distal parts of the lung.
- The respiratory system is divided according to major function:

Conducting zone:
- For conduction of air to the lower zone. Includes the nasal cavity,
pharynx, larynx, trachea, bronchi and bronchioles (up to the terminal
bronchioles).
Respiratory zone:
- For gas exchange. Includes the respiratory bronchioles and alveolar
sacs (alveolar ducts and alveoli).
Fig 7.2: Physiological divisions of the respiratory system

Important anatomical points
The tracheo-bronchial tree
- Is formed by about 23 divisions.
- The first 16 divisions (starting from the trachea to the terminal
bronchioles) form the conducting zone whereas the other divisions
(starting from the respiratory bronchioles to the alveoli) form the
respiratory zone.
- The trachea and bronchi have cartilage in their walls but little
smooth muscle while the bronchioles have smooth muscle in their
walls but no cartilage.
- The cartilage supports walls of the trachea and large bronchi and
prevents their collapse when the pressure inside them is decreased
(as occurs during inspiration).
- This support is lost in cases of tracheomalacia; that’s why patients
suffer from an inspiratory sound due to URT obstruction (stridor).
The lungs
- The lungs (the right and the left lungs) are found within the thoracic
cavity, protected by the rib cage.
- Each lung consists of parenchymal tissue supporting airways, blood
vessels, nerves and lymphatics.
- Each lung is divided, by horizontal and oblique fissures, into lobes.
The right lung (consisting of 3 lobes) is larger than the left lung
(consisting of 2 lobes due to presence of the heart).
- The lungs provide a surface for gas exchange.
- LRT diseases mainly affect the lungs. They include: inflammation of
the lung (pneumonia), acute airway obstruction (asthma), chronic
airway obstruction “COPD” (emphysema), lung fibrosis ...

The Pleural cavity
- Each lung is covered by a membrane that’s attached tightly to its
outer surface (the visceral pleura). The membrane continues to line
the inner surface of the chest wall (the parietal pleura).
- The potential space which is formed between the visceral and
parietal pleurae is called the pleural cavity.
- The pleural cavity contains a few millimeters of fluid that acts as a
lubricant. It allows easy expansion of the lungs and resists separation
of the two membranes, therefore normally, no cavity is actually
present.
Fig 7.3: The pleural cavity
FUNCTIONS OF THE RESPIRATORY SYSTEM

 Provides oxygen to the tissues
 Eliminates carbon dioxide from the tissues
 Participates in regulation of pH of the blood

- These are the major functions of the respiratory system; however,
participation of other systems is essential to perform these functions;
especially the blood, cardiovascular system and the renal system.
Other functions of the respiratory system:

 Participates in regulation of body temperature. Hyperventilation
increases heat loss by evaporation from the mucus membranes.
This is especially important in animals like dogs “panting”.
 Has some important metabolic functions. Theseinclude:
- Conversion of angiotensin I to angiotensin II (by angiotensin
converting enzyme (ACE) which is produced by the pulmonary
endothelium).
- Inactivation of certain vasoactive substances like bradykinin
(also by ACE).
- Breakdown of arachidonic acid metabolites like prostaglandins
and leukotriens.
- Synthesis of surfactant (see below).
 Has many important defense mechanisms:
- Hairs within the nose for filtration of air (removes particles > 10
µm in diameter).
- Mucus on the surface of respiratory epithelium for trapping of
smaller particles (2-10 µm in diameter).
- Cilia on cells for transporting the trapped particles upwards
towards the nasopharynx to be swallowed or coughed out (= This
is known as muco-ciliary clearance).
- Cough or sneezing reflexes for ejection of unwanted substances
through the mouth to the outside.

- IgA antibodies and complement proteins within the respiratory
secretions for certain antigens.
- Antiproteases (e.g. alpha 1-antitrypsin) for proteases released
from dead bacteria or WBCs.
- Alveolar macrophages for ingestion of bacteria, debris and
foreign particles that reach the alveoli (usually less than 2 µm in
diameter).
Remember these clinical notes:
 ACE inhibitors are used for treatment of hypertension. They block
the conversion of angiotensin 1 to angiotensin II; however, they
also block the breakdown of bradykinin by the angiotensin
converting enzyme. This results in many side effects caused by
the bradykinin, including angioedema and irritating cough. For this
reason, the angiotensin receptor blockers are very important for
patients who suffer from these side effects. The receptor blockers
block effects of angiotensin II without affecting the converting
enzyme; therefore the enzyme inactivates bradykinin.
 Congenital or acquired deficiency of one or more of the above
defense mechanisms results in certain respiratory problems, for
example: deficiency of IgA antibodies causes repeated respiratory
infections, deficiency of alpha 1-antitrypsin causes destruction of the
lung tissue by proteases (as occurs in emphysema) and impaired
muco-ciliary clearance due to immotile cilia causes repeated
respiratory infections (as occurs in primary ciliary dyskinesia, also
known as Kartagener's syndrome).

VENTILATION
Definitions
- Ventilation is the process of getting air into and out of the lungs
during breathing. It is always adjusted to meet the metabolic
demands of the body (i.e. to provide sufficient oxygen and to
eliminate excess carbon dioxide).
- Hyperventilation refers to ventilation in excess of the metabolic
demands of the tissues. It usually results in hypocapnia (low Pco2).
- Hypoventilation refers to ventilation less than the metabolic
demands of the tissues. It results in hypercapnia (high Pco 2).
Mechanism of ventilation
- Air moves into or out of the lungs due to pressure gradient (when
the atmospheric pressure is higher than the intrapulmonary pressure
it gets into the lungs (= inspiration); and when the atmospheric
pressure is lower than the intrapulmonary pressure it gets out of the
lungs (= expiration)).
Fig 7.4: Ventilation

- According to Boyle’s law: there is an inverse relationship between
pressure of gases and volume. Therefore, there is an inverse
relationship between pressure within the lungs and their size.
- Inspiration results in inflation of the lungs and therefore reduction in
intrapulmonary pressure (IPP) whereas expiration does the reverse.
- The following table shows variations in IPP during respiration:
Table 7.1: The intrapulmonary pressure
Phase of respiration (with closed glottis) IPP
End of normal inspiration -1 mmHg
End of normal expiration +1 mmHg
End of maximum inspiration -30 mmHg
End of max expiration (valsalva maneuver) > +50 mmHg
Remember that:
 The atmospheric pressure is 760 mmHg. Values of the IPP
indicate difference from the atmospheric pressure. A value of -1
mmHg indicates a pressure less than the atmospheric by 1 (i.e.
759 mmHg) whereas +1 indicates a higher pressure (761 mmHg).
 Closure of the glottis at the upper part of the larynx isolates the
respiratory system from the atmosphere. Therefore, there is no
equilibration between IPP and atmospheric pressure.
 Opening of glottis allows equilibration of IPP with the atmospheric
pressure. That’s why the IPP at the end of all respiratory phases
equals zero (i.e.=760 mmHg similar to the atmospheric pressure).
Intrapleural pressure (IPLP)
- The intra pleural pressure (IPLP) undergoes similar changes;
however, opening and closure of the glottis do not change its values.
- The following table shows variations in IPLP during respiration:

Table 7.2: The intrapleural pressure
Phase of respiration IPLP
End of normal inspiration -6 mmHg
End of normal expiration -2.5 mmHg
End of maximum inspiration -30 mmHg
End of max expiration (valsalva maneuver) > +50 mmHg
Remember that:
 The intra-pleural pressure is subatmospheric (-ve) during normal
inspiration and expiration whereas the IPP is –ve during
inspiration and +ve during expiration.
- Negativity of intra-pleural pressure is explained by the tendency of
the lung and the chest wall to recoil into opposite directions (the lung
tends to recoil inwards, due to its elastic properties, whereas the
chest tends to recoil outwards, due to position of the ribs).
- The point when recoil of the lung equals recoil of the chest is the
end of normal expiration. Here the volume of air within the lungs
equals the functional residual capacity (see below).
- In the upright position, there is difference in intrapleural pressure
between apex and base of the lung, because of gravity. The pressure
at the apex is lower than that at the base. That’s why there is higher
tendency of bullae at the apex of an emphysemayous lung to rupture
more than bullae at the base.
Mechanism of Inspiration:
 Contraction of inspiratory muscles
 Expansion of the chest
 Reduction of intra-pleural pressure

 Expansion of the lungs
 Reduction of intra-pulmonary pressure
 Air moves into the lungs
- Inspiration is an active process because it involves contraction of
inspiratory muscles. The inspiratory muscles can be grouped into:
Inspiratory muscles working at rest (and during exercise):
 The diaphragm:
- Responsible for about 75% of inspiration
- Descends down during contraction (about 1.5 up to 7cm). This
increases the vertical diameter of the chest
- Supplied by the phrenic nerve (C4)
- Consists of central tendon, costal fibers and crural fibers
 The external intercostals muscle
- Contraction causes expansion of the chest by increasing the
antero-posterior and transverse diameters of the chest
Accessory inspiratory muscles working during forced inspiration only:
 Scalene
 Sternocleidomastoid
 Serratus anterior
 Trapezius
Mechanism of Expiration:
 Relaxation of inspiratory muscles
 Increased intrapleural pressure
 Recoil of the lungs to the expiratory position
 Increased intra-alveolar pressure
 Air moves out of the lungs

- Expiration at rest is a passive process since it does not involve
contraction of any expiratory muscle.
- However forced expiration requires the action of the following
expiratory muscles that decrease the size of the chest:
 Internal intercostals muscle
 Abdominal muscles
Measurement of ventilation
- Volumes of air that enter or leave the lungs can be measured by
special devices (e.g. the Benedict Roth Spirometer).
Fig 7.5: The Benedict Roth Spirometer

Volumes and capacities measured by the Spirometer:
 Tidal volume (TV)
- Volume of air inspired or expired each breath. = 0.5L in adult
males and females at rest.
 Inspiratory reserve volume (IRV)
- Volume of air inspired by maximum inspiratory effort following
tidal inspiration. = 3L in adult males and 1.9L in adult females.
 Inspiratory capacity (IC)
- Volume of air inspired by maximum inspiratory effort following
tidal expiration. = TV + IRV
 Expiratory reserve volume(ERV)
- Volume of air expired by maximum expiratory effort following tidal
expiration. = 1L in adult males and 0.7L in adult females.
 Vital capacity (VC)
- Volume of air expired by maximum expiration following maximum
inspiration. (= IRV + TV + ERV or = IC + ERV).
- Normal values: About 5L in adult males, 4L in adult females.
- Like other lung volumes, it differs according to age, gender, body
size (height or weight), position (higher during standing) and ethnic
background (higher in Western population than African ones).
- It is an important index of disease. For this reason it is usually
measured to diagnose certain respiratory problems.
- During measurement, the subject is asked to inspire air maximally
and then to expire maximally into the mouth piece of the Spirometer.
- When the subject is asked to expire forcefully and as quickly as
possible, the measured volume is called forced vital capacity (FVC).
- The FVC is an important parameter in chest medicine (see below).

The forced vital capacity (FVC)
- Volume of air expired forcefully by maximum expiration following
maximum inspiration.
- Expiration normally takes about 4 s up to 6 s. Forced expiratory
time that takes longer than 6 seconds indicates airway obstruction.
- The volume of air expired during the first second of the FVC is
called the forced expiratory volume in the first second (FEV 1). It
equals more than 3 quarters of the FVC (i.e. more than 75%).
- For example when the FVC is 5 L, the FEV1 is about 4 L (i.e.
FEV1/FVC ratio = 80%).
- The values of the FEV1 and the FVC can be measured by a
vitalograph. The device provides FVC and FEV1 values on a graph
paper in the Y axis; whereas X axis represents time in seconds.
Fig 7.6: The vitalograph
- The FEV1/FVC ratio is usually measured to differentiate between

obstructive and restrictive lung diseases.
- Normal ratio is about 80% (see above).

- In obstructive lung diseases (in which FEV1 is lower than normal)
the ratio is less than 75%, e.g. asthma, emphysema and chronic
bronchitis (see curve B in fig 7.7).
- In restrictive lung diseases (in which both FEV1 and FVC are lower
than normal) the ratio is normal or increased (up to 100%), e.g. lung
fibrosis and lung collapse (see curve C in fig 7.7).
- In combined problems (obstructive and restrictive problems), all the
parameters are lower than normal (i.e. low FEV1, low FVC and low
FEV1/FVC ratio), e.g. an asthmatic patient with lung fibrosis (see
curve D in fig 7.7).
Remember that:
 When the FEV1 = 5 L and the FVC = 5 L; the FEV1/FVC ratio =
100%. This indicates that the expiratory time is only one second
(i.e. wrong maneuver); however, the values indicate normal test.
 The use of the vitalograph is replaced by the digital spirometer
which gives FEV1, FVC and the FEV1/FVC ratio directly.
Fig 7.7: The vitalograph in different cases

Table 7.3: Spirometry in different cases
Lung condition FEV1 FVC FEV1/FVC ratio
Normal Normal Normal Normal
Obstructive diseases Low Normal Low
Restrictive diseases Low Low Normal
Obstructive + Restrictive Low Low Low
Volumes and capacities not measured by the Spirometer:

 Residual volume (RV)
- Volume of air that remains in the lungs after maximum expiration.
= 1.2 L in adult males and 1.1 L in adult females.
- Higher volumes are found in obstructive lung diseases (due to
difficulty in expiration) and lower volumes in restrictive lung diseases.
- The residual volume has the following functions:
o Allows easy expansion of the lungs
o Allows continuous gas exchange throughout the respiratory cycle.
o Prevents complete lung collapse
 Functional residual capacity (FRC)
- Volume of air that remains in the lungs following tidal expiration.
= ERV + RV
 Total lung capacity (TLC)
- Volume of air accommodated by the lungs at the end of max.
inspiration.
= (IRV + TV + ERV + RV) or (IC + FRC) or (VC + RV)
= 6L in adult males and 5L in adult females.
- The RV & FRC are higher in:
o Males compared to females

o Adults compared to children (i.e. increase with age)
o Obstructive lung diseases (asthma, chronic bronchitis and
emphysema) compared to restrictive (lung fibrosis).
- The above volumes and capacities can be measured by the
following methods; Body plethysmography, Helium Dilution
Technique or Nitrogen Washout Technique.
- Revise the last topic in this chapter (Lung function tests).
Pulmonary ventilation (or respiratory minute volume)
- The volume of air inspired or expired per minute
=TV X RR (where TV= tidal volume & RR= respiratory rate)
=500 X 12= (6L/min) at rest.
Alveolar ventilation
- The volume of air that ventilates the alveoli per minute
= (TV-dead space volume) X RR
= (500-150) X 12= (4200 ml/min) or (4.2L/min) at rest.
Fig 7.8: The spirogram

Dead space volume (DS)
- Defined as volume of air that does not participate in gas exchange.
- Includes two types:
o Anatomical DS: volume of air that occupies the conducting zone.
o Physiological DS: volume of air that occupies the conducting zone
(anatomical DS) plus volume of air in the respiratory zone but not
participating in gas exchange (e.g. air within the upper alveoli that
receive low blood supply because of the gravity).
- The anatomical DS is about 150 ml in an average adult male (or
roughly it equals the weight of the body in pounds).
- The physiological DS volume = the anatomical dead space volume
+ any additional alveolar air not participating in gas exchange.
- Normally, the physiological is almost equal to the anatomical dead
space. The difference being less than 5 ml of air.
- The anatomical dead space volume can be measured by the single
breath nitrogen test (see lung function tests).
- The physiological dead space volume can be measured by the Bohr
equation: VD/VT = PACO2 - PECO2)/PACO2
Where: VD = Volume of dead space, VT = Tidal volume, PACO2=
Partial pressure of carbon dioxide in alveolar air and PECO2= Partial
pressure of carbon dioxide in expired air.
- Normally PACO2 is the same as PaCO2 (= Partial pressure of carbon
dioxide in arterial blood). Therefore measurement requires an arterial
blood sample to measure CO2 in arterial blood and a gas analyzer to
measure CO2 in expired air.
- Notice that CO2 expired from the alveoli that contain DS air is zero
(similar to the atmosphere) because there is no gas exchange.

ELASTIC PROPERTIES: SURFACTANT AND COMPLIANCE
- The elastic properties of the lung are caused by:
o Elastic fibers in the lung tissue
o Surface tension of fluid in the alveoli (see below)
- These act against inflation of the lung.
- For ventilation to take place, it should overcome these two causes.
However, the two causes are affected by many factors. These are
discussed below:
SURFACTANT
 A phospholipid produced by type II alveolar cells.
 Acts to reduce surface tension of fluid in the alveoli. This is
achieved by covering the surface of water, separating it from air
(because the surface tension occurs at the water/air interface).
 The surface tension is a physical property of liquids. It arises
because the cohesive forces between water molecules attract
each other, tending to contract their surface and eventually cause
alveolar collapse.
 Reduction of the surface tension prevents:
o Alveolar collapse
o Development of pulmonary edema (due to negative interstitial
pressure caused by the alveolar collapse)
 The presence of surface tension in the lung was first noticed
when air and saline were compared during inflation of excised
lungs. Inflating lungs with saline was found to be easier than
inflating them with air. This is because there is no surface tension
acting against inflation when saline was used.

 Surfactant effects are mainly exerted on small alveoli; especially
during expiration. This is because these small alveoli have higher
tendency to collapse.
 The higher tendency of small alveoli to collapse can be explained
by the law of Laplace:
P = 2T/r
Where: P= pressure inside the alveolus (= distending pressure), T=
tension and r= radius of an alveolus.
 This indicates that the smaller the radius the higher the distending
pressure needed to keep it patent.
 Production of surfactant starts late in pregnancy (after the 32 nd
week of pregnancy). Therefore it is deficient in pre term babies.
 These babies develop cyanosis & difficulty in breathing at birth. A
serious condition known as infant respiratory distress syndrome
(IRDS) or (hyaline membrane disease); characterized by collapse
of alveoli and retention of fluids in the interstitium and alveoli.
 Retention of fluid in the alveoli occurs because surfactant is
needed for maturation of epithelial sodium channels (ENaC)
responsible for absorption of sodium and water from the alveoli
after birth. Failure of maturation of these channels due to
deficiency of surfactant results in fluid retention.
 Treatment of IRDS requires, in addition to high oxygen supply
and fluid balance, inhalation of phospholipid or synthetic
surfactant.
 Surfactant production is increased by: Glucocorticoids (that’s why
pregnant women who develop premature labor contractions are
given injections of hydrocortisone, to increase its production).

 Surfactant production is decreased by:
o Occlusion of the pulmonary artery
o Occlusion of a main broncus
o Chronic inhalation of (100%) oxygen
o Cigarette smoking
LUNG COMPLIANCE
 Compliance is defined as change in volume per unit change in
pressure.
 Lung compliance is described as the distensibility or stretchibility
of the lungs (i.e. the capacity of the lungs to expand or stretch).
 It differs from elasticity which is the resistance to that stretch (i.e.
compliance = 1/elasticity). Therefore when elasticity is decreased,
compliance is increased.
 It is measured in terms of change in volume per unit change in
pressure (i.e. C =  V/  P).
 Here a pressure volume curve is used for its measurement. For
example the relaxation pressure curve.
 To obtain the relaxation pressure curve, a subject breathing
through Spirometer is asked to inhale a given amount of air and
then to relax his respiratory muscles while his mouth and nose
are shut. During the process, the intrapulmonary pressure is
measured by a device in his mouth.
 Then the amount of inhaled air is increased and the procedure is
repeated until he takes max. inspiration, folled by max. expiration.
 The intrapulmonary pressure is plotted against volume as
appears in the following figure.

 Notice that the relaxation pressure equals zero at the end of quiet
expiration (i.e. when the lung volume equals the functional
residual capacity, the point of equilibrium between the inward
recoil of the lungs and the outward recoil of the chest).
Fig 7.9: The relaxation pressure curve
 The slope of the curve equals compliance. However, it differs in

different lung volumes. For this reason the term specific lung
compliance is sometimes used. It equals the value of the lung
compliance divided by the lung volume
Specific compliance = Lung compliance / Lung volume
 The compliance obtained in this way is known as static lung
compliance.

 It is important to notice that static lung compliance during inflation
is slightly lower than static lung compliance during deflation.
Therefore the relaxation pressure curves during inflation and
deflation are not the same. This is known as “hysteresis of the
lung”.
 When the change in lung volume is measured during breathing;
the resistance within the airways affects the value of compliance;
here the measured compliance is known as the dynamic lung
compliance.
 Normal values:
o Compliance of the lung (CL) = 0.2 L/cm H2O
o Compliance of the chest (CC) = 0.2 L/cm H2O
o Compliance of both (CL&C) = 0.1 L/cm H2O
- Notice that: 1/CL + 1/CC = 1/CL&C (like resistances connected in
parallel).
 Factors that increase lung compliance:
o Emphysema & old age (due to loss of elastic fibers in the lung)
 Factors that decrease lung compliance:
o Lung fibrosis, pulmonary edema, high surface tension of fluid
in alveoli (surfactant deficiency) and small lung size (children).
 Factors that decrease lchest compliance:
o Stiffness of joints, obesity and deformity of the chest wall (e.g.
kyphosis, scoliosis).
Remember that:
 High lung compliance decreases work of breathing whereas low
lung compliance increases work of breathing.
 Surfactant decreases work of breathing.

Bronchial tone
- The smooth muscle in the bronchial wall is controlled by the
autonomic nervous system. The sympathetic dilates it (e.g. during
inspiration) and the parasympathetic constricts it (e.g. during
expiration); however, there are multiple irritants, chemicals and
hormones that may affect the normal tone of the bronchial tree; these
include:
Factors causing bronchoconstriction:
o Irritants & chemicals: e.g. sulfur dioxide
o Cool air
o Exercise (possibly by the cool air during hyperventilation)
o Substance P
o Adenosine
o Many inflammatory modulators & cytokines involved in the
pathogenesis of asthma (e.g. leukotriens); that’s why anti-
leukotriens are added for treatment of asthma.
Factors causing bronchodilation:
o Catecholamines
o VIP (vasoactive intestinal polypeptide)
- There is circadian rhythm in bronchial tone throughout the day, with
maximal constriction early in the morning. That’s why asthmatic
patients usually suffer from symptoms of airway obstruction early in
the morning.

Pulmonary circulation
- Each lung receives its blood supply from two sources: the
pulmonary artery (which supplies the alveoli) and bronchial arteries
(which supply the airways and the pleurae).
- The pulmonary artery carries deoxygenated blood from the right
ventricle. It forms an extensive network of capillaries that surround
the alveoli to allow gas exchange. Oxygen is taken up into the blood
while carbon dioxide diffuses into the alveoli. The oxygenated blood
returns through pulmonary veins to the left atrium.
- The bronchial arteries carry oxygenated blood from the aorta. They
supply the lung parenchyma, airways and pleurae with oxygen and
nutrients. They also equilibrate temperature of inspired air with that of
the body. Deoxygenated blood is drained through bronchial veins to
the azygos vein and therefore to the right atrium via the inferior vena
cava; however, there are anastomoses between some bronchial
capillaries and pulmonary capillaries. This allows some
deoxygenated blood in bronchial capillaries to drain into the
pulmonary capillaries and then into the pulmonary vein, resulting in
the physiological shunt (mixture of oxygenated blood with some
deoxygenated blood).
- In addition, there is another source for the physiological shunt. It is
from small cardiac veins (thebesian veins) that drain deoxygenated
blood into the left side of the heart, which contains oxygenated blood.
- The physiological shunt results in reduction of arterial PO2 by 2
mmHg and reduction of arterial oxygen saturation by 0.5% compared
to oxygenated blood coming from alveolar capillaries.

GAS EXCHANGE IN THE LUNGS
- There are two sites of gas exchange in the body:

o Between alveoli & pulmonary capillaries (in the lungs)
o Between tissue cells & systemic capillaries (in the tissues).
- Gas exchange in the lungs depends on the following factors:
o Pressure gradient of the gas
o Surface area of the respiratory membrane
o Thickness of the respiratory membrane
o Physical properties of the gas
1) Pressure gradient
- Gases move passively from an area of high pressure to an area of
low pressure.
- The pressure of a single gas in a container containing mixture of
gases is called its partial pressure.
- The partial pressure of a gas is calculated by multiplying its
fractional concentration times the total pressure of all gases. The
following table explains calculation of partial pressures of gases in
the atmosphere (dry air):
Table 7.4: Calculation of partial pressures of gases
Gas Percentage (%) Partial pressure
Nitrogen 78.06 78.06 x 760 = 593.3 mmHg
Oxygen 20.98 20.98 x 760 = 159.4 mmHg
Carbon dioxide 0.04 0.04 x 760 = 0.3 mmHg
Inert gases 0.92 0.92 x 760 = 7 mmHg
Total 100 760 mmHg

Partial pressure of oxygen (Po2)
o In dry air = 159 mmHg
o In inspired air (after humidification in the airways) = 149 mmHg
20.98% x [760 - 47]; PH2O = 47 mmHg at body temperature
o In alveolar air = 100 mmHg (due to rapid diffusion of oxygen
into pulmonary capillaries & diffusion of CO2 into alveoli)
o In venous blood (coming to pulmonary capillaries) = 40 mmHg
(Prior to gas exchange)
o Po2 in arterial blood (leaving pulmonary capillaries)= 100 mmHg
(After the gas exchange; however, this value is decreased by the
physiological shunt).
Fig 7.10

Partial pressure of carbon dioxide [Pco2 ]
o In dry air = 0.3 mmHg
o In inspired air = 0.29 mmHg (0.04% x [760 - 47]
o In alveolar air = 40 mmHg (due to rapid diffusion of CO2 from
pulmonary capillaries to alveoli)
o In venous blood (coming to pulmonary capillaries) = 45 mmHg
(Prior to gas exchange)
o Pco2 in arterial blood (leaving the pulmonary capillaries)= 40 mmHg
(After the gas exchange)
Fig 7.11

2) Thickness
- The respiratory membrane consists of the following layers (fig 7.11):
o Fluid in the alveoli
o Alveolar wall (basement membrane + epithelium)
o Interstitial fluid
o Capillary wall (basement membrane + endothelium)
- Normal thickness = 0.5 micrometer
- Gas exchange is inversely proportional to thickness of the
respiratory membrane. For example when the thickness is
decreased (as occurs during exercise), gas exchange is increased.
- It is impaired when the thickness is increased (e.g. due to lung
fibrosis or pulmonary edema). This causes hypoxemia (low oxygen in
blood); however, thickness of the respiratory membrane is a less
common cause of hypoxemia than ventilation: perfusion mismatching
(see below).
Fig 7.12; The

3) Surface Area
- The available area for gas exchange is called the effective surface
area. It indicates well ventilated alveoli in contact with well perfused
capillaries.
- Gas exchange is directly proportional to the effective surface area.
- For example when the surface area is increased (as occurs during
exercise), gas exchange is increased.
- The effective surface area is increased during exercise because:
o More alveoli are ventilated (due to increased ventilation)
o More capillaries are perfused (due to increased perfusion)
- Total surface area equals about 70 m 2 (normal range: 50-100 m2).
4) Diffusion Coefficient
- Defined as the amount of gas that diffuses across the respiratory
membrane per unit pressure difference per unit surface area per unit
time. It depends on:
o Solubility of the gas (direct relation)
o Molecular weight of the gas (inverse relation)
- Although molecular weight of CO2 is larger than O2, its diffusion
coefficient is higher than O2. This is due to the high solubility of CO2.
Diffusion capacity of the respiratory membrane:
- The volume of gas that crosses the respiratory membrane per unit
partial pressure difference per unit time. It is affected by:
o Thickness of the membrane (inverse relationship)
o Surface area of the membrane (direct relationship)
- It is measured by using carbon monoxide which is highly soluble in
blood (unlike other gases it is “diffusion limited”)
- Normal diffusion capacity equals 25 ml/min/mmHg.

The Ventilation : Perfusion Ratio (V/Q ratio)
- The ratio of alveolar ventilation to pulmonary blood flow (perfusion).
- Alveolar ventilation is about 4 L/min whereas pulmonary blood flow
is about 5 L/min; therefore V/Q ratio = 0.8 (≈ 1.0).
- It is affected by: Gravity and lung diseases
Effect of gravity on V/Q ratio:
- In the upright position, the V/Q ratio differs in different parts of the
lung due to the effect of gravity.
At the apex
- Blood flow (Q) is decreased and ventilation (V) is also decreased
but to a lesser extent. Therefore the ratio is increased.
- When perfusion is decreased to zero, the ratio is increased to
infinity (V/Q =V/0 = Infinity).
- Since ventilation > perfusion, the extra air ≡ wasted ventilation (or
dead space ventilation).
At the base
- Blood flow (Q) is increased and ventilation (V) is also increased but
to a lesser extent. Therefore the ratio is decreased.
- Since ventilation < perfusion, the extra blood ≡ wasted perfusion (or
shunt flow).
Effect of lung diseases on V/Q ratio:
- Many lung diseases are characterized by V/Q inequality.
- These may result in either: wasted ventilation (e.g. pulmonary
embolism) or wasted perfusion (e.g. Lung collapse); the ratio is
changed accordingly.
- Remember that, V/Q inequality is the most common cause of
hypoxemia.

Effect of V/Q mismatching on PO2 and PCO2 of alveolar air
 If ventilation to an alveolus is reduced relative to its perfusion (i.e.
less O2 supply from environment and less CO2 removal):
o PO2 in alveoli (PAO2) decreases
o PCO2 in alveoli (PACO2) increases
- This normally occurs in some alveoli at the base of the lung.
 If perfusion to an alveolus is reduced relative to its ventilation (i.e.
less carbon dioxide reaches the alveoli from blood):
o PO2 in alveoli (PAO2) increases
o PCO2 in alveoli (PACO2) decreases
- This normally occurs in some alveoli at apex of the lung.
- The lung apex is the most favorable site of infection for the tubercle
bacilli (because of the high PAO2).
GAS TRANSPORT IN THE BLOOD

TRANSPORT OF OXYGEN
- Oxygen is transported in the blood in two forms:
o Dissolved in plasma ……... 2%
o Bound to hemoglobin..…....98%
Dissolved oxygen:
= Solubility of oxygen x PO2
• Solubility of oxygen = 0.003 ml/100ml blood/mmHg
• Po2 = 100 mmHg (in arterial blood) and 40 mmHg (in venous blood)
- Therefore dissolved oxygen in 100 ml arterial blood=
100 x 0.003 = 0.3 ml oxygen/ 100 ml blood
- Dissolved oxygen in 100 ml venous blood=
40 x 0.003 =0.12 ml oxygen/ 100 ml blood

Remember that PO2 in arteries (PaO2) is actually less than 100
mmHg (= 95 mmHg) because of the physiological shunt.
Oxygen bound to hemoglobin:
- Oxygen binds to hemoglobin in a rapid reversible oxygenation
reaction (iron remains in the ferrous state)
- The reaction takes less than 0.01 s.
- Each gram of Hb can carry up to 1.34 ml oxygen (If 100%
saturated; as in arteries).
- Oxygen bound to Hb in arterial blood can be calculated as follows:
o O2 = [Hb] x 1.34 x (% saturation of Hb with oxygen)
o [Hb] = 15 g/100 ml blood
o There fore O2 = 15 x 1.34 x 100% = 20 ml O2 /100 ml blood
- Oxygen bound to Hb in venous blood can be calculated as follows:
o O2 = [Hb] x 1.34 x (% saturation of Hb with oxygen)
o [Hb] = 15 g/dL
o Therefore O2 = 15 x 1.34 x 75% = 15 ml O2 /100 ml blood
- The relation between Po2 & percent saturation of Hb with oxygen is
explained by the oxygen hemoglobin dissociation curve:
The Oxygen-Hemoglobin Dissociation Curve

- Indicates direct relation between PO2 and % saturation of Hb with
oxygen.
- Sigmoid shaped. (starts slowly, becomes steep in the middle and
then reaches a maximum).
- The sigmoid shape can be explained as follows:
o Oxygen binds to the subunits of Hb successively (not all of them
at the same time).

o The binding with the first subunit facilitates binding with the
second subunit and this facilitates binding with the third subunit &
so on.
o The facilitation occurs due to changes in the configuration of Hb
from the tense (T) form to the relaxed (R) form.
- Therefore, binding:
o Starts slowly: indicating low affinity of Hb to oxygen (occurs when
oxygen is binding to the first subunits).
o Becomes steep in the middle: indicating high affinity of Hb to
oxygen (occurs when oxygen is binding to the other subunits).
The affinity is increased up to 500 folds.
o Reaches maximum at the end (indicating full saturation).
Fig 7.13: The oxygen hemoglobin dissociation curve

Notes to remember from the curve:
 PO2 of 40 mmHg gives oxygen saturation of 75% (as in veins)
 PO2 of 95 mmHg gives oxygen saturation of 97% (as in arteries)
 PO2 of 97 mmHg gives oxygen saturation of 97.5% (as in
oxygenated blood in pulmonary capillaries). Less saturation in
arteries (0.5%) is due to the physiological shunt.
 PO2 of 26 mmHg gives oxygen saturation of 50%. This is known
as the P50.
 The P50 is defined as the PO2 when Hb is 50% saturated with O2.
It is used to describe the affinity of Hb to O 2 (e.g. high P50
indicates low affinity of Hb to O2 whereas low P50 indicates the
reverse.
Affinity of hemoglobin to oxygen:

- The affinity of Hb to oxygen is affected by certain factors. These
factors can shift the curve to the right or to the left.
- The P50 gives information about affinity of hemoglobin to oxygen.
Normal value = 26 mmHg; higher values indicate shift to the right
(low affinity) & lower values indicate shift to the left (high affinity).
Shift to the right:
o Indicates lower affinity of Hb to oxygen (high P50)
o Indicates increased release of oxygen to tissues
o Caused by:
• High carbon dioxide,
• High Hydrogen ions (low pH)
• High 2,3 DPG
• High temperature

- The 2-3 diphosphoglycerate (2,3 DPG) is a product of glycolysis. It
is highly present in RBCs when metabolism is increased. It is also
increased in exercise, high altitude and by some hormones like
growth hormone, thyroid hormones and androgens. Its binding to the
beta chain of Hb decreases the binding of Hb to oxygen).
Shift to the left:
o Indicates increased affinity of Hb to oxygen (low P50)
o Indicates decreased release of oxygen to tissues
o Caused by:
• Low carbon dioxide,
• Low hydrogen ions,
• Low 2,3 DPG (e.g. due to acidosis or in stored blood)
• Low temperature
• Myoglobin
• Hemoglobin F
Fig 7.14: Shifts of the oxygen-hemoglobin dissociation curve

Remember that:
- Shift to the right occurs in tissues, where CO2, H+ & temperature are
high whereas shift to the left occurs in the lung where these factors
are decreased.
- Hb F & Myoglobin have very high affinity to oxygen. They shift the
curve to the left.
- Hb F binds less avidly to 2,3 DPG; this increases its affinity to O2.
- Anemia does not affect the shape of the curve. That’s because PO2
is normal and therefore the % saturation of Hb is normal.
Bohr effect
- The affinity of Hb to oxygen is decreased when the pH of the blood
falls.
- That’s why increase in CO2 content of the blood decreases the
affinity of Hb to O2 & causes shift of the curve to the right.
TRANSPORT OF CARBON DIOXIDE

- Carbon dioxide is transported in 3 forms:
o As Bicarbonate (the main form of transport)
o Bound to proteins (carbamino compounds)
o Dissolved
Dissolved CO2
- The solubility of CO2 is higher than O2 (up to 20 times).
- The dissolved CO2 constitutes about 5% of total CO2 in arterial
blood and 6% of total CO2 in venous blood.
- Generally there is no reaction between CO2 & water in the plasma
(due to absence of carbonic anhydrase enzyme in the plasma).

Transport as Bicarbonate
- This is the main form of CO2 transport in the blood.
- CO2 diffuses inside RBCs and reacts with water in the presence of
carbonic anhydrase enzyme to produce carbonic acid & then
bicarbonate & hydrogen ion.
CO2 + H2O = H2CO3 = HCO3- + H+
- Hydrogen ions are buffered by hemoglobin.
- About 70% of bicarbonate diffuses to the plasma in exchange to
chloride (= Chloride shift).
Fig 7.15: Chloride shift
Remember that:
- Due to diffusion of CO2 into RBCs, the number of active osmotic
particles in RBCs is increased (by either HCO3- or Cl-)
- So, in venous blood water enters RBCs by osmosis, increasing the
size of RBCs. Then it passes out in the lung; when chloride leaves
out and the RBCs return to their normal size in arteries.
- That’s why PCV of venous blood is higher than arterial blood by
about 3%.

Bound to proteins
- CO2 forms carbamino-compounds by binding to proteins (plasma
proteins in plasma and hemoglobin in RBCs).
- About 11% of CO2 in the blood is carried to the lungs as carbamino-
CO2.
Haldane effect
- Deoxy Hb in venous blood binds CO2 more readily than oxy Hb in
arterial blood.
- Therefore binding of oxygen to Hb in the lungs facilitates release of
CO2 from Hb; this is known as the Haldane effect.
- For this reason, arteries (containing oxygenated blood) carry less
carbon dioxide than veins (containing deoxygenated blood).
Summary
- CO2 is transported in plasma as:
o Dissolved
o Carbamino-CO2
o HCO3
- CO2 is transported RBCs as:
o Dissolved
o Carbamino Hb
o HCO3
- About 70% of the HCO3 enters the venous blood in exchange to
chloride (chloride shift).
- PCV of venous blood is higher than arterial blood by about 3%.

CONTROL OF RESPIRATION
- Can be studied as: Neural control and Chemical control
Neural Control
- Two types:
o Involuntary control
- By the respiratory center
o Voluntary control
- By the cerebral cortex
The respiratory center

- Collection of neurons in the medulla & pons
- Arranged into 4 groups:
o Dorsal group
o Ventral group
o Apneustic center
o Pneumotaxic center
The dorsal group
o Found at the dorsal aspect of the medulla.
o It contains inspiratory neurons (it is responsible for inspiration).
o It is called the rhythmicity center because it can discharge
impulses rhythmically.
o The rhythmic discharge is initiated in the pre-Botzinger complex in
the medulla.
The ventral group
o Found in the ventral aspect of the medulla.
o Contains expiratory neurons + some inspiratory neurons.
o Inactive at rest (that’s why expiration occurs passively).

o Inactivated when the dorsal group is stimulated & vice versa
(reciprocal innervation).
o Responsible for forced expiration.
Fig 7.16: The respiratory center
The Apneustic center

o Found in the lower part of the pons.
o Stimulates the dorsal group to increase depth of inspiration.
o Inhibited by: The vagus and the pneumotaxic center.
The Pneumotaxic center
o Found in the upper part of the pons.
o Its function is unknown, may be switching between inspiration &
expiration.
- Functions of the different groups of the respiratory center are

studied in animals by performing sections at various levels in the
brain stem.

Section 1 [below the medulla]
o Results in death if the lesion is above C4. That’s because the
descending impulses from the respiratory center fail to reach
the phrenic nerve which supplies the diaphragm.
Section 2 [between medulla & pons]
o Results in gasping (shallow) respiration. That’s because the
apneustic center fails to increase depth of inspiration.
Section 3 [mid pontine section, + cutting the vagal supply]
o Results in apneustic breathing (deep inspiration). That’s
because the pneumotaxic center fails to inhibit the apneustic
center.
Section 4 [Above pons]
o No effect on involuntary respiration; however, it impairs the
voluntary control of respiration.
Fig 7.17: Sections below and above the respiratory center

Factors affecting the respiratory center
- The respiratory center is affected by impulses coming from:
 Higher centers
• Cerebral cortex
• Hypothalamus
• Limbic system
• Other brain stem centers
 Baroreceptors
 Chemoreceptors
 Lung stretch receptors
 Proprioceptors
 Other receptors
Higher centers
- The cerebral cortex:
o For voluntary modification of respiration
o E.g. voluntary hyperventilation or voluntary apnea
- The hypothalamus (temperature center):
o Stimulates heat loss by increasing respiration
o E.g. panting in dogs
- The limbic system:
o Emotions may affect respiration (e.g. fear)
- Other brain stem centers:
o Stimulation or inhibition of the cardiac or the vasomotor centers
in the medulla, results also in stimulation or inhibition of the
respiratory center (impulses radiate between the centers).
That’s why hyperventilation is associated with tachycardia and
hypoventilation is associated with bradycardia.

The Baroreceptors
- Stretch receptors found in the aortic & the carotid sinuses;
connected to the cardiac & vasomotor centers in the medulla by the
cranial nerves 9 & 10; send inhibitory impulses to these centers when
stimulated by stretch caused by high blood pressure.
- The inhibitory impulses decrease the sympathetic discharge from
these centers to the heart & blood vessels. This lowers the blood
pressure by:
o Decreasing the heart rate
o Decreasing contractility
o Vasodilatation
- The inhibitory impulses also inhibit the respiratory center. For this
reason, hypertension is associated with hypoventilation &
hypotension is associated with hyperventilation but mainly due to
activity of the chemoreceptors.
The Chemoreceptors
- See chemical control of respiration below.
The Proprioceptors
- Found in the joints, ligaments & tendons of muscles.
- Stimulated by movement (even passive movement).
- Send impulses directly to the respiratory center to increase
respiration.
The Lung stretch receptors
- Stretch receptors.
- Found in the smooth muscles of bronchioles.
- Stimulated by stretch during inflation of the lung.
- Send inhibitory impulses through the vagi to stop further inspiration.

- This protective reflex is called Hering Breuer inflation reflex.
- It is not active in humans (except with very high tidal volume).
- There is also Hering Breuer deflation reflex stimulated by deflation
of the lung.
- Here excitatory impulses are carried also through the vagi to restart
inspiration.
Other receptors
(I) receptors:
o Found in upper respiratory tract
o Stimulated by irritants (dust, smoke, ...)
o Mediate coughing reflex, sneezing reflex...
(J) receptors:
o Found in juxtaposition to pulmonary capillaries
o Stimulated when the capillaries become distended with blood
o Function unknown, may be mediation of the sense of dyspnea
Chemical Control
- By chemoreceptors that detect chemical changes in blood or CSF
- There are two types of chemoreceptors:
o Peripheral chemoreceptors
o Central chemoreceptors
The peripheral chemoreceptors
- Special receptors found in: Aortic bodies and Carotid bodies
- Aortic bodies are found in aortic arch and carotid bodies are found
in carotid bifurcation.
- They are stimulated by:
o Hypoxia (the main stimulus)

o Hypercapnia
o Acidosis
- They send excitatory impulses through the cranial nerves 9 & 10 to
stimulate the respiratory center in the medulla.
- This results in hyperventilation to correct the stimulus.
- The blood supply per gram tissue to these structures is very high,
e.g. the carotid bodies receive 2000 ml/100 gram tissue whereas 100
gram tissue in the kidneys receives 420 ml and in the brain receives
54ml. That’s why they can detect minor changes in the chemical
composition of the blood.
The central chemoreceptors

- Found on the anterolateral surface of the medulla; in contact with
the CSF.
Fig 7.18: The central chemoreceptors

- The central chemoreceptors are stimulated by:
o High carbon dioxide (in blood and therefore in CSF)
o High hydrogen ions (in the CSF not that in blood)
- Hydrogen ions in the blood cannot cross the blood brain barrier
“BBB” easily. Hydrogen ions in the CSF are formed from carbon
dioxide as follows: Carbon dioxide crosses the BBB & reacts with
water in the CSF to produce carbonic acid & then dissociates into
bicarbonate & hydrogen ions. Then hydrogen ions in the CSF
stimulate the central chemoreceptors.
- In other words, carbon dioxide stimulates the central
chemoreceptors directly (by CO2 itself) and indirectly (by H+).
Remember that:
 In patients with chronic hypercapnia (e.g. patients with COPD),
respiration is stimulated by hypoxia not hypercapnia (because the
receptors become used to the high CO2).
 Treatment with high pressure O2 in these patients corrects
hypoxia and stops respiration. That’s why they should be treated
with low pressure O2 (e.g. 24% or 28%; not 80% or 100% O2).
HYPOXIA AND CYANOSIS
Hypoxia
 Defined as oxygen deficiency at the level of tissues or low tissue
oxygenation (Notice that hypoxemia is reduction of oxygen in the
blood).
 Classified into 4 types:
–Hypoxic hypoxia
–Anemic hypoxia
–Stagnant hypoxia
–Histotoxic hypoxia
Hypoxic hypoxia
 Oxygen delivery to tissues is reduced because of low oxygenation
of blood.
 This is caused by:
–High altitude,
–Hypoventilation due to:
–Lung diseases
–Respiratory center depression
–Paralysis of respiratory muscles
–Venoarterial shunts
 It is characterized by:
–Low PO2 (in arterial blood)
–Low % saturation of Hb
–Low total oxygen content of the blood
 All these parameters are also low in venous blood.
 Oxygen therapy is useful in this type of hypoxia; however, when
the cause of hypoxia is veoarterial shunt, oxygen therapy fails to
increase oxygen content of the blood. This differentiates
venoarterial shunt from other types of hypoxia.
Anemic hypoxia
 Decreased oxygen carrying capacity of the blood as a result of:
–Decreased Hb (e.g. iron deficiency anemia).
–Abnormal Hb (e.g. methemoglobinaemia).
–Unavailable Hb (e.g. carbon monoxide poisoning).
 Characterized by:
–Normal PO2 in arterial blood

–Normal % saturation of Hb
–Low total oxygen content of the blood
 These parameters are lower than normal in venous blood.
 Oxygen therapy is slightly useful in this type of hypoxia because it
only increases dissolved oxygen.
 Heavy smoking in a closed room may cause coma due to carbon
monoxide poisoning.
 Treatment of carbon monoxide poisoning requires administration
of oxygen within a container under high pressure “hyperbaric
oxygen”. That’s because the affinity of hemoglobin to CO is
higher than oxygen by 250 times.
Histotoxic hypoxia
 Inability of the tissues to take oxygen as a result of:
–Poisoning of the oxidative enzymes (cyanide poisoning)
–Long distance between blood & cells (edema)
–Normal PO2 (in arterial blood)
–Normal % saturation of Hb
–Normal total oxygen content of the blood
 All these parameters are higher than normal in venous blood.
 Oxygen therapy is not useful in this type of hypoxia.
Stagnant hypoxia
 Reduced blood flow to tissues as a result of:
–Obstruction of a supplying vessel (localized hypoxia)
–Heart failure (generalized hypoxia)
–Normal or low PO2 (in arterial blood)

–Normal or low % saturation of Hb
–Normal or low total oxygen of blood
 When heart failure is mild, these parameters are low in venous
blood because of high uptake of oxygen in tissues; and then
corrected in the lungs to return to normal.
 In moderate-severe heart failure, all these parameters are lower
than normal in both venous and arterial blood; because the lungs
fail to oxygenate blood back to normal.
 Oxygen therapy is useful in this type of hypoxia.
CYANOSIS
 Bluish coloration of the skin & mucus membranes
o Appears when the concentration of reduced hemoglobin is
more than 5g/dL. For this reason it is rarely seen in anemia
and commonly seen in polycythemia.
 Types of cyanosis:
–Peripheral
o Appears at the tips of the fingers
o Due to peripheral vasoconstriction in response to cold
–Central
o Appears in the skin & mucus membranes
o Due to causes of hypoxic hypoxia & stagnant hypoxia
 Cyanosis is extremely rare in anemic hypoxia (anemic patients
may die when > 5g/dL of Hb become deoxygenated). It is also
extremely rare in CO poisoning (also anemic hypoxia) because it
gives reddish color. No cyanosis occurs in histotoxic hypoxia.
 Patients with methemoglobinemia may acquire a dark color that
resembles cyanosis.

LUNG FUNCTION TESTS
Importance of lung function tests
- Depending on history and examination to diagnose a respiratory
problem, without objective measurement of lung function, may result
in wrong diagnosis.
- This was confirmed by many studies that recommend the use of
lung function tests as objective tools for:
o Diagnosis of respiratory diseases
o Follow up of respiratory problems
o Assessment of fitness for anesthesia
o Insurance purposes
o Clinical research
Types of lung function tests:
o Tests of mechanical properties
o Gas diffusion
o Blood gas interpretation
o Exercise testing
 Tests of mechanical properties
o Lung volumes and capacities
o Spirometry & the flow volume loops
o The peak expiratory flow
o Static compliance
o Airway resistance
o Respiratory muscle power
- This is a brief account about some of the devices and techniques

used in lung function tests:

MEASUREMENT OF LUNG VOLUMES AND CAPACITIES
Benedict Roth spirometer
- Measures the tidal volume, inspiratory reserve volume, expiratory
reserve volume and the vital capacity (see above).
The helium dilution technique
- For measurement of many volumes and capacities especially total
lung capacity, residual volume and functional residual capacity.
- This method depends on the fact that helium does not diffuses
through the respiratory membrane into the blood.
- The subject is connected to a helium container at the end of:
o Maximum expiration (when measuring the residual volume)
o Tidal expiration (when measuring the functional residual capacity)
o Maximum inspiration (when measuring the total lung capacity)
- The subject breathes into a bag containing a known volume and
concentration of Helium (V1 & C1). This changes the concentration
of helium to C2 and expands the volume to V1 + the volume being
measured in the lung.
- Since C1 x V1= C2 x V2; V2 can be obtained by calculation.
- V2 = V1 + the required volume in the lung.
- Therefore the required volume can be obtained.
Body plethysmography (or body box)
- For measurement of all types of lung volumes and capacities
including the total lung capacity, residual volume and functional
residual capacity.
- Depends on the equation of gases: P1V1 = PV
- The subject sits within an airtight box. He breathes through a
mouthpiece that can be closed electrically (For example when it is

closed at the end of normal expiration, the functional residual
capacity (FRC) can be measured). Then the subject inhales against
the closed shutter; his chest volume is increased while the volume
within the box is decreased. The pressure within the box can be
measured by a device connected to the box. The pressure within the
lung can be measured by a device within the mouth.
- At first the change in volume within the box is calculated using the
formula (P1V1 = PV). P1 is the pressure within the box (known), V1 is
the volume within the box (known), P is the new volume within the
box after inspiration (known), and V is the new volume within the box
after inspiration (unknown). The change in volume within the box =
V1 – V = X; this equals the change in volume within the lung.
- Then the formula (P1V1 = PV) is used again to calculate the lung
volume before inspiration (the FRC). P1 is the intrapulmonary
pressure before inspiration (known), V1 is the FRC (unknown), P is
the new intrapulmonary pressure at the end of inspiration (known),
and V is the new volume within the lung at the end of inspiration (=
FRC + X). X is known from the previous step; therefore the formula is
solved to obtain the FRC.
Single breath nitrogen washout test
- For measurement of the, residual volume, functional residual
capacity, uneven ventilation, anatomical dead space and closing
volume.
- The subject takes full inspiration of pure oxygen (100% O 2), then he
exhales slowly (not more than 0.5 L/S).
- A nitrogen analyzer near his mouth detects nitrogen concentration
in expired air.

- Four phases appear when plotting nitrogen% against lung volume
as follows:
Fig 7.19
 Phase I = pure oxygen (from the dead space)

 Phase II = nitrogen + oxygen (mixture of dead space air +
alveolar air)
 Phase III = plateau of nitrogen (alveolar air); flat in normal people
& has increased slope in uneven ventilation
 Phase IV = rapid rise in [N2] from upper alveoli (following closure
of the distal airways).
- Dead space volume = volume of phase I + mid portion of phase II
- Phase III terminates at the closing volume
- The closing volume is the volume within the lung when the distal
airways begin to close because of less intra-mural pressure.
- The rise in the slope of phase IV and to some extent phase III is
due to expiration of air in the upper portions of the lung which contain
higher proportion of nitrogen (i.e. less diluted by the inspired oxygen).

Spirometry (by the vitalograph or the digital spirometer)
- For measurement of the forced vital capacity (FVC), the forced
expiratory volume in the first second (FEV1) and the FEV1/FVC ratio
(read the section of volumes and capacities above).
- Other parameters and tests that can be measured by spirometry
include:
The forced expiratory volume 25-75% (FEF 25-75)
- The forced expiratory flow at the middle of the FVC
- Normally equals or exceeds 50% of the predicted FVC
- Has good correlation with the FEV1 in obstructive lung diseases.
- Has the advantage that it avoids the effort dependent first quarter of
the FVC.
- May diagnose mild airway obstruction while other spirometric
parameters are normal.
Bronchodilator studies
- See reversibility below
Bronchial Provocation Testing (challenge tests)
- These tests measure the response of the airways to chemical
substances known to cause broncho-constriction.
- This determines the extent of airway hyper-responsiveness which is
a characteristic of asthma.
- They are used to support the diagnosis of asthma when the results
of spirometry are not conclusive.
- The subject inhales increasing concentrations of a provocative
substance, followed each time by spirometry.
- A 20% fall in FEV1 is considered as a positive test.
- Examples of provocative substances: histamine & methacholine.

- The provocative dose needed to decrease FEV1 by 20% is called
PD20%
- PD20% is lower in patients with bronchial hyper-responsiveness
than normal individuals.
- Other indirect provocative tests include exercise, adenosine and
non isotonic saline.
The spirometric flow volume loops
- The flow volume loops are a plot of inspiratory and expiratory flow
against volume. Flow is recorded on the Y-axis while volume is
recorded on the X-axis.
- When a subject completes his forced expiration during the FVC
maneuver, he immediately takes a deep inspiration to obtain a loop
as appears in the following figure:
Fig 7.20: the flow volume loop

- The normal expiratory portion of the flow-volume curve is
characterized by a rapid rise to the peak flow rate, followed by a
nearly linear fall in flow as the patient exhales towards the residual
volume.
- Changes in the contour of the loop can aid in the diagnosis of
obstructive and restrictive lung diseases. However, it is not the
primary diagnostic tool of these disorders.
The peak expiratory flow (by the Peak Flow Meter)

- The PEF is the highest velocity of air flow achieved transiently
during forced expiration from the total lung capacity (i.e. after max
inspiration).
- The device used (the peak flow meter) is small, portable &
inexpensive device. It is manufactured in many designs: Wright peak
flow meter, Mini Wright peak flow meter and other designs
Fig 7.21: The peak flow meter

- For interpretation of PEF readings (and other lung function test
parameters), it should be compared to predicted values (reference
values) that vary according to age, sex and body size (height).
- Normal value in an average adult male is about 600 L/min (or 10
L/s). Therefore a value of 300 L/min is low since it is 50% of
expected. Values more than or equal 80% of expected are normal.
- The PEF readings are used for:
1- Diagnosis of asthma (by variability and/or reversibility)
Variability:
- The PEF readings are normally variable. Lowest values are
obtained early in the morning (see the bronchial tone).
- Variability more than 20% indicates asthma. It is detected by
measuring and recording the PEF twice daily (morning and evening)
for two weeks. Variability= Highest PEF – Lowest PEF/Highest PEF
Fig 7.22: PEF variability

Reversibility:
- The PEF is measured before and then 15 minutes after
administration of salbutamol (bronchodilator).
- Improvement of the PEF reading by more than 15% indicates
reversible airways, which is an important characteristic of asthma.
- The FEV1 is used more than the PEF for detection of reversibility,
because it is more reproducible. Here improvement of the FEV1 by
more than 12% (or 200 ml) indicates reversibility.
2- Assessment of severity of asthma
- Reduction of PEF to less than 50% of expected indicates acute
severe asthma whereas reduction to less than 33% of expected
indicates life threatening asthma.
3- Other uses of the PEF
- The PEF is used to guide therapeutic decisions in asthmatic
patients. It is also used to measure the degree of response to
therapy (i.e. follow up).
Lung compliance
- Read about compliance above
Airway resistance
- The force needed to inflate the lungs is greater than that needed to
overcome the elastic recoil alone.
- The additional impedance is the airway resistance.
- The airway resistance is defined as the pressure difference
between the alveoli and the mouth per unit of air flow. It is generated
from friction between air and mucosa.

- Air way resistance = Mouth pressure –alveolar pressure/flow of air;
(Alveolar pressure is measured by the body plethysmograph).
- Airway resistance is higher when the airflow is turbulent than when
it is laminar. It is also increased by many other factors, including the
factors that increase the bronchial tone.
Respiratory muscle power

- Investigated by many tests to exclude respiratory muscle
weakness. These include the following tests:
Vital capacity
- It is a useful screening test to exclude respiratory muscle
weakness. When measured in an erect and then supine posture, the
difference is within 5%. This is because the abdominal viscera in
supine posture exert more loads on the respiratory muscles.
- A difference more than 25% indicates respiratory muscle weakness.
Maximum inspiratory pressure
- Measured during maximum inspiratory effort against an occluded
airway at RV or FRC. Normal value varies with age and sex. Values
above 80 cm H2O excludes respiratory muscle weakness.
Maximum expiratory pressure
- Measures the power of expiratory muscles at TLC.
- It is less useful in predicting the ability to breathe.
Transdiaphragmatic pressure
- Measures diaphragmatic function.
- Estimated from difference between pleural and abdominal
pressures (i.e. esophageal and gastric pressures).

- Balloon catheters are used for measurement during spontaneous
breathing and during phrenic nerve stimulation.
Gas Diffusion studies

The transfer factor:
- Measures the transfer of carbon monoxide (CO) across the
respiratory membrane, from the alveoli to the RBCs.
- It is measured by many techniques. However, the single breath
technique is the best. Here the subject exhales maximally and then
inspires the test gas (containing 0.3% CO, 10% Helium in addition to
oxygen and nitrogen) to the total lung capacity.
- After 10 s he exhales into a bag, after discarding the first 0.5 L of
expired air.
- The sample is analyzed for CO and Helium. The change in
concentration of CO and Helium is used to calculate the transfer
factor.
- The transfer factor obtained by this method is a measure of the
diffusing capacity of the lung for carbon monoxide (D LCO). It is also
known as (TLCO), the transfer factor of the lung for CO.
- It is affected by diseases that affect the thickness of the respiratory
membrane and the V/Q ratio.
- For example it is reduced in lung fibrosis, emphysema, pulmonary
embolism …
- When the DLCO is corrected for differences in lung volume, it is
known as the transfer coefficient (KCO); (i.e. KCO = DLCO /alveolar
volume).

Blood gas interpretation
- In addition to data obtained by the tests that assess mechanical
properties of the lung, diagnosis of respiratory problems may need
blood gas interpretation.
- This requires information about:
o Blood oxygenation (obtained by arterial blood gas analysis )
o Oxygen saturation of hemoglobin (see below)
o V/Q distribution (read about V/Q ratio above)
o Acid base status (read volume 2)
Pulse oximetry:
- The pulse oximeter probes, placed on fingers or earlobes are used
widely to assess oxygen saturation of Hb (SpO2).
- Light originating from the oximeter probe is absorbed by Hb at a
degree proportional to its level of oxygenation. This is calculated by a
processor to obtain the degree of saturation.
- Normal readings are higher than 95%. Readings lower than 88%
raises the suspicion of hypoxemia and indicates the need for arterial
blood gas analysis (ABG).
- There are certain conditions that give false estimation of the oxygen
saturation when using the pulse oximeter. For example
Carboxyhemoglobin and Methemoglobin give overestimation of O 2
saturation (higher readings) while fingernail polish and motion
artifacts underestimate the O2 saturation (lower readings).

Exercise testing
- The cardiopulmonary exercise test is used to assess dyspnea that’s
not explained by other lung function tests. It is also used to assess
fitness for anesthesia, disability and response to therapy.
- The test assesses the responses of the respiratory, cardiovascular
and muscular systems to increasing workload offered by a bicycle
ergometer or treadmill.
Fig 7.23: Body plethysmography

1. At the end of normal inspiration:
a. Intra-alveolar pressure equals -6 mmHg
b. Intra-pleural pressure equals zero when the glottis is open
c. The transverse diameter of the chest is increased by about 3 cm
d. The accessory muscles of inspiration are contracted
e. The abdominal muscles are relaxed
2. Surfactant:
a. Is a glycoprotein
b. Is produced in the fetus early in pregnancy
c. Prevents development of pulmonary edema
d. Acts to increase surface tension of fluid in the alveoli
e. Deficiency causes hypoventilation
3. Carbon dioxide (CO2):
a. Partial pressure in venous blood is about 40 mmHg
b. Partial pressure in arterial blood is about 100 mmHg
c. Is less soluble than oxygen in body fluids
d. Is not carried in hemoglobin
e. Is not the primary stimulus for hyperventilation in metabolic acidosis
4. Hypoxic hypoxia is caused by:
a. Heart failure
b. Cyanide poisoning
c. Carbon monoxide poisoning
d. Lung fibrosis
e. Anemia
5. Bronchodilatation is caused by:
a. ß blockers
b. Acetylcholine
c. Leukotriens
d. VIP
e. Substance P
6. Oxygen - Hemoglobin Dissociation curve is shifted to the right by:
a. Low CO2
b. Low 2,3 DPG
c. Low temperature
d. Low pH
e. Low metabolism
7. Acute hypoventilation increases:
a. PO2
b. PCO2
c. pH
d. Hemoglobin concentration
e. Blood viscosity

8. The main form of carbon dioxide transport in the blood is:
a. Bound to hemoglobin
b. Bound to plasma protein
c. Dissolved in plasma
d. Bicarbonate
e. As carbonic acid
9. Volume of air that can be expired by maximum expiration
following maximum inspiration is the:
a. Tidal volume
b. Inspiratory reserve volume
c. Vital capacity
d. Expiratory reserve volume
e. Residual volume
10. Gas exchange in the lungs is increased by:
a. increasing thickness of the respiratory membrane
b. decreasing surface area of the respiratory membrane
c. increasing the pressure gradient of a gas between the two sides of
the respiratory membrane
d. decreasing the diffusion coefficient of the gas
e. hypoventilation
11. Gas exchange in the lungs is increased by:
a. Increasing thickness of the respiratory membrane
b. Decreasing surface area of the respiratory membrane
c. Increasing the pressure gradient across the respiratory membrane
d. Decreasing the diffusion coefficient of the gas
e. Hypoventilation
12. The diffusing capacity of the respiratory membrane:
a. Is not affected by thickness of the respiratory membrane
b. Increases in exercise
c. Is normal in anemia
d. Is best measured using helium
e. Is best measured using carbon dioxide
13. The partial pressure of oxygen in venous blood is:
a. About 60 mmHg
b. Normal in stagnant hypoxia
c. Higher than normal in histotoxic hypoxia
d. The same in all veins in the body
e. Gives accurate information about gas exchange in the lung
14. The functional residual capacity is best measured by:
a. Helium dilution method
b. Plethysmography
c. Challenge test
d. Spirometry
e. Nitrogen washout method

15. Which of the following does not occur as blood passes through
systemic capillaries:
a. Hematocrit increases
b. Hemoglobin affinity to oxygen decreases
c. Viscosity decreases
d. pH decreases
e. red blood cell size increases
16. Histotoxic hypoxia is caused by:
a. Heart failure
b. Cyanide poisoning
c. Carbon monoxide poisoning
d. Ascending to high altitude
e. Anemia
17. Normal quiet expiration is associated with contraction of:
a. The diaphragm
b. Internal intercostal muscles
c. External intercostal muscles
d. Abdominal muscles
18. Reduced affinity of Hemoglobin to O2:
a. Is known as the haldane’s effect
b. Favors uptake of O2 at the lung
c. Is caused by low (H+)
d. Indicated by high P50
e. Does not occur in Bohr’s effect
19. When TV is 500 ml, DS volume is 150 ml, RR is 10 breath/min and
COP is 5 L/min. All the following are correct except:
a. V/Q is 1
b. Pulmonary ventilation is 5 L/min
c. Vital capacity cannot be calculated
d. Dead space ventilation is 1.5 L/min
e. Alveolar ventilation is 4.2 L/min
20. Regarding activity of carotid bodies, which of these is not correct:
a. They are highly stimulated during hyperpnoea of high altitudes
b. Glomus cells release dopamine in response to hypoxia
c. Peripheral chemoreceptors are activated by low hemoglobin
d. They are not the major site of CO2 action on ventilation
e. Hypoxia causes closure of special type of potassium channels
21. High in 2-3 diphosphoglycerate is found in all the following except:
a. Exercise
b. High basal metabolic rate
c. Stored blood
d. High altitudes
e. Hyperthyroidism

22. The physiologic dead space:
a. Is exactly equal to the anatomical dead space in normal people
b. Decreases during exercise
c. Is primarily due to the presence of the physiological shunt
d. Is normally about 50% of pulmonary ventilation
e. Is measured by the single breath nitrogen analysis
23. Cyanosis is:
a. Always present in fingers during cold exposure
b. Usually caused by carboxy-hemoglobin
c. Commonly seen in severe stagnant hypoxia
d. Rarely occurs in severe histotoxic hypoxia
e. Never expected in anemic hypoxia
24. The rhythemicity center:
a. Is located in the pons
b. Its damage causes apnoea
c. Activity causes expiration
d. Activity is increased by pneumotaxic center
e. Activity is increased by a rise in blood pressure
25. The functional residual capacity of an average adult male is about:
a. 1 liter
b. 2 liters
c. 3 liters
d. 3.5 liters
e. 4 liters
26. Which of the following is expected to be lower than normal in
obstructive lung disease:
a. TV
b. FVC
c. RV
d. FEF25-75
e. FRC
27. When total lung capacity 6 liters, vital capacity 4 liters, tidal
volume 0.5 liter, the residual volume is:
a. 1.5 liter
b. 2 liters
c. 2.5 liters
d. 3.5 liters
e. 1 liter
28. During normal quiet breathing:
a. The intrapelural pressure is always negative
b. Expiration is an active process
c. The antero-posterior diameter of the chest changes by 4 cm
d. The apex and base of the lung are equally ventilated
e. The apex and base of the lung are equally perfused

29. Which of the following is not expected in a patient with anemia:
a. Normal PAO2
b. Normal PaO2
c. Normal % of Hb saturation with oxygen
d. Low oxygen carrying capacity of blood
e. High P50 of O2-Hb dissociation curve
30. At an altitude where the atmospheric pressure 600 mm Hg, the
partial pressure of O2 in dry air is approximately:
a. 120 mmHg
b. 125 mmHg
c. 130 mmHg
d. 135 mmHg
e. 150 mmHg
31. Carbon dioxide (CO2):
a. Partial pressure in venous blood is about 40 mmhg
b. Partial pressure in arterial blood is about 100 mmhg
c. Is more soluble than oxygen in body fluids
d. Is carried mainly in hemoglobin
e. Diffuses through biological membranes less easily than oxygen
32. ventilation is most sensitive to changes in:
a. pH of arterial blood
b. PO2 in arterial blood
c. Oxygen concentration in arterial blood
d. PCO2 in arterial blood
e. Noreadrenaline
33. Regarding the normal oxygen hemoglobin dissociation curve,
which of the following relations is not correct:
a. PO2 40 - percent saturation 75
b. PO2 60 - percent saturation 90
c. PO2 95 - percent saturation 98
d. PO2 50 - percent saturation 50
e. PO2 500 - percent saturation 100
Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Answer e c e d d d b d c c c b
Question 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24.
Answer c b c b e d e c c b c b
Question 25. 26. 27. 28. 29. 30. 31. 32. 33.
Answer b d b a e b c d d

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2010/548 :‫رقم االيداع‬

CHAPTER (8)
THE GASTROINTESTINAL TRACT
INTRODUCTION
- Also known as the digestive tract, alimentary tract, or gut.
Functions of the Gastro-intestinal tract (GIT):
- Breaks down complex food particles into simpler ones (Digestion).
- Transports products of digestion to the blood stream (Absorption).
- Expels the remaining waste to outside of the body (Excretion).
Structure of the GIT:
o Organs:
 Upper GIT (mouth, pharynx, esophagus and stomach)
 Lower GIT (small intestine, large intestine and anus)
o Associated glands:
1- Salivary glands 2- Pancreas 3- Liver
Fig 8.1: Structure of the GIT
The core of medical physiology (vol 2) ed 2 1

Histology of the GIT:
- The wall of the GIT consists of the following layers:
1- Mucosa (epithelium, lamina propria & muscularis mucosae)
2- Submucosa
3- Muscular layer: (inner circular & outer longitudinal)
4- Serosa (mesothelium)
Fig 8.2: Histology of the GIT
Control of the GIT:

o Neural control by:
- Extrinsic nerves (Autonomic nervous system)
- Intrinsic nerves (Enteric nervous system)
o Hormonal control by:
- Peptide hormones released by endocrine cells scattered
throughout the GIT.
- These hormones include gastrin, secretin, cholecystokinin-
pancreozymin “CCK-PZ”, vasoactive intestinal polypeptide “VIP”,
somatostatin and other hormones.

The autonomic nervous system: “Sympathetic and parasympathetic”
o The sympathetic:
- Inhibits GIT motility by relaxing walls & contracting sphincters.
- Inhibits GIT secretion.
o The parasympathetic:
- Stimulates GIT motility by contracting walls & relaxing sphincters.
- Stimulates GIT secretion.
The enteric nervous system

- It is a part of the nervous system consisting of large number of
neurons that form networks within the wall of the GIT.
- The neurons are distributed into two plexuses (see fig 8.2):
o The submucus plexus: Also known as Meissner’s plexus. It is
found in the submucus layer to control GIT secretion.
o The myenteric plexus: Also known as Auerbach’s plexus. It is
found between the 2 muscular layers to control GIT motility.
Remember that: The enteric nervous system (ENS) is connected with
the autonomic nervous system. Through this connection, the
parasympathetic increases motility & secretion whereas the
sympathetic decreases motility & secretion.
- This connection is not essential for the function of the enteric nervous
system because it can act independently after cutting the sympathetic
and the parasympathetic innervations.
- That is why the enteric nervous system may be regarded as a second
brain.
- The neurotransmitters released by the neurons of the ENS include
vasoactive intestinal polypeptide “VIP”, substance P, nitric oxide “NO”
and others.

THE MOUTH
- Also known as the buccal cavity or the oral cavity.
Functions of the mouth:
1- Orifice for food and water intake.
2- Mastication "or chewing" (the process by which food is crushed by
teeth into smaller parts to increase its surface area for the action of the
digestive enzymes).
3- Mixes food with saliva.
4- Initiates swallowing.
Mastication
- It is started and stopped voluntarily; however, it proceeds as an
involuntary reflex.
- The involuntary reflex is initiated by presence of food in the mouth; this
causes reflex inhibition of muscles of mastication, the lower jaw drops
causing a stretch reflex that contracts muscles of mastication and closes
the jaw. The compressed food within the mouth again causes reflex
inhibition of the same muscles followed by dropping of the jaw and then
reflex contraction of the muscles & so on the cycle repeats itself.
- The muscles of mastication are the temporalis, the masseter and the
pterygoid muscles. They are supplied by the fifth cranial nerve.
SALIVA
- Fluid in the mouth produced by the following salivary glands:
1- The parotid gland: The largest gland. Secretes 20-25% of saliva
2- The submandibular gland: The main gland. Secretes 70% of saliva
3- The sublingual gland: The smallest gland. Secretes 5% of saliva
4- Minute glands in the mouth and pharynx: Secrete 5% of saliva

Fig 8.3: Major salivary glands
- Each salivary gland is an exocrine gland consisting of acini and ducts

- The acini have one or two types of cells: Serous cells (secrete water,
electrolytes & enzymes) & mucus cells (secrete mucus)
- Each acinus may be purely serous, purely mucus or mixed, for example:
o Acini of the parotid glands are purely serous
o Acini of the submandibular glands are mixed
o Acini of the sublingual glands are mixed but mainly mucus
o Acini of the minute glands in the mouth & pharynx are purely mucus
except Ebner’s glands in the circumvallate papillae of the tongue,
which secrete serous fluid.
- The ducts are intercalated ducts that join to form striated ducts and then
a main secretory duct that opens in the mouth.
Fig 8.4: Acini and ducts of an exocrine gland

Characteristics of saliva:
- Volume: 0.5 - 1.5 L/day.
- Osmolarity: hypotonic (due to aldosterone action, see below).
- pH: ranges between 6 & 7. It becomes alkaline (rises up to 8) in high
rates of secretion.
Contents:
- Water
- Inorganic substances
- Organic substances
o The inorganic substances are electrolytes (Na+, K+, Cl-, HCO3- …)

o The organic substances include the following:
- Mucus (glycoprotein, lubricates food & protects the oral mucosa)
- Immunoglobulins (IgA)
- Proline rich proteins (protect tooth enamel)
- Lactoferrin (bacteriostatic substance, binds iron)
- Lysozyme (bactericidal substance)
- Carbonic anhydrase enzyme
- Digestive enzymes:
• α amylase (ptyaline): for digestion of starch
• Lingual lipase: from Ebner’s glands of the tongue; for digestion
of lipids
- ABO blood group antigens (antigen H +/- A &/or B)
Remember that: The ABO blood group antigens are present in saliva of
about 80% of individuals who are known as “secretors”; whereas those
who do not secrete these antigens in saliva are known as “non-secretors.”
- It is worth noting that the non-secretors have higher incidence of oral
disease, peptic ulcer & diabetes than the secretors.

Changes in ionic composition of saliva:
- Saliva is secreted by acinar cells as isotonic fluid. In the ducts, Na+ and
Cl- are absorbed whereas K+ and HCO3- are secreted.
- Aldosterone stimulates Na+ absorption and K+ secretion; however, Na+ is
not followed by water that is why saliva becomes hypotonic.
- When the rate of salivary flow through the ducts is very high, there is less
time for this exchange to occur, that’s why concentrations of Na+ & Cl- are
increased (Na+ & Cl- concentrations in saliva are flow dependent).
- The concentrations of potassium and bicarbonate vary greatly in different
species.
- The pH of saliva is also flow dependent (like sodium & chloride). It is high
in rapid rates of secretion and low in slow rates of secretion (it is thought
that as the rate of saliva production increases, more bicarbonate ion is
produced as a by-product of cell metabolism).
Functions of saliva:
1- Protection against microorganisms by mucus, lysozyme, lactoferrin and
IgA antibodies
2- Digestion of carbohydrates by α amylase and lipids by lingual lipase
3- Lubrication to facilitate swallowing, speech and taste
4- Buffer to neutralize gastric acid during vomiting and to relieve heartburn
5- Excretion of certain substances like mercury, iodide and lead
Control of saliva
- Exclusively neural (i.e. there is no hormonal control), by two reflexes:
 Conditioned reflex
 Non-conditioned reflexe
- The conditioned reflex “or response”:
- Here, sight, smell or even thoughts about appetizing food stimulate
salivary secretion.

- The term “conditioned response” indicates a reaction that has been
acquired by learning. It was first described by Pavlov in the 1890s.
- In his famous experiment, Pavlov used a bell to call a dog to his meal
and, after a few repetitions; the dog learned that the bell sound is
followed by food; so it started to salivate in response to the bell sound.
- The excitatory impulses that travel from the salivary nuclei in the
medulla to supply the salivary glands are carried through:
 The chorda tympani branch of the facial nerve (VII): The
preganglionic neurons relay in the submandibular ganglion, then
postganglionic supply the submandibular & sublingual glands
 The glossopharyngeal nerve (IX): The preganglionic neurons relay
in the otic ganglion, then postganglionic supply the parotid gland
- The non-conditioned reflex:
- Presence of food in the mouth stimulates salivary secretion.
- Components of this neural reflex include:
 Afferents: from taste receptors in the mouth
 Center: salivary nuclei in the medulla (superior & inferior)
 Efferents: the glossopharyngeal & the facial nerves to the salivary
glands
- Other factors affecting salivary secretion:
1- Sympathetic stimulation: Increases secretion (small amount, mainly
mucus) and causes vasoconstriction
2- Parasympathetic stimulation: Increases secretion (large amount,
watery) and causes vasodilatation. The vasodilatation is mediated by
VIP not acetylcholine; that is why it is not blocked by atropine
3- Muscarinic blockers like “atropine”: Decreases secretion (results in
dry mouth) by blocking acetylcholine. Atropine injection is used before

anaesthesia to inhibit salivary secretion and keep the mouth dry. This
allows insertion of the endotracheal tube through the mouth with
minimal risk of saliva aspiration into the respiratory system
4- Dehydration: Decreases secretion
5- Sleep: Decreases secretion to a very low level
Abnormal salivary secretion:

Xerostomia:
= Dry mouth, due to lack of saliva. It results in difficulty in speech and
swallowing, halitosis (unpleasant odor exhaled in breathing), dental caries
and increased susceptibility to oral infections.
- It is caused by:
o Dehydration (as in uncontrolled diabetes)
o Sjogren’s syndrome (caused by auto-antibodies directed against the
lacrimal and salivary glands resulting in absent tears and dry mouth
(primary Sjogren’s). It may be associated with a connective tissue
disease like rheumatoid arthritis (secondary Sjogren’s). It is more
common in females.
o Radiation (also destroys the salivary glands)
o Drugs (anticholinergics, antidepressants …)
Ptyalism:
= Drooling of saliva to outside the mouth; due to either increased
production or decreased swallowing.
- Although it may occur normally (e.g. in children due to teething), it may
indicate acute poisoning, tonsillitis retropharyngeal abscess or a
neurological problem like Parkinsonism.

THE PHARYNX & THE ESOPHAGUS
THE PHARYNX
- Lies immediately posterior to the mouth and the nasal cavity
- Common route for both air & food
- Involved in vocalization and in the swallowing reflex
- Divided into three parts: Nasopharytnx (posterior to the nasal cavity),
Oropharynx (posterior to the oral cavity) and Laryngopharynx (extends
down to the larynx and the esophagus).
Fig 8.5: The pharynx
Swallowing Reflex
- Swallowing (or deglutition) is the process by which solids or liquids in the
mouth reach the stomach through the pharynx & the esophagus.
- It occurs in three stages: Buccal (voluntary), pharyngeal (involuntary) and
esophageal (involuntary).
 The Buccal stage:
- The tongue moves upwards & backwards to propel the bolus into the
pharynx while the soft palate rises to close the nasopharynx.
- The larynx starts to rise. The lips & jaw should be closed (swallowing is
difficult when they are open).

 The Pharyngeal stage:
- The bolus is pushed backwards by the tongue against the epiglottis.
- The epiglottis bends over the larynx to cover its opening; however, this
bending is not essential to close the larynx since it is closed by other
factors like contraction of the glottis (its upper part) and approximation of
the vocal cords (adduction of vocal cords).
- The swallowing reflex is initiated. The reflex components include:
o Receptors: in the wall of the pharynx
o Afferents: cranial nerves (5, 9 & 10)
o Center: swallowing center in the medulla
o Efferents: cranial nerves (5, 7 & 12)
o Effectors: muscles of the pharynx, larynx & tongue
o Response: coordinated contractions to propel the bolus towards
the esophagus, avoiding the larynx, with inhibition of respiration.
- The upper esophageal sphincter opens for only one second to allow
entry of the bolus into the esophagus.
 The esophageal stage:
- Contraction of the upper esophageal sphincter proceeds down as
primary peristalsis. If the bolus is sticky or too large, secondary peristalsis
occurs to move the remnants towards the lower esophageal sphincter.
- Vagal impulses during swallowing relax the lower esophageal sphincter
to allow entry of the bolus into the stomach whereas vagal impulses
between meals close the lower esophageal sphincter.
Peristalsis:
- Occurs in all parts of the GIT starting from the pharynx.
- In peristalsis, stretch of the wall of the esophagus results in contraction
behind the bolus (by release of acetylcholine and substance P) and
relaxation in front of it (by release of NO, VIP or ATP).

- This pushes the bolus downwards & then the process repeats itself.
- It is integrated in the myenteric plexus, increased by parasympathetic
stimulation, and decreased by sympathetic stimulation.
- Rate of peristalsis in the esophagus = 4 cm/s.
THE ESOPHAGUS
- Connects the pharynx to the cardiac part of the stomach.
- Ranges from 25 to 35 cm in adults.
- Guarded by two sphincters: The upper esophageal sphincter (UES) and
the lower esophageal sphincter (LES)
Fig 8.6: The esophagus
The upper esophageal sphincter (UES):

- The upper 3cm of the esophagus form the UES. Unlike the lower
sphincter, it is an “anatomical sphincter” (formed by the cricopharyngeal
muscle; and it is known as “the cricopharyngeal sphincter”. It is closed at
rest at a high pressure (40-100 mmHg). It opens for one second during
swallowing.
The lower esophageal sphincter (LES):
- The lowest 3 cm of the esophagus form the LES. It is not formed by a
definite muscle (= Physiological sphincter). It is an area of high pressure

(15-35mmHg) when compared to the rest of the esophagus, which is sub
atmospheric (except at the UES). It is closed at rest and opens for few
seconds with swallowing.
- Factors, which close the lower esophageal sphincter:
o Gastrin, the vagus (between meals) & acetylcholine
- Factors, which open the lower esophageal sphincter:
o Hormonal or humoral factors: Secretin, CCK, VIP & NO
o Neural factors: the vagus (during swallowing)
o Other factors: Coffee, alcohol, smoking, excess amounts of
vitamin C, chocolate, milk & fat
Competence of the lower esophageal sphincter (LES):
- Although there is no definite muscle to form the LES, it is competent in
preventing reflux of gastric contents into the esophagus.
- This competence is due to the following factors:
 Its high resting pressure (15-35 mmHg).
 The intra-abdominal location which is compressed from outside by high
pressure (this is unlike the intra-thoracic part of the esophagus which is
surrounded by the negative intrapleural pressure).
 The crural fibers of the diaphragm, which act as an external sphincter
& cause narrowing of the esophagus.
 The mucosal folds of the stomach (act as valves that close the opening
of the esophagus).
 The oblique entry of the esophagus into the stomach (results in
narrowing of its opening).
Abnormalities of the lower esophageal sphincter
 Achalasia:
- Massive dilatation of the esophagus proximal to the LES resulting from
failure of the LES to relax during swallowing.

- This occurs due to loss of the neurons which release the relaxing factors
NO & VIP in the myenteric plexus at the LES whereas acetylcholine and
substance P are released causing contraction of the LES.
Medical treatment: Botulinum toxin to inhibit release of acetylcholine.
Surgical treatment: Dilatation of the constricted area (Heller myotomy).
 Gastro-esophageal reflux disease (GERD):
- Incompetence of the LES due to a defect in the factors that normally
close it or due to protrusion of upper part of the stomach into the thorax
through a defect in the diaphragm (Hiatus hernia). Theses result in
regurgitation of gastric acid into the esophagus causing mucosal damage.
- Patients complain of heartburn when they lie down after heavy meals.
Medical treatment: Lifestyle modifications e.g. weight loss, elevating foot
of the bed and avoidance of heavy meals before going to sleep. In
addition, some patients may need anti-acid treatment (see peptic ulcer).
Surgical treatment: Nissen fundoplication (if medical treatment failed as
in cases of hiatus hernia)
Fig 8.7: GERD and Achalasia of the esophagus

THE STOMACH
INTRODUCTION
- The stomach is a “J”-shaped hollow muscular organ of the GIT, acting as
a reservoir for food and involved in its digestion.
- It is divided into 4 parts:
o Cardia: the region where esophageal contents empty into the stomach
o Fundus: the upper curvature
o Body: the main central region
o Pylorus or pyloric antrum: the lower part that facilitates gastric
emptying
- As in other parts of the GIT, the wall of the stomach consists of mucosa,
submucosa, muscular layer, and serosa.
- The muscular layer is divided into three layers: Outer longitudinal, middle
circular and inner oblique.
Fig 8.8: Structure of the stomach
- The mucosa of the stomach contains many deep exocrine glands (gastric
glands). Many of the glands open through a common opening (gastric pit).

Types of cells in a gastric gland:
1- Mucus cells: At the neck of the glands (in the cardiac & pyloric regions
of the stomach)
- Secrete mucus.
2- Parietal cells (oxyntic cells): At the isthmus & body of the gastric gland
(in the body & fundus of the stomach)
- Secrete hydrochloric acid “HCL” & intrinsic factor.
3- Chief cells (peptic, zymogen): At the isthmus & body of the gastric gland
(in the body & fundus of the stomach)
- Secrete Pepsinogens
 In addition, there are endocrine cells near the gastric glands:
- G cells: Secrete Gastrin
- ECL cells (Enterochromaffin like cells): Secrete histamine
Fig 8.9: The gastric gland
Functions of the stomach

1- Storage of food: up to about 4 hours, and controls its release into the
duodenum.
2- Digestion of proteins & lipids: by pepsin and gastric lipase enzymes.
However, these enzymes are less important than the enzymes of the
exocrine pancreas.

3- Protection: by HCL which kills bacteria & vomiting which removes
harmful substances.
4- Synthesis of the intrinsic factor (IF): this glycoprotein binds vitamin B12
in the stomach and then facilitates its absorption in the terminal ileum.
5- Facilitates absorption of iron in the intestine: by maintaining iron in the
ferrous state.
6- Absorption: the stomach absorbs small amount of water, ions, alcohol
and some drugs.
7- Endocrine function: produces many hormones like gastrin, glucagon,
somatostatin, ghrelin and VIP.
Remember that: Ghrelin is the growth hormone releasing horomone
screted by the hypothalamus. It is also released from fundus of the
stomach to give sensation of hunger (opposite to leptin from adipose
tissue, which gives sensation of satiety).
GASTRIC SECRETION
Features of gastric secretion:
 Volume: 2-3 L/day
 pH: Highly acidic (about 0.9). May increase up to 4 depending on the
type of diet, its time and other factors
 Osmolarity: Isotonic
 Contents:
o Water and electrolytes (H+ / Cl- / K+ / HCO - / Na+)
o Intrinsic factor
o Digestive enzymes (pepsin & gastric lipase)
o Mucus

Hydrochloric acid (HCL)
- Secreted by parietal cells (which also secrete the intrinsic factor).
- Each parietal cell is characterized by the following: It is pyramidal in
shape, apical membrane of the active cell contains canaliculi for secretion
of HCL (the canaliculi in an inactive cell are found within the cytoplasm)
and its cytoplasm contains large number of mitochondria (to provide
energy for the active pumps that secrete hydrogen ions.
 Synthesis of HCL
- HCL is synthesized from hydrogen ions (H+) and chloride ions (Cl-).
- Sources of hydrogen ions (H+):
1- From dissociation of H2O into H+ & OH-: (H2 O = H+ + OH-)
2- From the reaction of CO2 with water at the presence of carbonic
anhydrase enzyme: (CO2 + H2O = H2CO3 = H+ + HCO3-).
- H+ is secreted into the canaliculi against a very high concentration
gradient by the H+-K+ ATPase pump (The proton pump).
- HCO3- enters the blood in exchange to Cl-, which enters the parietal cell.
- Cl- enters the canaliculi with K+.
- K+ returns back to inside the cell by the H+-K+ ATPase pump (i.e. K+
recycles between the cytoplasm and the canaliculi).
- In the canaliculi, HCL is formed as follows: (H+ + Cl- = HCL).
- HCL escapes from the canaliculi to the lumen (through the gastric pits).
Remember that: For each H+ ion secreted to the lumen, HCO3+ enters the
blood.
- If secretion of HCL is increased e.g. following a meal or due to repeated
vomiting, large amount of bicarbonate enters the blood.
- This changes pH of the blood to become more alkaline (= a condition
known as post-prandial alkaline tide).

Fig 8.10: HCL synthesis in a parietal cell
 Receptors on parietal cells for HCL secretion

- HCL secretion is stimulated through activation of the following receptors,
which are found on the basolateral membrane of parietal cells:
1- Muscarinic receptors (M3): stimulated by acetylcholine to increase
intracellular Ca++, protein kinases and then the proton pump.
2- G receptors: stimulated by gastrin to increase intracellular Ca++.
(Note: gastrin acts mainly on enterochromaffin like cells (ECL) to
release histamine).
3- H2 receptors: stimulated by histamine (which is released by the ECL
cells) to increase intracellular cAMP, protein kinases and then the
proton pump.
Remember that:
- In absence of cAMP, activity of the proton pump becomes very low
- Unlike acetylcholine and gastrin, histamine increases cAMP
- Therefore, H2 blockers inhibit, in addition to histamine, gastrin and
acetylcholine mediated acid secretion.

 Receptors on parietal cells against HCL secretion
- These are prostaglandin receptors stimulated by prostaglandins; they
inhibit HCL secretion.
- Prostaglandins also stimulate secretion of mucus, which protects the wall
of the stomach from the action of HCL.
- Therefore, inhibition of prostaglandin synthesis by aspirin increases HCL
synthesis & decreases mucus secretion. This predisposes to peptic ulcer.
 Functions of HCL
- Kills ingested bacteria
- Activates pepsinogen to pepsin & allows its action
- Maintains iron in the ferrous state to facilitate its absorption
- Facilitates absorption of calcium
- Stimulates flow of bile (by stimulating release of secretin)
The hormone which increase HCL secretion:

Gastrin
 Characteristics of gastrin
- Peptide hormone (half life: 2-3 min).
- Similar to CCK (The gastrin family of hormones include gastrin & CCK).
- Found in different lengths: (17, 34, 14 aa …). However, G 17 is the
principal form.
 Gastrin release & catabolism
- Released by:
o G cells in the pyloric antrum of the stomach and upper small intestine.
o Fetal pancreas (this stops gastrin release after delivery).
o Some neural structures outside the GIT (e.g. brain, vagus and sciatic
nerves).
- Catabolism: Kidney and small intestine.

 Stimuli of gastrin release
o Gastric distention
o Luminal peptides and amino acids (e.g. tryptophan & phenylalanine)
o Vagus (through the neurotransmitter “gastrin releasing peptide” (GRP),
not acetylcholine; that is why gastrin is not inhibited by atropine).
o Calcium ions (hypercalcemia)
o Epinephrine
 Inhibitors of gastrin release:
o Acid in pyloric antrum (inhibits G cells either directly or through release
of somatostatin). This is an example of a negative feedback
mechanism.
o Somatostatin (also inhibits many other hormones).
o Secretin family of GIT hormones (secretin, GIP, VIP & glucagon).
o Calcitonin (calcium lowering hormone released by the thyroid gland).
 Actions of gastrin
Physiologic actions:-
o Stimulates gastric acid secretion
o Stimulates pepsin secretion
o Trophic effect on the mucosa of the stomach, intestine and colon
o Stimulates gastric motility
In large doses (non-physiologic actions):-
o Stimulates pancreatic secretion (the enzymes mainly)
o Stimulates water & HCO- secretion from pancreatic ducts and
biliary ducts
o Stimulates insulin secretion (following a protein meal)
o Relaxes the ileo-cecal valve
o Contracts the lower esophageal sphincter (LES)
o Stimulates gastric & intestinal motility & slows gastric emptying

 Abnormalities associated with high gastrin level:
1- Gastrinoma =“Zollinger Ellison Syndrome”.
o A tumor (usually in the pancreas) that secretes gastrin excessively
o Gastrin results in rapid secretion of HCL causing multiple peptic ulcers
(in the stomach, esophagus and small intestine)
o Modalities of treatment include anti-ulcer treatment plus surgery or
chemotherapy.
2- Pernicious anemia:
o This is a severe megaloblastic anemia caused by auto-antibodies that
result in failure of parietal cells to secrete the intrinsic factor, which is
important for absorption of vitamin B12.
o The parietal cells also fail to secrete HCL; this results in loss of the
negative feedback exerted by acid on gastrin causing gastrin excess.
 Hormones which decrease HCL secretion
1- Somatostatin: Released from D cells in the pyloric antrum to inhibit
gastric acid secretion and gastrin.
- It is also released from other sites (like intestine, pancreas and
hypothalamus) to inhibit other hormones (like growth hormone, insulin,
glucagon and many other hormones).
2- Secretin: See control of pancreatic secretion.
3- VIP: Vasoactive intestinal polypeptide is released from GIT, brain &
autonomic nerves. It inhibits gastric cid secretion, stimulates intestinal
secretion and relaxes smooth muscles in the intestine, blood vessels and
bronchioles.
4- Glucagon: See the pancreas in the endocrine system.
5- Enterogastrone: Is thought to be the hormone that is released from the
intestine to inhibit gastrin stimulated acid secretion. Its identity is unsettled
(may be the peptide YY).

6- GIP: Gastric inhibitory peptide is released by K cells in the duodenum in
response to luminal glucose or fat.
- Its name refers to its action when administered in high doses (inhibits
gastric motility and secretion).
- However, its physiologic role appears to be stimulation of insulin release
following ingestion of glucose; that is why it is called the glucose-
dependent insulinotropic hormone.
Other factors that decrease HCL secretion:
Vagotomy:
- Cutting the vagus nerve causes loss of the parasympathetic supply to the
stomach. This decreases HCL secretion and that is why it is used for
treatment of peptic ulcer.
- Vagotomy can be:
o Truncal (cutting the nerve supply to the whole abdomen)
o Selective (cutting the branch that supply the whole stomach)
o Highly selective (cutting the branch that supply the acid secreting area
at the proximal part of the stomach).
- Vagotomy is usually complicated by decreased gastric emptying; this can
be treated by pyloroplasty (surgical widening of the pylorus).
Acute stress (fear):
- Associated with reduced HCL secretion due to decreased vagal
discharge.
GASTRIC LIPASE
- This enzyme is released by mucosa of the fundus.
- It causes hydrolysis of triglycerides into monoglycerides and fatty acids.
- Not important except in the absence of pancreatic lipase (its activity =
1/5th of pancreatic lipase activity).

PEPSIN
- This enzyme is secreted by peptic cells as pepsinogens (inactive
enzymes). Pepsinogens are activated by HCL to pepsin & then by pepsin
itself which activates other pepsinogens (auto-activation or auto-catalysis).
- It causes protein digestion (acts in acidic pH (1.5-3.5) - i.e. HCL activates
it and provides for it a suitable pH). It is worth noting that pepsin is not
essential for protein digestion; unlike proteolytic enzymes of the pancreas.
RENNIN ENZYME
- This enzyme is not found in humans, it is found in calf stomach.
- It causes digestion of proteins.
MUCUS
- Glycoprotein.
- Protects the stomach from auto-digestion by HCL & pepsin
- For this reason, the mucus layer (aided by bicarbonate ions) are known
as “the mucosal barrier.”
- Mucus is stimulated by:
o Mechanical & chemical irritation
o Sympathetic & parasympathetic stimulation
o Prostaglandins
INTRINSIC FACTOR
- Glycoprotein secreted by parietal cells to facilitate absorption of vitamin
B12 at the terminal ileum. It is lost in pernicious anemia (due to
autoantibodies attacking parietal cells or the intrinsic factor).
CONTROL OF GASTRIC SECRETION

- Controlled by neural & hormonal mechanisms.
- These mechanisms are activated during the following phases: Cephalic
phase, gastric phase and intestinal phase.

 Cephalic phase
- When food is in front or within the mouth (not in the stomach).
- Two neural reflexes are activated:
1- Conditioned reflex (activated by sight, smell, or thought about food)
2- Non conditioned reflex (activated by food in the mouth)
- Both reflexes are mediated through the vagus nerve.
- Cutting the vagus nerve abolishes this reflex.
 Gastric Phase
- It is the phase when food reaches the stomach.
- Here gastric secretion is mediated by both neural & hormonal
mechanisms.
The neural mechanism:
- Distention of the stomach stimulates gastric secretion by long and short
reflexes as follows:
o Vagovagal reflex (long reflex mediated by the vagus & integrated in the
brain stem. It can be abolished by vagotomy).
o Intramural reflex (short reflex integrated in the submucus plexus within
the wall of the stomach).
Hormonal mechanism:
- Food in the stomach stimulates release of gastrin, which stimulates
gastric secretion.
- Gastrin stimuli include: Gastric distention & L-amino acids.
 Intestinal phase
- Activated when chyme reaches the intestine.
- Here gastric secretion is initially inhibited (due to stimulation of an
intestinal hormone that inhibits HCL secretion; this hormone is known as
enterogastrone). Then after 1-3 hours, HCL secretion may increase (due
to release of gastrin from the intestine).

PEPTIC ULCER
- Defect in the mucosa of the stomach or intestine caused by gastric
secretion.
- Patients of peptic ulcer suffer from severe epigastric pain, nausea,
vomiting and sometimes gastric bleeding.
Causes of peptic ulcer:
1- Infection of the gastric mucosa with Helicobacter pylori bacteria.
- This is the main cause of peptic ulcer in most cases.
- The bacteria lives within the mucus layer, it protects itself from the effect
of the gastric acid reaching it by releasing the enzyme urease; this
enzyme converts urea into ammonia and bicarbonate, both of which are
basic substances that neutralize the acid.
- On the other hand, its presence within the mucus layer protects it from
the immune system of the body.
- Ammonia and the products of leucocytes which attack the bacteria result
in disruption of the mucosal barrier or direct damage to the gastric mucosa
causing peptic ulcer.
2- Non-steroidal anti-inflammatory drugs (NSAID) like aspirin.
- These inhibit synthesis of prostaglandins from arachidonic acid.
- Since prostaglandins inhibit HCL synthesis and increase mucus
secretion, then chronic use of aspirin, which inhibits its formation from
arachidonic acid, results in increased HCL secretion and decreased
mucus production causing peptic ulcer.
3- Zollinger Ellison Syndrome.
- Described by Zollinger and Ellison in 1955.
- Caused by a tumor in the pancreas or other part in the GIT.
- The tumor cells release gastrin (= gastrinoma). This causes excessive
secretion of HCL resulting in multiple peptic ulcers.

Medical treatment of peptic ulcer:
- Treatment starts by eradication of the primary cause (e.g. antibiotics
against Helicobacter pylori and cessation of NSAID).
- In addition, some of the following drugs should be used for at least 4-6
weeks to allow the ulcer to heal:
o Drugs that inhibit HCL secretion= allow the ulcer to heal:
 Proton pump inhibitors: Effective drugs in treatment of peptic ulcers.
They block the proton pump (the H+-K+ ATPase pump).
Example: omeprazole.
 H2 blockers: Block histamine receptors type 2 (H2 receptors).
Examples: cimetidine, ranitidine and famotidine.
 Muscarinic blockers: Block the effect of acetylcholine at the muscarinic
receptors. However, they are less effective than other drugs.
Example: pirenzepine.
 Prostaglandin analogues: Inhibit HCL secretion and induce mucus and
bicarbonate secretion.
Example: Misoprostol.
o Drugs that neutralize HCL= releive symptoms:
 Antacids: Are used to neutralize existing acid in the stomach. They are
used mainly to relief symptoms.
o Drugs that cover the ulcer= prevent further digestion of the ulcer:
 Sucralfate: This sucrose octasulphate compound binds to proteins in
the ulcer slouph, protecting it from further digestion.
Surgical treatment of peptic ulcer

Vagotomy:
- Indicated when there is failure of all types of medical treatment.
- Vagotomy blocks the cephalic phase & part of the gastric phase.
- This decreases HCL secretion, giving chance for the ulcer to heal.
- The problem with vagotomy is the impairment of gastric emptying (see
above). That is why pyloroplasty (dilatation of the pylorus) is usually done
with the procedure.
- Vagotomy can be tested by insulin injection to induce hypoglycemia
because hypoglycemia stimulates the vagus nerve, which increases
gastric secretion. Therefore, any increase in gastric secretion following the
injection indicates that vagotomy is not successful.
GASTRIC MOTILITY
- Many types of movement appear in the stomach as food enters it. These
movements allow storage of food for some time with minimal rise in intra-
gastric pressure and facilitate gradual gastric emptying. They include:
1- Receptive relaxation:
- Occurs at the upper part of the stomach to accommodate food with
minimal increase in pressure (Laplace law). It is mediated by the vagus.
2- Peristalsis:
- Sweeps down towards the lower part of the stomach to allow chyme to
pass through the pylorus. Its frequency is about 3-4 times per min. It is
controlled by the basic electrical rhythm (see below).
3- Migrating Motor Complex (MMC):
- Also known as hunger contractions. These are peristaltic waves that
occur every 90 minutes during the fasting state (between meals) and
disappear upon eating. They pass from the empty stomach through the
small intestine, to reach the ileocecal valve.
- Their exact function is unknown. However, they remove remnants of food
& therefore prevent growth of bacteria.
- The hormone “motilin” which is secreted by upper small intestine during
the interdigestive period may be responsible for initiation of MMC.

The basic electrical rhythm (BER):
- These spontaneous rhythmic fluctuations in the membrane potential vary
between (-45 & -65 mv). It occurs in smooth muscle of all parts of the GIT
except the esophagus and the proximal part of the stomach.
- It is recorded in form of slow waves & spikes. Depolarization in each
spike is caused by Ca++ influx & repolarization is caused by K+ efflux.
Fig 8.11: The basic electrical rhythm
- The frequency of slow waves (i.e. rate of BER) is 4/min in stomach,

12/min in duodenum, 8/min in ileum, 9/min in cecum and 16/min in
sigmoid colon.
- The number of spikes per each wave is increased by acetylcholine and
decreased by norepinephrine.
- The function of the BER is co-ordination of peristalsis & other types of
GIT motility (This is confirmed by the finding that in its absence peristalsis
becomes irregular).
The pyloric sphincter

- An atypical sphincter (since it is open except when peristalsis reaches it).
- It acts with the duodenum and the antral part of the stomach to control
gastric emptying.
- When peristalsis reaches the lower part of the stomach, it causes
sequential contraction of the antrum followed by the pylorus and then the
duodenum.
- The pylorus takes slightly longer time in contraction; this prevents reflux
of duodenal contents into the stomach and allows grinding and mixing of
solid particles in the stomach.
Factors affecting gastric emptying

o Longitudinal mucosal folds in the stomach: Allow rapid emptying of
liquids.
o Amount of food: Emptying is faster with higher intra-gastric volume.
o Type of food: Emptying of liquids is faster than solids & emptying of
CHO is faster than protein and proteins faster than lipids.
o Osmolarity of chyme: Emptying of hypotonic chyme is faster than
hypertonic chyme (this is due to a neural mechanism stimulated by
distention or shrinkage of osmoreceptors in duodenum).
o pH of chyme: Emptying of alkaline chyme is faster than acidic (due to a
neural mechanism stimulated by chemoreceptors in the duodenum).
o Hormones: Secretin, CCK & GIP decrease gastric emptying.
Concerning gastrin, it increases gastric motility; however, it also
increases intestinal motility. This increases resistance in the intestine
against evacuation of gastric contents. Therefore, the overall effect is
reduction in gastric emptying.
o Other factors that decrease emptying include:
 Distention of the duodenum
 Vagotomy
 Emotions like “fear” (unlike excitement, which increases gastric
emptying).

VOMITING “or EMESIS”
- This is a protective reflex for expulsion of harmful materials in the
stomach forcefully through the mouth.
- It consists of the following components:
 Receptors (and their stimuli “emetics”)
o Some of the receptors that induce vomiting are situated in the GIT
(pharynx, stomach, & duodenum).
- They are stimulated by chemical irritation, mechanical irritation or over-
distention.
- Other sites that can be stimulated to cause vomiting:
o The bile ducts, peritoneum, heart and many other organs. Signals from
these organs reach the vomiting center in response to certain diseases
affecting them; for example, myocardial infarction and obstructive
jaundice.
o Vestibular system: stimulated by motion sickness.
o The Chemoreceptor trigger zone (CRTZ) on lateral wall of the fourth
ventricle in the medulla. It discharges directly to the vomiting center.
- It is stimulated by circulating chemicals (including drugs). The effects
of these chemicals on the CRTZ can be inhibited by serotonin
antagonists or dopamine antagonists.
- It is also stimulated by vestibular stimulation (motion sickness).
o Frontal lobe: stimulated by psychic stimuli “like shocking sites or
smells.”
(Note: the last 3 stimuli are known as central receptors).
 Afferents from the stomach:
- Autonomic nerves (sympathetic & vagus)
 Vomiting center:
- Present bilaterally in the medulla oblongata

 Efferents:
- The cranial nerves and the spinal nerves that supply the effectors
 Effectors:
- All the following effectors participate in the act of vomiting: Abdominal
muscles, diaphragm, intestine, stomach, esophagus & mouth.
The act of vomiting:
- Vomiting starts with cessation of respiration at mid inspiration (= closure
of the glottis & nasopharynx).
- Violent contractions of abdominal muscles & diaphragm occur to
squeeze the stomach and increase its pressure.
- Reverse peristalsis occurs to evacuate the upper intestine into the
stomach.
- In the mean time: the wall of the stomach relaxes, the lower esophageal
sphincter open and the upper esophageal sphincter suddenly open.
- The high intra-gastric pressure allows gastric contents to be expelled
through the esophagus to the outside.
Associated with vomiting:
o Salivation
o Nausea
o Sweating
o Skin vasoconstriction
o Slowing of the heart rate
Remember that: Because vomiting causes slowing of the heart rate,
induction of vomiting is used sometimes for treatment of supraventricular
tachycardia

QUESTIONS FOR SELF ASSESSMENT-1 (MCQS)
1. Receptive relaxation of the stomach is abolished by:
a. Ingestion of a heavy meal
b. Parasympathetic stimulation
c. Sympathetic stimulation
d. Vagotomy
e. Administration of CCK-PZ
2. Saliva is characterized by:
a. HCO3- concentration lower than plasma
b. Presence of proteolytic enzymes
c. Absence of glucose
d. pH similar to that of plasma
e. Hypotonicity relative to plasma
3. Slow waves in smooth muscle of lower part of the stomach are:
a. Local potentials
b. Action potentials
c. Resting membrane potential
d. Due to action of gastrin
e. Receptive relaxation electrical activity
4. A patient with gastric ulcer is treated with the drug omeprazole. The
basis of omeprazole’s inhibition of gastric acid secretion is that it:
a. Blocks H2 receptors
b. Increases intracellular cAMP
c. Stimulates M3 receptors
d. Inhibits the proton pump
e. Potentiates effects of prostaglandins
5. A patient with Zollinger-Ellison syndrome is expected to have:
a. Auto-antibodies against parietal cells
b. Iron deficiency anemia
c. Multiple peptic ulcers
d. Insulinoma
e. Absent mucus barrier of the stomach
6. Gastric emptying is stimulated by:
a. Fatty meal
b. Hypertonic fluids
c. Low pH in the duodenum
d. Gastric inhibitory peptide
e. Parasympathetic stimulation
7. Peptic ulcer:
a. Is caused primarily by excessive secretion of HCl
b. Can be treated with non steroidal anti-inflammatory drugs like aspirin
c. Is associated with Helicobacter pylori infection in the majority of
patients
d. Treatment involves reduction of cAMP within the cell
e. Is caused by H2 receptor blockers

8. Hydrochloric acid:
a. Is secreted by the chief cells
b. Converts iron from the ferrous state to the ferric state
c. Activates trypsinogen
d. Secretion is stimulated by acetylcholine
e. Is essential for vitamin B12 absorption
9. The parietal cells of gastric glands:
a. Secrete gastrin
b. Are stimulated by prostaglandin E2
c. Do not contain carbonic anhydrase
d. Secrete intrinsic factor
e. Have H-K ATPase on basolateral membranes
10. Which of the following statements about gastric emptying is correct?
a. Acidification of the antrum decreases gastric emptying
b. Emptying of solids is faster than liquids
c. Indigestible food empties during the interdigestive period
d. CCK accelerates gastric emptying
e. Enterogastrone increases gastric emptying
11. Feedback inhibition of gastric acid secretion is achieved by:
a. Gasrin
b. Acetylcholine
c. Enterogastrone
d. Somatostatin
e. Histamine
12. Gastric emptying increases with an increase in:
a. Intra-duodenal osmolarity
b. Intra-duodenal pH
c. Intra-gastric volume
d. Intra-gastric osmolarity
e. Duodenal fat content
13. Secondary esophageal peristalsis differs from primary peristalsis in that
it is:
a. Localized to the esophagus
b. Preceded by oropharyngeal phase
c. Involves activation of medullary swallowing centers
d. Abolished by vagotomy
e. Results in relaxation of the lower esophageal sphincter
14. In the buccal stage of swallowing the:
a. Mouth should be open
b. Larynx moves down
c. Movement is involuntary
d. Tongue moves upward and backward
e. Upper esophageal sphincter relaxes
15. Gastric secretion:
a. Is 1 L per day
b. Contains intrinsic factor that helps in vitamin B6 absorption

c. Is stimulated by gastrin
d. Is inhibited by histamine
e. Converts iron from ferrous to ferric state
16. Opening of the lower esophageal sphincter occurs due to:
a. Arrival of a peristaltic wave
b. A vago-vagal reflex.
c. Stimulation of muscarinic receptors
d. Stimulation of alpha receptors
e. A Rise in gastric pressure above 15 mmHg
17. H -K+ ATPase pumps in an inactive parietal cell is found in the:
+
a. Basolateral membrane
b. Apical membrane
c. Cytoplasm
d. Golgi apparatus
e. Mitochondria
18. Receptive relaxation of the stomach:
a. Occurs during the cephalic phase
b. Mediated by the vagus
c. Causes the stomach to double its volume
d. Occurs just before vomiting
e. Occurs in the lower part of the stomach
19. Which of the following statements about saliva is correct:
a. Volume is about 3 L/day
b. Produced mainly by the parotid glands
c. Contains bactericidal substances like lactoferrin
d. Secretion is stimulated by muscarinic blockers
e. Secretion is not controlled by hormonal factors
20. Migrating motor complex:
a. Is a mixing type of movement
b. Occurs immediately following ingestion of food
c. Starts in the esophagus
d. Removes undigested particles from the large intestine
e. It is initiated during the inter-digestive phase
21. The cephalic phase of gastric secretion:
a. Depends on purely neural mechanisms
b. Is associated with receptive relaxation of the stomach
c. Is mainly due to vagal release of gastrin
d. Is both neural & hormonal
e. Depends on conditioned reflexes
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
d e c d c e c d d c d
12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
c a d c a c b e e a

THE EXOCRINE PANCREAS
STRUCTURE
- Consists of lobules. Each lobule consists of acini & ducts.
- The ducts are joined together to form the main pancreatic duct. This
opens together with the common bile duct into the duodenum at the
ampulla of Vater.
- The opening at the ampulla is guarded by the sphincter of Oddi
(choledocho-duodenal sphincter).
Fig 8.12: The pancreas
PANCREATIC SECRETION
Characteristics:
o Volume: 1.5 L
o Osmolarity: Isotonic
o pH: Alkaline (8) to neutralize gastric acid (together with bile and
intestinal secretion)
o Contents: Water, electrolytes (secreted by ductular & centroacinar
cells) & digestive enzymes (secreted by acinar cells)

The pancreatic enzymes:
- The main digestive enzymes in the GIT. These enzymes are essential for
digestion (i.e. absence of these enzymes impairs digestion and
consequently absorption is also impaired).
- The enzymes include:
o Enzymes for protein digestion
- Produced in an inactive form.
- Include: Trypsinogen, chymotrypsinogen, proelastase and
procarboxypeptidase.
- Activation occurs as follows: 1st trypsinogen is activated to trypsin in the
duodenum by enteropeptidase enzyme (also known as enterokinase), and
then trypsin activates the other enzymes (autocatalysis) as follows:
Other trypsinogen is activated to trypsin
Chymotrypsinogen is activated to chymotrypsin
Proelastase is activated to elastase
Procarboxypeptidase is activated to carboxypeptidase
Remember that: These enzymes are secreted in inactive form to prevent
autodigestion of the pancreas. They are activated within the intestinal
lumen, not in the pancreatic duct. Activation within the pancreatic duct is
inhibited by a trypsin inhibitor found in the pancreatic juice.
o Enzymes for carbohydrate digestion
- Pancreatic α amylase: Acts on starch.
o Enzymes for lipid digestion
- Pancreatic lipase: For triglycerides
- Co-lipase: Bound to lipase to increase its activity. It needs activation by
trypsin.
- Cholesterol esterase: For cholesterol esters
- Phospholipase A2: For phospholipids. It also needs activation by trypsin.

o Enzymes for nucleic acid digestion
- Ribonuclease: For RNA digestion
- Deoxyribonuclease: For DNA digestion
Changes in ionic composition of pancreatic secretion:

- After secretion into the duct lumen, bicarbonate is reabsorbed back in
exchange to chloride which is secreted. Therefore high flow rate
decreases this exchange resulting in more bicarbonate and less chloride
in pancreatic secretion (i.e. bicarbonate & chloride are flow dependent).
- Sodium & potassium concentrations remain constant without difference
in concentrations between high or slow rates of secretion (i.e. sodium &
potassium are flow independent).
CONTROL OF PANCREATIC SECRETION

- By neural & hormonal mechanisms.
- These mechanisms are activated during the following phases: Cephalic
phase, gastric phase & intestinal phase.
Cephalic phase
- It is the phase when food is in front or within the mouth (not in the
stomach).
- Two neural reflexes are activated:
o Conditioned reflex (activated by sight, smell or thoughts about
appetizing food).
o Non-conditioned reflex (activated by presence of food in the mouth).
- Both reflexes are mediated through the vagus nerve.
- The vagus acts on acinar cells to release pancreatic enzymes by two
ways: Directly by acting on acinar cells & indirectly by stimulating gastrin
release from the stomach (see above).

Gastric Phase
- It is the phase when food reaches the stomach.
- Here pancreatic secretion “rich in enzymes” is mediated by both neural &
hormonal mechanisms.
The neural mechanism: Distention of the stomach stimulates pancreatic
secretion by a vagovagal reflex.
Hormonal mechanism: Food in the stomach stimulates release of gastrin
(through gastric distention &/or L-amino acids). Gastrin stimulates
pancreatic secretion rich in enzymes.
Intestinal phase
- This is the main phase for pancreatic secretion. It is mediated through
hormonal mechanisms. The hormones are released when chyme reaches
the small intestine; they are two hormones: Secretin & CCK-PZ.
SECRETIN
- Peptide hormone (27aa), released by S cells in the duodenum.
- Similar in structure to VIP, GIP & Glucagon (these hormones constitute
the Secretin family).
History: Bayliss and Starling in 1902 suggested that a chemical
substance released by the small intestine into the blood stimulates
pancreatic secretion. This led to the identification of secretin, the first
hormone to be discovered.
Stimuli:
o Low pH (mainly)
o Amino & fatty acids
- Secretin has cell membrane receptors.
- Its effects are mediated via the second messenger “cAMP”.

Actions:
 Acts on ductular & centroacinar cells of the pancreas to release
water & electrolytes (especially bicarbonate).
 Acts on the biliary tract to release water & electrolytes (it increases
flow of bile, i.e. it is choleretic).
 Inhibits gastrin and gastric acid secretion.
 Inhibits intestinal motility.
 Relaxes the lower esophageal sphincter & contracts the ileo-cecal
valve.
 Contracts the pyloric sphincter and decreases gastric emptying.
 Augments actions of CCK on the pancreas.
CCK-PZ (CHOLECYSTOKININ-PANCREOZYMIN)
- Peptide hormone; similar in structure to gastrin (both hormones
constitute the gastrin family)
- Produced by: I cells of the duodenum and by some neurons in the brain
and GIT
- Like gastrin it is found in many forms (5, 12, 33, 39, 58 amino acids)
Stimuli:
o Luminal amino & fatty acids (mainly)
o Low pH in the duodenum
- Has cell membrane receptors.
- Its effects are mediated via “phospholipase C”.
Actions:
 Acts on pancreatic acinar cells to stimulate secretion of enzymes.
 Contracts the gall bladder (cholagogue) & relaxes the Oddi
sphincter.

 Augments actions of secretin on the pancreas.
 Inhibits gastric emptying.
 Inhibits gastrin and gastric acid secretion (in large doses).
 Relaxes the lower esophageal sphincter & contracts the ileo-cecal
valve.
 Contracts the pyloric sphincter (decreases gastric emptying).
 Stimulates intestinal motility.
ABNORMALITIES OF THE PANCREAS

Acute pancreatitis
- Occurs due to activation of pancreatic enzymes within the pancreatic
duct, resulting in autodigestion of the pancreas; as occurs when the
common bile duct is obstructed by gallstones.
- Symptoms include severe upper abdominal pain, nausea and vomiting.
- High amount of pancreatic enzymes may enter the blood (e.g. amylase &
lipase). Presence of high concentration of these enzymes in the plasma
can be used for diagnosis.
Chronic pancreatitis
- Characterized by release of low amount of pancreatic enzymes in the
duodenum, resulting in maldigestion & malabsorption of protein and fat.
- Large amounts of fat (> 5 grams/day) appear in stool (= fatty stool or
steatorrhoea).

THE LIVER AND BILE
THE LIVER
Anatomy:
- Weight: about 1.5 Kg.
- Consists of lobules, each lobule consists of many cellular plates radiating
between a central vein & a portal tract.
- Between the cellular columns in each plate are bile canaliculi.
- Between the cellular plates are hepatic sinusoids (lined by endothelial
cells & kupffer cells).
- The hepatic sinusoids receive blood supply from both hepatic artery and
portal vein (the total liver blood flow = 1.5 L/min; 1L/min from the portal
vein & 0.5 L/min from the hepatic artery. Then blood drains to central
veins, which drain to hepatic veins and then to the inferior vena cava
(IVC).
Fig 8.13: Histology of the Liver

- Between the sinusoids & cellular plates there are spaces of Disse.
- These spaces drain lymph to lymphatic vessels (The liver produces one
half of all lymph formed in the body; lymphatic flow= 1 ml/min).
- Because of the large pores in the hepatic sinusoids, they are permeable
to both fluid and protein. Therefore large quantities of protein move into
the spaces of Disse (Protein concentration in the lymph is only slightly
lower than that of the plasma).
The functional unit:
- The functional unit of the liver is the hepatic acinus. It represents the
hepatocytes that lie more near to afferent vessels (i.e. vessels in the portal
triads, away from central veins).
- Each acinus can be divided into 3 zones: 1, 2 and 3.
- Zone 1 is the nearest zone to afferent vessels (hepatic arterioles carrying
well oxygenated blood). For this reason interruption of hepatic blood flow
results in necrosis of cells at zone 3 rather than zone 1 (anoxic damage).
Fig 8.14: Hepatic acinus

Functions of the Liver
 Synthesis of plasma proteins (albumin, globulins & fibrinogen).
- Note that the liver forms α and β globulins (most of which are clotting
factors). However, gamma globulins (= the immunoglobulins) are not
synthesized by the liver.
 Synthesis & secretion of bile (see functions of bile).
 Metabolism of CHO, proteins, fats and hormones (especially steroid
hormones).
 Excretion of end products of metabolism (excreted through bile).
 Storage of glycogen, iron and vitamins (vitamin A, D & B 12).
 Detoxification of toxic substances, drugs and ammonia.
- Note that the liver converts ammonia, which is toxic, to urea, which is
non toxic except in very high levels as in renal failure.
 Immunity by Kupffer cells (phagocytic cells derived from monocytes).
BILE
- Yellowish to greenish fluid secreted continuously by hepatocytes into the
biliary system.
Characteristics of bile:
o Color: Golden yellow or greenish fluid
o Taste: Bitter taste
o Osmolarity: Isotonic
o pH: Slightly alkaline
o Contents:
- Water & electrolytes (K+/ Na+/ Ca+/ HCO3-/ Cl- …)
- Bile salts
- Bile pigments (bilirubin)
- Cholesterol/Phospholipids
- Alkaline phosphatase enzyme

The gall bladder (Cholecyst)
Characteristics of the gall bladder:
- A pear shaped structure, dark green in color.
- About 10-12 cm in length.
- Connected to the liver and duodenum by the biliary system.
Functions of the gall bladder:
o Storage of bile (Between meals bile is stored in the gall bladder. The
full capacity of the gall bladder is about 50 ml. This is released into the
duodenum up to 10 times per day (i.e. volume of bile released into the
intestine = 0.5 L/day)).
o Concentration of bile (the mucosa of the gall bladder absorbs water).
o Acidification of bile (the mucosa also absorbs bicarbonate).
- Note: The gall bladder also controls release of bile through the cystic &
common bile ducts into the duodenum (in response to CCK).
Differences between hepatic bile & gall bladder bile:
- The gall bladder absorbs Na+, Cl- & HCO3- actively, followed by passive
water absorption.
- This results in less water, [Na+], [Cl-], [HCO3] and pH in bile of the gall
bladder compared to hepatic bile; but higher concentrations of the other
substances (e.g. bile salts, bile pigment, cholesterol and phospholipids).
Functions of bile:
1- Neutralization of acid chyme
- By the high bicarbonate content in bile (alkaline pH).
- Note that bile, pancreatic secretion and duodenal secretion all act
together to neutralize acid in the duodenum.
2- Fat digestion & absorption
- By the Bile salts; the bile salts result in: Emulsification (for fat digestion) &
Micelle formation (for fat absorption).

- Emulsification = Breakdown of large fat droplets into smaller ones. This
facilitates digestion by increasing surface area of fat droplets for the action
of pancreatic lipase.
- Micelles = Cylindrical structures formed by bile salts and phospholipids
in bile. Bile salts are arranged in away that their hydrophilic parts project to
the outside and their hydrophobic parts project to the center inside. Large
lipid molecules are enclosed in the center of these micelles. This makes
lipids soluble in water & facilitates their transport to the intestinal wall for
absorption.
3- Excretion
- Bile is an important excretory route for bile pigment (bilirubin),
cholesterol, some drugs, some dyes and some inorganic substances.
Fig 8.15: Emulsification & micelle formation
Bile Salts
- Bile salts are sodium & potassium salts of bile acids.
- Bile acids are formed in the liver from cholesterol as two primary bile
acids: Cholic acid & chenodeoxycholic acid.
- They are found conjugated to the amino acids glycine and taurine.
- In the small intestine, bile salts exert the following effects:
o Participate in fat digestion & absorption
o Reduce surface tension of fluid in the small intestine.
o Stimulate CCK (indirectly, by the products of lipid digestion).
- Most of the bile acids (90-95%) are absorbed in the terminal ileum
actively to the entero-hepatic circulation (they return to the liver and then
re-secreted again in bile). The recycling occurs about 6-10 times every
day (twice/meal). The amount of bile acids that recycles is about 2-4g.
- In the large intestine, bacteria deconjugate the primary bile acids &
convert them into secondary bile acids as follows:
o Cholic acid to deoxycholic acid
o Chenodeoxycholic acid to lithocholic acid.
- Deoxycholic acid is absorbed back to the liver for re-conjugation or
secretion whereas most lithocholic acid is excreted in stool.
- The amount of bile acids lost daily in stool is about 0.2-0.4g; this is
replaced daily by the liver (i.e. the liver forms only 0.2-0.4 g/day).
- Note: Intestinal bacteria also deconjugate bile pigments into
urobilinogens (see RBC destruction in volume 1).
CONTROL OF BILE
- By two types of factors:
1- Choleretics:
- Factors that increase secretion of bile from the liver and its flow within the
bile ducts.
- They include: Bile salts, secretin, vagus, gastrin & glucagon.
- Note that bile salts recycle through the enterohepatic circulation. This
recycling increases flow of bile & decreases synthesis of bile acids.
- Therefore it is the most important choleretic factor. It is responsible for
about 90% of bile flow.
2- Cholagogues:
- Factors that contract the gall bladder & increase flow of bile into the
duodenum. They include CCK & vagus. However, sodium sulphate &
phosphate are also included.
DISORDERS
1- Gallstones (Cholelithiasis)
- Gallstones are caused by:
 Bile stasis.
 Super saturation of bile with cholesterol or excessive calcium ions.
 Damage or infection of the gall bladder.
- They vary in size and appearance depending on their contents.
- Their types include: Cholesterol stones, pigment stones, or calcium salts
stones.
- They may obstruct the common bile duct and the pancreatic duct
resulting in obstructive jaundice and pancreatitis respectively.
- Gallstones in the gall bladder are best treated by surgical removal of the
gall bladder (cholecystectomy).
2- Cholecystectomy
= Surgical or laparoscopic removal of the gall bladder.
- After cholecystectomy, bile is released constantly into the duodenum (i.e.
not following fatty meals as occurs normally).
- This is not going to impair digestion & absorption of fats. However,
patients with cholecystectomy are generally advised not to eat diets with
high fat content.
3- Jaundice
- Yellowish coloration of the skin, sclera and mucus membranes.
- Due to high bilirubin level in plasma (see jaundice in volume 1).

THE SMALL & LARGE INTESTINE
THE SMALL INTESTINE
- The small intestine is essential for life because it is the most important
site for digestion & absorption.
- Removal of a large segment results in malabsorption syndrome.
Anatomy
- The small intestine is formed of three segments: Duodenum = the first 25
cm; jejunum = the first 40% distal to the duodenum & ileum = the
remaining 60%, distal to the jejunum.
- The length is about 285 cm (3m) in a living adult subject; however, it
elongates after death to reach 7m. The surface area is increased 600 fold
to reach 200m2 by mucosal folds, villi and microvilli.
- Important histological points:
 Crypts of Lieberkuhn: At the base of villi. Secrete intestinal secretion
 Brunner’s glands: In the duodenum. Secrete mucus
 Peyer’s patches: Lymphoid tissue in the ileum
 Endocrine cells: Mainly in the duodenum. Secrete GIT hormones like
secretin,CCK …
Fig 8.16: The small intestine

INTESTINAL SECRETION
Characteristics:
 Volume: 1L/day
 Osmolarity: Isotonic
 pH: Alkaline
 Contents: Water, electrolytes, mucus & digestive enzymes
The digestive enzymes:
 Enteropeptidase (or enterokinase), which activates trypsinogen
 Peptidases, which complete digestion of protein
 Disaccharidases (sucrase, maltase and lactase), which digest the
disaccharides
 Nucleases (RNAase & DNAase), which digest RNA & DNA.
Stimuli for intestinal secretion:
 Neural stimuli: Vagus (for mucus secretion)
 Hormonal stimuli: VIP, Gastrin, CCK & Secretin
 Mechanical irritation
 Chemical irritation
The small intestine is presented with 9 liters of fluid per day as
follows:
 1.5 L from saliva
 2.5 L from stomach
 1.5 L from pancreas
 0.5 L from bile
 1.0 L from intestine
 2.0 L from drinking
- It absorbs about 7 L, leaving about 1-2 L to reach the large intestine. The
large intestine absorbs 90% of this leaving about 200 ml to be excreted in
stool.

THE LARGE INTESTINE (COLON)
Segments:
Cecum, ascending colon, transverse colon, descending colon, sigmoid
colon and rectum.
- The large intestine differs from the small intestine because it has:
1- No villi (the surface area is not increased because it is not a major
absorptive site)
2- Higher number of goblet cells (secrete mucus to allow stool movement )
3- Higher number of intestinal bacteria (the bacteria has many functions,
see below)
4- Haustra (sacculations in the wall of the large intestine)
5- Shorter length (about 1.5 meter, elongates after death)
6- Larger diameter
7- Teniae coli (incomplete longitudinal smooth muscle layer in its wall).
Fig 8.17: The large intestine

Intestinal bacteria (flora)
- Found in all parts of the GIT, but especially in the colon.
- Not pathogenic (i.e. does not cause disease in normal subjects).
- Functions:
 Antagonize pathogenic bacteria. Therefore, prolonged use of
antibiotics changes the normal flora and predisposes to infection of
the large intestine “colitis”.
 Important for normal development of the immune system.
 Formation of vitamin K, which is needed for formation of some
clotting factors in the liver (II, VII, IX & X).
 Formation of other vitamins like folic acid and some B vitamins.
However, this is not important because of the poor absorption at the
large intestine.
 Formation of ammonia (toxic substance) that is absorbed to reach
the liver where it is converted into urea (non-toxic). However,
patients with liver failure fail to form urea. They get into coma
because of ammonia toxicity (= hepatic encephalopathy). That is
why management of hepatic failure includes antibiotics (oral
streptomycin or neomycin) for eradication of flora (= Sterilization of
the bowel).
 Formation of amines (histamine, tyramine) and gases (hydrogen,
hydrogen sulfide, carbon dioxide and methane). These gases
(together with the unabsorbed swallowed gas) are excreted as
flatus (note that the daily production of gas is 500-1500 ml).
 Deconjugation of bile acids and bile pigments (revise “bile” above).

INTESTINAL MOTILITY
- There are two types of intestinal motility:
1- Propulsive movements:
- Pushes food forward towards the anus (e.g. peristalsis).
2- Mixing movements:
- Mixes food with enzymes and exposes it to the intestinal surface
for absorption (e.g. segmentation contractions).
MOTILITY OF THE SMALL INTESTINE
- Controlled by the basic electrical rhythm (BER) that originates from
pacemaker tissues in the small intestine.
- Its rate is 12 /min in the duodenum and 8/min in the ileum.
- Types of motility:-
1-Migrating motor complex (MMC)
- Propulsive (described above with gastric motility).
2-Peristalsis
- Propulsive (described above with swallowing).
- Peristalsis in the opposite direction “anti- peristalsis” may occur in
vomiting to evacuate the duodenal contents into the stomach.
Fig 8.18: Peristalsis

3-Segmentation contractions
- Ring like contractions of circular muscle layer appearing at regular
intervals on the wall of the small intestine. These rings alternate between
contraction and relaxation resulting in forward & backward movements of
chyme (= mixing movements).
- They are integrated in the myenteric plexus; that is why they persist after
cutting the extrinsic innervations of the small intestine.
Fig 8.19: Segmentation contractions
4- Tonic contractions
- Prolonged contractions that isolate one segment of the intestine from
another. This decreases movement of chyme and allows absorption.
5- Gastro-ileal reflex
- When food leaves the stomach, the cecum relaxes. his opens the
ileocecal valve and allows passage of some chyme into the cecum.
- The reflex is mediated by the vagus.
- Remember that the ileocecal valve is also opened by gastrin and closed
by CCK and secretin.

MOTILITY OF THE LARGE INTESTINE
- Also controlled by the BER.
- Frequency of discharge increases from 9/ min in the cecum to 16/ min in
the sigmoid colon.
- Types of motility in the large intestine:-
1- Segmentation contractions
- Mixing (see above).
2- Peristalsis
- Propulsive (see above).
3- Mass action contraction
- This is a special type of peristalsis (i.e. it is a propulsive movement).
- It is mass movement that propels stool through a long distance in the
large intestine (e.g. from the transverse colon to the rectum).
- When stool reaches the rectum, the process of defecation may be
initiated.
- Frequency of mass action contraction (and therefore defecation) is one
to three times/ day.
Transit time through the small and large intestine

- If a test meal (e.g. barium meal) is followed radiologically, its first part
reaches the following regions approximately at the stated time (= transit
time):
 Cecum in 4 hours
 Hepatic flexure in 6 hours
 Splenic flexure in 9 hours
 Pelvic colon in 12 hours
- From the pelvic colon to the rectum it moves slowly. After 3 days, 75% of
the meal is excreted in stool; however, total excretion may take more than
a week.
CONTROL OF INTESTINAL MOTILITY
- Like other functions of the GIT, it is controlled by neural and hormonal
factors.
Neural control:
 Extrinsic nerves:
- The parasympathetic: increases motility.
- The sympathetic: decreases motility.
 Intrinsic nerves:
- The myenteric plexus: acts in integration with the extrinsic nerves.
However, it can act independently.
Note: The pacemaker tissues of the BER: control peristalsis.
Hormonal control:
- Intestinal motility is affected by the following hormones &
neurotransmitters:
 Gastrin: stimulates intestinal motility
 CCK: stimulates intestinal motility
 Secretin: inhibits intestinal motility
 Acetylcholine: stimulates motility (contracts intestinal walls and
relaxes sphincters)
 Catecholamine: inhibits motility (relaxes walls and contracts
sphincters)
 Substance P: stimulates intestinal motility (contracts intestinal wall
in peristalsis)
 VIP: relaxes walls and sphincters
 NO: relaxes walls and sphincters
- Remember that: in peristalsis, acetylcholine and substance P contract
the wall of the intestine behind the food whereas NO and VIP relax the
wall in front of it.

ABNORMALITIES OF INTESTINAL MOTILITY
Intestinal obstruction
- Two types:
 Mechanical obstruction
 Paralytic obstruction (adynamic ileus)
Mechanical obstruction:
- Caused by stool impaction, tumor, stricture, or hernia.
- Characterized by increased peristalsis and distention of bowel proximal
to the site of obstruction. This causes severe colicky abdominal pain.
- Blood supply in the distended area is reduced with a risk of perforation.
- Treatment: Surgery
Paralytic (adynamic) ileus
- Occurs following abdominal operations, peritonitis or due to hypokalemia.
- These result in either direct inhibition of smooth muscle or indirect
inhibition through increased noradrenergic discharge.
- It is characterized by:
 Inhibition of peristalsis= no pain
 Abdominal distention
 Vomiting
 Electrolyte disturbance
- Following abdominal operations, peristalsis usually returns after 6-8 h (in
the small intestine & then the stomach) and after 2-3 days (in the large
intestine).
- Treatment (Medical treatment): Patients should take nothing per mouth,
should have nasogastric tube suction of gastric contents and their
electrolyte disturbances should be corrected.

DEFECATION
- Spinal reflex initiated by distention of the rectum with feces.
- It results in contraction of the rectum and relaxation of the internal anal
sphincter (in response to parasympathetic stimulation).
- This reflex can be facilitated or inhibited by relaxing or contracting the
external anal sphincter (Skeletal muscle under voluntary control through
the pudendal nerve).
- The pudendal nerve is a somatic nerve originating from the sacral
segments S2, 3 & 4.
- The components of this reflex are:
Receptors: Stretch receptors in the wall of the rectum, stimulated when
the rectum is full and its pressure reaches 18 mmHg (e.g. following mass
action contraction).
Afferents: Parasympathetic nerves (pelvic splanchnic nerve).
Center: Sacral segments (S2, 3 & 4).
Efferents: Parasympathetic nerves (pelvic splanchnic nerve).
Effectors: Smooth muscle in the wall of the rectum and smooth muscle of
the internal sphincter.
- The response of the reflex is contraction of the wall of the rectum and
relaxation of the internal sphincter to allow defecation.
- This is facilitated (in suitable conditions) by relaxing the external
sphincter voluntarily. In unsuitable conditions, the subject contracts the
external sphincter to inhibit defecation.
- When the pressure in the rectum reaches 55 mmHg, the stool is forced
out through the external sphincter in spite of its resistance.
- Note that the sympathetic neurons contract the internal sphincter and
relax the wall of the rectum; however, they are not part of the defecation
reflex.

Abnormalities of defecation:
- Transection of the spinal cord above the sacral segments impairs the
descending orders from the brain to the external sphincter (resulting in
loss of the voluntary control). However, since the external sphincter is in
state of contraction, stool is not evacuated until the rectal pressure
reaches 55mm Hg. Here it forces its way out.
Fig 8.20: The defecation reflex
The gastro-colic reflex

- When food enters the stomach, the rectum contracts to allow
defecation.
- This reflex occurs mainly in children who defecate after meals.
- It is not mediated by a neural mechanism.
- The hormone gastrin may be responsible for his reflex.

DIGESTION & ABSORPTION
- Complex substances are broken down into absorbable units in the small
intestine.
- The absorbable units enter either the portal blood or the lymphatic
system.
- Non-digestible & absorbable units like cellulose & lignin (dietary fiber) are
excreted in stool.
- These vegetable products add bulk to stool.
- When they are present in high amount in food (high fiber diet), they
decrease incidence of colonic cancers, diabetes mellitus, ischemic heart
disease and other problems.
CARBOHYDRATES
CHO Digestion
- Types of CHO in diet:
o Monosaccharides:
- Glucose
- Fructose
o Disaccharides:
- Maltose (2 glucose)
- Trehalose (2 glucose)
- Sucrose (glucose + fructose)
- Lactose (glucose + galactose)
o Polysaccharides (glucose polymers):
- Starch
- Derivatives of starch (Amylose, amylopectin)
- Glycogen

In the mouth: Salivary α amylase (acts on polysaccharides "starch")
In the stomach: No specific enzyme. Salivary α amylase is inhibited
(by the low pH).
In the intestine: Pancreatic α amylase (also acts on starch).
Note: Salivary α amylase may resume its activity in the intestine (suitable
pH)
- Products of starch digestion by α amylase enzymes:
1- Disaccharides: maltose
2- Trisaccharides: maltotriose
3- Short polymers: α dextrins
- Further digestion requires the following intestinal enzymes found in the
brush border:
o α dextrinase: Acts on alpha dextrins, maltose & maltotriose
o Maltase: Acts on maltose to give glucose + glucose
o Sucrase: Acts on sucrose to give glucose + fructose
o Lactase: Acts on lactose to give glucose + galactose
o Trehalase: Acts on trehalose to give glucose + glucose
CHO Absorption
- Only occurs for the monosaccharides (e.g. glucose, galactose …)
- Absorption is almost 100%
- The absorbed units enter portal circulation
Glucose absorption:
- Co transported with sodium
- Na+ facilitates glucose absorption & vice versa.
- Water follows sodium; that is why oral rehydration solutions (ORS) are
used for treatment of diarrhea. These solutions contain salt and sugar.

- Transporters of glucose and sodium:
1- On luminal membrane (carriers for co-transport to inside the cell):
o Sodium-glucose transporters 1 & 2 (SGLT1 & SGLT2)
2- On basolateral membrane (carriers for facilitated diffusion to the ISF):
o Glucose transporters 1 & 2 (GLUT1 & GLUT2)
- Remember that: Glucose transporters are also found in the cells of the
proximal convoluted tubules in the kidney for reabsorption of sodium and
glucose (see chapter 9).
- Glucose transporters are also found in other cells in the body. They are
seven types; among these types, only GLUT-4 is sensitive to insulin
(found in fat & muscle cells).
Galactose absorption: Similar to glucose (i.e. co transported with sodium
“secondary active transport”)
Fructose absorption: Facilitated diffusion
Pentose absorption: Produced from metabolism of nucleic acids.
Absorbed by simple diffusion.
Abnormalities of CHO digestion & absorption

- Deficiency of the digestive enzymes in the intestinal brush border (by a
congenital or acquired cause) results in diarrhea, abdominal distention and
flatulence. This usually follows ingestion of a carbohydrate meal and its
breakdown by the intestinal bacteria resulting in increased number of
osmotic particles (causing diarrhea) and excessive release of gases
(causing abdominal distention & flatulence).
- A good example is lactose intolerance due to deficiency of lactase
enzymes. Here symptoms follow ingestion of milk.
- The condition is treated by avoidance of milk and use of yogurt, which
contains bacterial lactase.

PROTEINS
Protein Digestion
- Sources of protein:
 Diet
 GIT secretions & desquamated cells.
 In the mouth: No enzyme for digestion.
 In the stomach: Pepsin, gelatinase and rennin (See gastric
secretion).
 In the intestine: Pancreatic endopeptidases (Trypsin, chymotrypsin,
and elastase) and pancreatic exopeptidase (Carboxypeptidases (A
& B)). Then further digestion occurs by proteolytic enzymes found in
the brush border (aminopeptidase, carboxypeptidase,
endopeptidase and dipeptidase).
- Products of protein digestion:
 Free amino acids
 Dipeptides and tripeptides
- These are further digested by peptidases in the cytoplasm of cells.
Protein Absorption
- About 95-98% of proteins are digested & absorbed.
- The absorbed units enter portal circulation.
Absorption of free amino acids:
- Co transport with sodium (mainly)
Absorption of dipeptides & tripeptides:
- By a mechanism involving hydrogen ions.
Complete proteins (undigested):
- Occurs in infants for IgA antibodies in milk by endocytosis.

Abnormalities of protein digestion & absorption
- Absorption of foreign proteins induces antibody formation; this explains
allergy to certain types of food.
- Congenital defects in the mechanisms of amino acid absorption result in
inborn errors of metabolism. Examples include: Hartnup disease &
Cystinuria.
LIPIDS
Lipid Digestion
- Lipids in diet:
 Triglycerides & cholesteryl esters
 In the mouth:
- Lingual lipase (acts on triglycerides).
 In the stomach:
- Gastric lipase.
 In the intestine: (from the pancreas and from the liver)
- From the pancreas:
o Pancreatic lipase & Colipase (revise contents of pancreatic
secretion)
o Bile salt activated lipase
o Cholesteryl ester hydrolase
- From the liver:
o Bile salts, which cause emulsification and micelle formation
(see functions of bile).
Lipid Absorption
- More than 95% of fats are absorbed in adults, but less than that in
infants.

- Most fats are absorbed by passive diffusion. However, carriers may be
involved.
- The absorbed units either enter portal circulation or lymphatics as
follows:
o Fats entering the portal blood have carbons < (10-12) e.g. short
chain free fatty acids (FFAs).
o Fats entering the lymphatics have carbons > (10-12) e.g. long
chain free fatty acids and cholesterol.
- Before entering the lymphatics, the long chain fatty acids and cholesterol
are re-esterified within the cytoplasm of intestinal cells and become coated
with protein & phospholipids to form chylomicrons.
- Chylomicrons are released to lymphatics by exocytosis.
Abnormalities of fat digestion & absorption
Steatorrhoea (fatty stool):
= loss of more than 5 grams of fat in stool per day.
- Steatorrhoea is caused by conditions that impair release of pancreatic
lipase or bile salts into the small intestine.
- For example: Chronic pancreatitis & obstruction of the common bile duct.
- Stool is usually bulky, offensive and difficult to flush, because of fats.
(Note that the total weight of normal stool is about 80-200 g/day but 75%
of this amount is water; also there are other constituents not dietary in
origin like bacteria & desquamated cells)
ABSORPTION OF ELECTROLYTES
Sodium:
- Absorbed throughout the small & large intestines, actively by the action
of the Na+-K+ ATPase pumps on the basolateral membranes of intestinal
cells.

- Glucose facilitates absorption of sodium on the apical membranes
(through the SGLTs, see above).
- Other substances that are co-transported with sodium on the apical
membranes include: galactose, mannose, amino acids, lactate, iodide, bile
acids and some short chain fatty acids).
Chloride:
- Absorbed passively with sodium and possibly actively in exchange
tobicarbonate.
- Secreted to the intestinal lumen through chloride channels.
- Enters enterocytes from ISF by (Na-K-2Cl) co transporters on the
basolateral membranes.
- Part of the cholera toxin enters enterocytes & increases cAMP. This
results in activation of the chloride channels through a protein kinase.
- The activation causes severe watery diarrhea because it increases
chloride secretion, decreases NaCl absorption and increases water loss.
Potassium:
- Secreted into the intestinal lumen by diffusion or active secretion.
- Aldosterone increases K+ secretion in the colon (by increasing Na+-K+
ATPase pump activity in the basolateral membranes of intestinal cells).
- In the distal colon some K+ is absorbed back by H+-K+ ATPase pump in
the luminal membrane.
- Chronic diarrhea decreases this absorption resulting in loss of K + (=
hypokalemia = paralytic ileus).
- See iron absorption in volume 1 & calcium absorption below in the
endocrine system.

1- Facilitated diffusion is used for absorption of:
a- Glucose
b- Galactose
c- Fructose
d- Pentose
e- Lactose
2- The hormone secretin:
a- Is stimulated by acid in the duodenum
b- Is produced by the pancreas
c- Stimulates contraction of the gall bladder
d- Stimulates secretion of pancreatic enzymes
e- Stimulates gastric emptying
3- The large intestine differs from the small intestine because:
a- It is a site for absorption of water and electrolytes
b- It moves its food contents by peristalsis
c- It has lower number of goblet cells
d- Its longitudinal muscle layer is incomplete
e- It is not supplied by the vagus nerve
4- When compared with bile in the common hepatic duct, bile in the gall
bladder contains lower concentration of:
a- Bile salts
b- Bile pigments
c- Sodium ions
d- Hydrogen ions
e- Cholesterol
5- Long chain fatty acids, after being processed within mucosal cells of the
intestine, are:
a- Extruded back to intestinal lumen
b- Released directly into portal circulation
c- Released to lymphatics in form of chylomicrons
d- Stored within the cells
e- Catabolised immediately for release of energy
6- Paralytic ileus is:
a- Caused by hypokalemia
b- Characterized by excessive peristalsis
c- Improved following discharge of noradrenaline
d- Often painful
e- Best treated by surgical operation
7- Peristaltic contractions
a- Are propulsive movements
b- Depend on extrinsic innervation
c- Occur in the absence of the myenteric plexus
d- In the small intestine are abolished by vagotomy
e- Are increased by sympathetic stimulation

8- Control of bile secretion depends on:
a- Vagal stimulation especially during the intestinal phase
b- CCK which relaxes the gall bladder to receive bile
c- Enterohepatic circulation of bile acids
d- High rate of bile acid formation in the liver
e- Secretin which causes contraction of the gall bladder
9- Digestion of lipids:
a- Occurs mainly in the large intestine
b- Requires bile pigment
c- Must be preceded by emulsification
d- Requires a lipid soluble enzyme
e- Is impaired in absence of both gastric and lingual lipase
10- Defecation:
a- Is exclusively an involuntary reflex
b- Is initiated by distension of the rectum
c- Is mediated via sympathetic neurons
d- Stops permanently after spinal cord transaction at L2
e- Usually occurs when rectal pressure reaches 55 mmHg
11- Removal of the terminal ileum results in:
a- Decreased glucose absorption in large intestine
b- Increased fat absorption in small intestine
c- Decreased hepatic formation of bile acids
d- Increased water content of feces
e- Prolonged constipation
12- Bile:
a- Is secreted by the gall bladder
b- Contains lipase for digestion of lipids
c- Is acidic due to bile acids
d- Release is stimulated by CCK
e- Becomes diluted in the gall bladder
13- Concerning pancreatitis, which of the following findings is correct?
a- Diarrhoea with high concentration of amylase in stool
b- Constipation with low concentration of lipase in intestinal
lumen
c- Steatorrhoea with high concentration of amylase in serum
d- Low concentrations of both amylase in lipase in serum
e- High concentrations of both amylase in lipase in intestinal
lumen
14- Bile salts:
a- Are synthesized from fatty acids
b- Are absorbed in the duodenum
c- Increases surface tension of intestinal fluid
d- Increases surface area of fat droplets
e- Are totally absorbed to the enterohepatic circulation
15- The gastro-colic reflex:
a- Is a neural reflex

b- Causes relaxation of the external anal sphincter
c- Usually follows a mass action contraction of large intestine
d- Occurs after release of gastric contents in the duodenum
e- Is more common in neonates than adults
16- The following enzyme is essential for protein digestion:
a- Alpha amylase
b- Lingual lipase
c- Pepsin
d- Trypsin
e- Alkaline phosphatase
17- Water and electrolyte in the GI tract are:
a- Derived mainly from ingested fluids
b- Absorbed mainly in the large intestine
c- Equilibrated with GI secretions at the stomach
d- Absorbed mainly in the jejunum
e- Absorbed in response to activity of GI hormones
18- The following vitamin is absorbed primarily by diffusion:
a- Vitamin C
b- Folic acid
c- Vitamin D
d- Vitamin B12
e- Niacin
19- Pancreatic secretion rich in bicarbonate is released in response to:
a- CCK
b- Vagal stimulation
c- Glucagon
d- Gasrtin
e- Secretin
20- Which of the following is directly activated by trypsin:
a- Enterokinase
b- Co-lipase
c- Pepsinogen
d- Pancreaatic lipase
e- Alpha amylase
21- Bile salts are
a- Synthesized from hemogobin
b- Absorbed in terminal ileum
c- Form chilomicrons within the enterocytes
d- Responsible for the color of stool
e- 50% are absorbed to the enterohepatic circulation
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
c a d c c a a c c b d
12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
d c d e d d c e b b

CHAPTER (9)
THE RENAL SYSTEM
STRUCTURE & FUNCTION
- The renal system consists of the following structures:
– 2 kidneys, 2 ureters, urinary bladder & urethra.
Fig 9.1: The renal system
- The kidneys are "bean shaped" retroperitoneal structures.

- They are located on each side of the vertebral column, approximately at
the level of T12 to L3.
- In a normal adult, each kidney is about 10 cm long, 5.5 cm in width and
about 3 cm thick, weighing 150 grams.
- The upper parts of the kidneys are partially protected by the eleventh and
twelfth ribs, and each whole kidney is surrounded by two layers of fat.
- The right kidney sits just below the liver, the left below the diaphragm and
adjacent to the spleen. Therefore, the right kidney is slightly lower than
the left one.

- The medial side of each kidney is concave. On the concavity there is an
opening known as the renal hilum. This admits the renal artery, the renal
vein, the renal nerves (mostly sympathetic) and the ureter.
- The outer portion of the kidney is called the renal cortex. This lies
immediately beneath the renal capsule (fibrous tissue).
Fig 9.2: The kidney
- The renal medulla lies deep to the cortex. It is divided into about 10
conical structures known as the renal pyramids.
- Each pyramid together with the associated overlying cortex forms a renal
lobe (supplied by an interlobar artery).
- The tip of each pyramid (called a papilla) empties into a minor calyx.
Each minor calyx empties into a major calyx. The major calices empty
into the renal pelvis. The pelvis transmits urine to the urinary bladder
through the ureter.

Fig 9.3: The minor and major calices
RENAL BLOOD VESSELS

- From the abdominal aorta the blood supply to the kidney comes through
and then drained by the following blood vessels (look at fig 9.4 & match
the vessels with the numbers):
1. Renal artery Fig 9.4: Renal blood vessels
2. Interlobar arteries
3. Arcuate arteries
4. Interlobular arteries
5. Afferent arteriole
6. Glomerular capillaries
7. Efferent arteriole
8. Peritubular capillaries
9. Interlobular veins
10. Arcuate veins
11. Interlobar veins
12. Renal vein
Rememer that: Peritubular capillaries in the Juxtamedullary nephrons (see
below) form U shaped capillaries known as vasa recta. These long and
straight capillaries play an important role in concentration of urine.

RENAL BLOOD FLOW (RBF)
= 1.2 L/min. This is about 20-25% of the cardiac output.
- It is directed mainly to the cortex (90% to the cortex and only 10% to the
medulla).
- This low blood flow to the medulla maintains its high osmolarity.
- The renal blood flow is autoregulated (i.e. it is maintained constant in
spite of the changes in mean arterial pressure between 80-180 mmHg).
- This autoregulation is explained by:
 Myogenic response (response from smooth muscle in walls of renal
blood vessels)
 Humoral factors (factors mixed with blood like NO & Angiotensin 2)
- The RBF is also regulated by the following neural & hormonal factors:
o Sympathetic stimulation: decreases RBF by constricting afferent
arterioles.
o Catecholamines: decrease RBF by constricting afferent arterioles.
o Dopamine: increases RBF by causing vasodilatation.
o Angiotensin II: decreases RBF by constricting mainly the efferent
arterioles.
o ADH (Vasopressin): decreases RBF by causing vasoconstriction.
o Prostaglandins: some of these local hormones are vasodilators (PGI2,
PGE2) & others are vasoconstrictors (thromboxane A2).
Therefore, chronic use of aspirin, which inhibits prostaglandin
synthesis, affects renal blood flow & renal function.
- The renal blood flow can be measured by:

o Flow meter devices.
o Fick principle (using clearance of para-aminohippuric acid (PAH), (see
below).

FUNCTIONS OF THE KIDNEY
1. Excretion of waste products (e.g. urea, uric acid …)
2. Control of ECF volume (by excretion of more or less water in urine)
3. Control of ECF osmolarity (by regulation of sodium and water
excretion)
4. Control of ECF electrolytes (by regulation of electrolyte excretion in
urine)
5. Control of B.P. (long term effect / see control of blood pressure)
6. Control of pH (see acid base balance)
7. Endocrine function:
–Synthesis and secretion of erythropoietin
–Activation of vitamin D
–Release of renin enzyme into the blood
THE NEPHRON
= The functional unit of the kidney.
- There are about 1.3 million nephrons in each human kidney. Each
nephron is about 45-65 mm in length, consisting of a glomerulus and
tubules.
- The Glomerulus is a tuft of capillaries enclosed within a Bowman’s
capsule. It is supplied by an afferent arteriole and drained by an efferent
arteriole. Its diameter is about 200µm and its function is filtration.
- The tubules are specialized for reabsorption and secretion.
- They include:
o The proximal convoluted tubule (PCT)
o The loop of Henle (LH)
o The distal convoluted tubule (DCT)
o The collecting ducts (CDs)
Fig 9.5 The nephron
- All glomeruli are found in the cortex. Most of them are found higher up in
the cortex whereas some of them are located in juxtaposition to the
medulla. Accordingly there are two types of nephrons:
o Cortical nephrons:
- About 85% of all nephrons. Their glomeruli are found higher up in the
cortex. They are characterized by short loops of Henle.
o Juxtamedullary nephrons:
- About 15% of all nephrons. Their glomeruli are located close to the
medulla. They are characterized by very long loops of Henle. They play an
important role in concentration of urine.
Fig 9.6 Types of nephrons

Important points in histology of nephrons
- The wall of glomerular capillaries consists of endothelial cells resting on
a basement membrane and surrounded by epithelial cells of Bowman's
capsule. These 3 layers (endothelium, basement membrane, and
epithelium) form the filtration membrane through which plasma is filtered.
- Each layer in the filtration membrane has a special characteristic:
o The endothelial cells of glomerular capillaries are fenestrated. The
fenestrations are 70-90 nm in diameter.
o The basement membrane is negatively charged. This is due to
presence of sialoproteins.
o The epithelial cells of Bowman's capsule have foot processes that
interdigitate with each other leaving slits between them. For this
reason, they are called podocytes. The slits are about 25 nm in
diameter.
Fig 9.7 The filtration membrane
- Cells of the proximal convoluted tubules are characterized by:

o Microvilli on the luminal surface forming brush border
o Large number of mitochondria to provide energy for active transport
o Tight junctions at the apical side between the cells
- Cells of the thin limbs of the loops of Henle are:
o Attenuated and flat cells.
- Cells of the thick limbs of the loops of Henle are characterized by:
o Cuboid shape, with some invaginations on the basilar membrane
o Large number of mitochondria to provide energy for transport
- Cells of the distal convoluted tubules are characterized by:
o A few microvilli and mitochondria
- Cells of the collecting ducts are two types:
o Principal cells (also known as “the collecting duct cells”)
- Higher in number (= about 75% of all cells)
- Contain receptors for the hormones: ADH, aldosterone, cortisol,
PTH, calcitonin, catecholamines (β) and ANP (the papillary part of
the collecting duct).
o Intercalated cells
- Less in number but contain more organelles
- Play an important role in pH control (secrete H+ or HCO3- ions)
Remember that: Cells of the proximal convoluted tubules also contain
receptors for: PTH, Angiotensin II and catecholamines (mainly α
receptors).
- Some cells of the distal convoluted tubules, together with other cells,
form the Juxtaglomerular apparatus.
Fig 9.8 The Juxta-glomerular apparatus

- These cells of the distal convoluted tubules are close to the afferent
arteriole (they are called the macula densa cells).
- They form the Juxta-glomerular apparatus together with cells of the
afferent arteriole "Juxta-glomerular cells" and “Lacis cells.”
- Lacis cells are mesangial cells lying outside the glomerulus. Their
function is unknown.
- The apparatus secretes the enzyme renin in response to:
 Hyponatremia
 Renal ischemia (e.g. due to hypotension or hypovolemia)
 Sympathetic stimulation.
- Renin converts angiotensinogen (a plasma protein produced by the liver)
into angiotensin I (deca peptide).
- Angiotensin I is converted to angiotensin II (octa peptide) by the
angiotensin converting enzyme (ACE) produced by endothelial cells in
pulmonary capillaries.
- Angiotensin II plays an important role in control of ECF volume and blood
pressure (causes vasoconstriction, stimulates the hormones ADH and
aldosterone, stimulates thirst, activates the sympathetic and directly
stimulates sodium reabsorption at the PCT).
FORMATION OF URINE
- Urine is formed by: (filtration) at the glomerulus & (reabsorption &
secretion) by the tubules.
GLOMERULAR FILTRATION
- It is the transport of fluid and crystalloid from glomerular capillaries to
Bowman’s space.
- The filtrate is similar to plasma. However, it does not contain proteins.
(i.e. filtrate = plasma – proteins).

- The rate of glomerular filtration is known as the glomerular filtration rate
(GFR). Normal GFR = 125 ml/min in an average adult male. It is less in
females (by about 10%).
CONTROL OF THE GFR

- GFR = kf ((HPGC - HPT) - (OPGC - OPT)), Where:
• kf = Glomerular filtration coefficient. Depends on permeability &
effective surface area.
• HPGC & HPT = Hydrostatic pressure of glomerular capillaries and
hydrostatic pressure of Bowman’s capsule respectively.
• OPGC & OPT = Oncotic pressure of glomerular capillaries & oncotic
pressure of Bowman’s capsule respectively.
From the above formula, the GFR is determined by these factors:

1- Hydrostatic pressure of glomerular capillaries (HPGC)
o For filtration
o = 45-60 mmHg (higher than hydrostatic pressure of systemic capillaries
which is about 15-35 mmHg).
o This is because:
a- Glomerular capillaries are drained by arterioles not venules.
(The arterioles have high hydrostatic pressures; whereas the venules have
low pressures; therefore, the higher resistance in the arterioles elevates
the HPGC)
Remember that: The hydrostatic pressure in the efferent arteriole is about
42 mmHg. Therefore, that of glomerular capillaries should be (45-60
mmHg) to allow blood flow.
b- Another explanation is the fact that renal blood vessels are short and
straight. This ensures transmission of the high hydrostatic pressure from
the abdominal aorta towards the glomerular capillaries.
2- Oncotic Pressure of glomerular capillaries (OPGC)
o It is the osmotic pressure of plasma proteins (mainly albumin).
o Against filtration
o = 20 - 25 mmHg at afferent arteriolar end. This increases to 35 mmHg
at efferent arteriolar end (because proteins become highly
concentrated after filtration of about one fifth of the plasma).
3- Hydrostatic pressure of Bowman’s space (HPT)
o Against filtration. = 10 mmHg (increased in urinary tract obstruction).
4- Oncotic Pressure of Bowman’s space (OPT)
o = Zero (because proteins are not filtered to the Bowman's space).
5- Permeability of the membrane
o Allows free passage of particles < 4 nm in diameter
o Prevents passage of particles > 8 nm in diameter
o Between (4-8 nm) passage depends on:
1- Electrical charge: (particles can not pass if negatively charged)
2- Shape: (particles cannot pass if irregular in shape)
6- Surface area of the membrane (SA)
o = 0.8 m2 (for both kidneys)
o Increases or decreases by contraction or relaxation of mesangial cells.
- Contraction of mesangial cells by Angiotensin 2, endothelin, ADH,
histamine, leukotrienes and catecholamine decreases the SA whereas
their relaxation by ANP, cAMP and Dopamine increases the SA.
The filtration pressure can be measured as follows:

- At the end of glomerular capillaries near the afferent arteriole:
Filtration pressure = HPGC - (OPGC + HPT) = 45 - (25 + I0) = 10 mmHg
- At the end of glomerular capillaries near the efferent arteriole:
Filtration pressure = 45 - (35 + 10) = 0, indicating that filtration occurs
normally at the first part of glomerular capillaries.
Fig 9.9 The filtration pressure
The GFR is affected by:

Changes in HPGC by:
o Changes in blood pressure: The blood pressure does not affect the
GFR unless the mean arterial pressure is above or below the
autoregulation range (i.e. < 80 or > 180 mmHg).
o Afferent arteriolar constriction: Decreases the GFR (by decreasing the
HPGC).
o Efferent arteriolar constriction: May be mild constriction (Increases the
GFR by increasing the HPGC) or severe constriction (Decreases the
HPGC & the GFR).
Changes in OPGC by:
o Hypoproteinemia: Increases the GFR (by decreasing the OPGC).
o Dehydration: Decreases the GFR (by increasing the OPGC).
Changes in HPT by:
o Edema of the kidney: Distention of the kidney within its tough capsule
increases the hydrostatic pressure within the tubules and decreases
GFR.
o Obstruction of the urinary tract: Decreases the GFR (by increasing the
HPT).

Changes in OPT
o Glomerulonephritis: Results in filtration of proteins into the Bowman’s
space (by causing loss of the negative charges in the basement
membrane). This increases the GFR by increasing the OPT.
Changes in permeability
o Glomerulonephritis: Increases the GFR.
Changes in surface area
o Removal of one kidney decreases the surface area and therefore the
GFR.
o Contraction or relaxation of mesangial cells affects the GFR by
decreasing or increasing the surface area respectively (read about
factors affecting mesangial cells above).
Changes in renal blood flow
o The renal blood flow is normally autoregulated. However, when
increased it increases the GFR and when decreased decreases the
GFR.
The Tubuloglomerular feedback
o When the tubular flow rate increases at the distal part of the nephron,
GFR decreases. The macula densa cells are the sensor for this
feedback & the response is adjusted by constricting the afferent
arteriole by a mediator (most probably ATP).
o On the other hand, when GFR increases, tubular reabsorption also
increases (this is called “Glomerulotubular balance”).
MEASUREMENT OF THE GFR

- By measuring clearance of substances with the following characteristics:
–Non toxic
–Not metabolized, stored or produced by the kidney

–Freely filtered
–Not reabsorbed by the renal tubules
–Not secreted by the renal tubules
- Since the substance (X for example) is not reabsorbed or secreted by
renal tubules: It’s Filtration = Excretion
GFR x Px = Ux V
GFR = Ux V/Px
This is the formula of clearance
Px= plasma concentration of x
Ux = urine concentration of x
V = urine flow rate (or urine volume per unit time)
- Examples of substances used to measure the GFR:
o Inulin: fructose polymer administered by intravenous (I.V.) infusion
(see below)
o Creatinine: produced from creatine kinase (phosphocreatine) in
muscles (see below)
o Iohexol: a contrast agent (known as omnipaque); used recently as
alternative to inulin.
o Radioisotopes: (e.g. 51Cr- EDTA)
CLEARANCE
- Defined as the volume of plasma, which is completely cleared of a
substance per unit time.
- Clearance of any substance is measured by the formula Cx = Ux V/Px
- It can be used for:
- Measurement of GFR (by inulin or creatinine clearance).
- Measurement of renal blood flow (by PAH clearance).
- Assessment of renal function

Measurement of GFR using inulin clearance:
1- Inulin is given by continuous intravenous (I.V.) infusion until its level in
plasma becomes constant.
2- A blood sample is taken to measure its concentration in plasma (Px).
3- Urine is collected for certain time (usually 24 hours) to measure urine
flow rate (V) and a sample is taken to measure inulin concentration in
urine (Ux).
4- The formula of clearance is applied to measure the GFR as follows:
GFR= UxV/Px.
Remember that:
- Inulin is the ideal substance for measurement of the GFR because it is
freely filtered, not reabsorbed or secreted. However, the method is time
consuming, needs I.V. infusion of inulin and accurate collection of timed-
urine samples.
- The classical method for measuring inulin clearance involves continuous
I.V. infusion of inulin until its level in plasma becomes constant; however,
an alternative method of administration (a single bolus dose) gives
comparable results, especially in children.
Measurement of GFR using creatinine clearance:

1- Urine is collected for 24 hours to measure urine flow rate (V) and a
urine sample is taken to measure creatinine concentration in urine (Ux).
2- A blood sample is taken to measure creatinine concentration in plasma
(Px).
3- The formula of clearance is applied to measure GFR (= UxV/Px).
Remember that:
- Creatinine does not need I.V. injection because it is produced
endogenously from phosphocreatine in muscles. This advantage makes it
more practical in measuring the GFR.
- The disadvantage of creatinine is its slight secretion by the proximal
convoluted tubules. This tends to give higher value for GFR. However, the
method used for measuring creatinine in plasma gives higher results. This
corrects the error and gives almost true GFR results.
Measurement of renal blood flow using PAH clearance:

- Blood flow to organs is usually measured by the Fick principle.
- The principle states, "the amount of a substance consumed or added by
an organ in a given time equals the arterio-venous difference in
concentration times the blood flow to the organ.”
- In summary: Q = ([A]-[V]) x Blood flow (where Q is the amount consumed
& the ([A]-[V]) is the arterio-venous difference in concentration).
- Therefore: Blood flow = Q/[A] – [V]
- Substances used in measurement of renal blood flow should be:
–Non toxic
–Not metabolized, stored or produced by the kidney
–Do not affect RBF
–Highly secreted to the extent that its concentration in renal veins =
0 (or, alternatively, the concentrations in renal artery and vein can
be measured).
- The para aminohippuric acid (PAH) is an example of a substance that is
highly secreted by renal tubules (secreted excessively by the PCT).
- The mechanism of secretion is an active mechanism (i.e. have an upper
limit for secretion). That is why PAH concentration in renal vein = zero only
when infused in small dose.
- When PAH concentration in renal vein is zero, this indicates that the
entire amount consumed by the kidney (Q) is excreted in urine (i.e. Q =
Excretion = UPAH x V).
- By applying Fick's principle (Blood flow = Q/[A] – [V]):
Blood flow = UPAH x V/[A] – zero
- Since PAH is measured in plasma, then the concentration in artery “[A]”
is actually a concentration in plasma “PPAH”; and the obtained
measurement is plasma flow rather than blood flow.
- Therefore: Effective renal plasma flow = UPAH x V/ PPAH (= Formula of
clearance for PAH)
- The obtained measurement is the effective renal plasma flow (ERPF=
625 ml/min) since not all renal plasma flow is filtered in the tubules. About
10% of the renal plasma flow (supplies the capsule and the fats around
the kidney) is not included in the measurement.
- Therefore the total renal plasma flow (RPF) can be measured from the
ERPF as follows: RPF= ERPF /90% or RPF= ERPF x 100/90= 700 ml/min
- Now the renal blood flow (RBF) can be calculated from the (RPF) as
follows: RBF = RPF x 100/100-PCV.
Filtration fraction
- Filtration fraction = GFR/RPF = 125/700 = 0.16-0.2.
- This indicates that one fifth of plasma is filtered every minute
- The filtration fraction is used as an index for glomerular function.
Clearance of other substances

o Glucose clearance:
- Equals zero as long as glucose is not excreted in urine (read below).
- When glucose concentration in plasma exceeds a certain value (the
renal threshold “180mg/dL”); the excess glucose starts to appear in urine
(because it is not reabsorbed). Therefore, glucose clearance rises as
glucose level in plasma is increased; until it approaches the value of inulin
clearance.
Fig 9.10: Comparison between inulin and glucose clearance
o PAH clearance:
- Equals the renal plasma flow because PAH is highly secreted in the
PCT. The mechanism of secretion is an active process (i.e. it has an upper
limit of secretion at which all the carriers are saturated (TmPAH)); that is
why it is absent in veins when given in a small dose, but it appears when
given in larger doses. For this reason, PAH clearance decreases as its
plasma concentration rises.
- In very high plasma level, PAH clearance may reach inulin clearance.
Fig 9.11: Comparison between inulin clearance and PAH clearance

o Free water clearance (Cwater) & osmolar clearance (COSM):
- Cwater is the volume of plasma that is completely cleared of free water per
unit time. It is the difference between urine volume and clearance of
osmoles (Cwater= V – UOSMV/POSM) where “V” is urine flow rate.
- COSM = the amount of water necessary to excrete the osmotic load in a
urine that is isotonic with plasma.
- Free water clearance can be used as an indicator of how water is
regulated. A free water clearance of zero means the kidney is producing
isotonic urine. Values greater than zero imply that the kidney is producing
dilute urine (through excretion of solute-free water). Values less than zero
imply that the kidney is conserving water.
- For example, during maximum antidiuresis with excess ADH, Cwater = -1.9
L/d whereas during absence of ADH Cwater = 20.9 L/day.
Notes to remember about clearance:

- Clearance ranges between "0" for totally reabsorbed substances & "625
ml/min" for highly secreted ones. Clearance of of 125 ml/min indicates that
a substance is neither absorbed, nor secreted (look at the following table).
Table 9.1: Clearance of substances with different characteristics:

Characteristic of the Clearance (ml/min) Example
substance
Totally reabsorbed 0 Glucose
Not reabsorbed or 125 = GFR Inulin
secreted
Highly secreted 625 = renal plasma flow PAH
Partially reabsorbed less than 125 & more than 0 Urea
Partially secreted more than 125 and less than 625 Potassium

TUBULAR FUNCTION
- Generally, the renal tubules perform the following functions:
o Reabsorption: Transport of a substance from the tubular lumen to the
blood in peritubular capillaries through or between the tubular cells.
o Secretion: Transport of a substance in the opposite direction (from the
peritubular capillaries to the tubular lumen).
- By these 2 processes the filtrate is changed into urine.
Fig 9.12: Reabsorption and secretion
Note: Transport of solutes and water between the tubular cells (through
the tight junctions) is known as "paracellular transport" whereas through
the cells is known as "transcellular transport.”
- The mechanisms of transport may be active or passive. They include:
1. Simple diffusion (down chemical & electrical gradient; across ion
channels; without use of carriers or consumption of energy).
2. Facilitated diffusion (down chemical & electrical gradient; with use of
carriers but without consumption of energy).
3. Primary active transport (against chemical or electrical gradient; with
use of carriers and consumption of energy).

4. Secondary active transport (involves indirect consumption of energy
and uses one of two types of carriers: symport (for co-transport with
another substance in the same direction) & antiport (for transport with
another substance in the opposite direction)).
5. Endocytosis (active transport for small proteins and peptides in the
PCT).
- Here are examples for reabsorption and secretion of some important
substances:
WATER REABSORPTION
- Volume of water filtered into the Bowman's capsule =180 L/day.
- Volume of water excreted in urine normally = 1-1.5 L/day.
- In abnormal conditions urine volume may be as low as 0.5 L/day (e.g.
due to ADH excess) or as high as 23 L/day (e.g. due to ADH deficiency).
- Most of the filtered water is reabsorbed passively by the renal tubules
through special water channels (aquaporins) as follows:
PCT
- Reabsorbs 60-70% of filtered water.
- Water moves passively (following Na+ reabsorption) through “aquaporin-
1 channels”.
- The filtered fluid remains isotonic.
Loop of Henle
- Reabsorbs about 15-20% of filtered water at the thin descending limb
(through aquaporin-1 channels). The ascending limbs are
o The thin descending limb reabsorbs water but not solute. The filtrate
becomes hypertonic.
o The thin ascending limb reabsorbs solute passively but not water. The
filtrate starts to be diluted.

o The thick ascending limb reabsorbs solute actively but not water. The
filtrate becomes hypotonic; for this reason, the thick ascending limb is
known as the diluting segment.
DCT
- Relatively impermeable to water.
- Reabsorbs 5% of filtered fluid.
- Solute is reabsorbed in excess of water. Therefore, the filtered fluid is
further diluted (remains hypotonic).
CDs
- Water reabsorption is hormonally dependent according to the needs of
the body.
- ADH stimulates reabsorption of about 7-13% of filtered water.
- It stimulates insertion of water protein channels (aquaporin II) to the
luminal membrane to allow passive water reabsorption (water moves from
the hypotonic fluid in the tubules to the cells and then to the hypertonic
medulla).
Mechanism of ADH action:
o ADH binds to V2 receptors on the basolateral membrane of principal
cells
o This activates adenylate cyclase enzyme resulting in hydrolysis of ATP
to cAMP
o cAMP activates protein kinase A
o The protein kinase A activates translocation of aquporin-2 channels
from intracellular vesicles to the apical membrane
o Water moves passively through the aquaporin-2 channels
- In presence of high level of ADH (Syndrome of inappropriate ADH
secretion “SIADH”), urine becomes highly concentrated. Its volume is only
about 0.5 L/day and its osmolarity may reach 1400 mosm/Kg.

- In absence of ADH (Diabetes Insipidus), large volume of diluted urine is
excreted. Urine volume may reach 23 L/day and its osmolarity is only
about 30 mosm/L.
- There are 2 types of diabetes insipidus (DI): Nephrogenic & neurogenic
o Nephrogenic DI: due to a defect in either V2 receptors or aquaporin-2
channels. This type does not respond to treatment with ADH agonist.
o Neurogenic DI: due a defect in synthesis or release of ADH from the
CNS. It responds to treatment with ADH agonist.
Remember that:
o In SIADH: Plasma is diluted whereas urine is highly concentrated.
o In DI: Plasma is concentrated whereas urine is highly diluted (in spite
of dehydration).
o In addition to aquaporins 1 & 2; humans have aquaporin 5 & 9 in
extra-renal tissues.
Fig 9.13: Water reabsorption

SODIUM REABSORPTION
- Filtered into the Bowman's capsule= ([Na] in plasma x GFR) = 26000
mmol/day. Excreted in urine = ([Na] in urine x urine volume per day) =150
mmol/day.
- Sodium excretion may be as low as 1 mmol/day or less (on a low salt
diet)) or as high as 400 mmol/day or more (on a high salt diet).
- Most of the filtered sodium is reabsorbed by the renal tubules as follows:
PCT
- Reabsorbs 60-70% of the filtered Na+.
- Reabsorption occurs actively by Na+ -K+ ATPase pump on the
basolateral membrane.
- The pump creates low sodium concentration in the tubular cells by taking
2 potassium ions to inside and extruding 3 sodium ions to the interstitium.
This allows passive sodium diffusion through the luminal membrane down
its chemical and electrical gradients. However, the overall process is
active transport, not passive transport.
- Water follows Na+ (Osmosis) to the interstitium; then from the interstituim
or peritubular space, water and sodium enter capillaries by solvent drag.
- Some substances are co-transported with Na+ (through the luminal
membrane):
o Glucose
o Amino acids
o Phosphate
o Organic acids (e.g. lactate)
o Bicarbonate (unlike the above, through the basolateral membrane)
- On the other hand, some substances are antiported with Na+:
o H+ ions
o Ammonium (NH4+)

Loop of Henle
- Reabsorbs 20-25% of filtered Na+.
- The thin descending limb does not reabsorb sodium.
- The thin ascending limb reabsorbs sodium passively.
- The thick ascending limb reabsorbs sodium actively (by 1Na +, 1K+ & 2Cl-
co-transport pump on the luminal membrane).
DCT & CDs
- Na reabsorption is hormonally dependent according to the body needs.
- Mineralocorticoids (e.g. aldosterone) act on intracellular receptors in
principal cells to stimulate Na+ reabsorption and K+ secretion.
Mechanism of aldosterone action:
o Aldosterone binds to cytoplasmic receptors.
o The receptor-hormone complex moves towards the nucleus where it
stimulates transcription of mRNA, mRNA is translated into proteins.
o The proteins result in rapid effects (within 10-30 min) and later effects.
o The rapid effects include:
- Activation of pre-existing epithelial sodium channels (ENaCs); thus
increasing the permeability of the luminal membrane to sodium.
- Activation of pre-existing Na+-K+ pumps; this decreases intra-cellular
sodium to allow its entry from the lumen to the cells.
o The later effects include:
- Increased number of ENaCs
- Increased number of Na+-K+ pumps
Other hormones affecting sodium excretion:
 Atrial natriuretic peptide: decreases sodium reabsorption (acts in CDs).
 Glucocorticoids (e.g. cortisol): have mineralocorticoid effect (in CDs).
 Angiotensin II: causes sodium reabsorption (acts in PCT).
 Local factors (PGE2, IL-1 & Endothelin): cause natriuresis.

Fig 9.14: Sodium reabsorption
Conditions associated with abnormal sodium excretion:

 Primary & secondary hyperaldosteronism:
- Primary hyperaldosteronism (Conn’s syndrome) is due to adenoma in the
adrenal cortex secreting excess aldosterone.
- It is characterized by sodium retention, hypertension, & hypokalemia.
- It is not characterized by edema. This is due to “aldosterone escape
phenomenon” caused by secretion of ANP (read about aldosterone in the
endocrine system).
- Secondary hyperaldosteronism, on the other hand, is characterized by
sodium retention and edema. It is associated with nephrotic syndrome,
heart failure and liver cirrhosis.
 Primary adrenal insufficiency ( Addison’s disease):
- Due to destruction of adrenal cortex (by tuberculosis or auto antibodies).

- The resulting features (tiredness, hypoglycemia, hyponatremia,
hypotension & hyperkalemia) are due to deficiency of both
mineralocorticoids and glucocorticoids.
 Bartter’s syndrome
- Occurs due to congenital defect in NaCl reabsorption in the thick
ascending limb of the loop of Henle. The resulting loss of sodium chloride
in urine causes hypovolemia. Hypovolemia causes secondary stimulation
of the renin-angiotensin-aldosterone system resulting in hypokalemia and
metabolic alkalosis. (Remember that: there is no hypertension in spite of
the high renin and aldosterone).
 Liddle’s syndrome
- Occurs due to a gene mutation that causes prolonged action of the
epithelial sodium channels (ENaCs). This causes sodium retention and
hypertension associated with excessive loss of potassium. The most
important feature is the low level of renin and aldosterone in plasma (i.e.
hypertension with low renin and aldosterone).
POTASSIUM HANDLING
- Filtered into the Bowman's capsule= ([K+] in plasma x GFR) = 600
mmol/day. Excreted in urine= ([K+] in urine x urine volume per day) = 90
mmol/day. However, the amount excreted varies according to the intake
(input = output). Potassium is reabsorbed & secreted in the renal tubules
as follows:
PCT
- Reabsorbs 60-70% (by an active mechanism).
Loop of Henle
- Reabsorbs about 20% actively in the thick ascending limb by the (1Na+,
1K+ & 2Cl- co-transporters).

DCT & CDs
- Here there is potassium secretion by the principal cells “the collecting
duct cells.” Secretion of K+ is hormonally dependent (depends on
aldosterone). Aldosterone stimulates Na+ reabsorption and K+ secretion.
Mechanism of K+ secretion:
- Potassium is secreted down its electrochemical gradient from the
principal cells to the tubular lumen (through the apical membranes).
- The chemical gradient is created actively by the “Na +-K+ ATPase pumps”
on the basolateral membranes which increase potassium concentration
inside the cells (activated by aldosterone).
- The electrical gradient occurs because the tubular lumen is negative
compared with the cells (Note: the negativity inside the cells is decreased
by Na+ reabsorption; that is why Na+ reabsorption facilitates K+ secretion
(= an electrical coupling)).
Fig 9.15: Potassium reabsorption and secretion
Factors affecting K+ secretion:

o Dietary K+
- Secretion is increased by high K+ intake & decreased by low intake.
- This is due to alterations in plasma level of potassium.
o Plasma K+
- Secretion is increased in hyperkalemia & decreased in hypokalemia.
- This is explained by the direct effect of potassium on aldosterone
secretion. It is also explained by direct effects of potassium ions on the
secretory cells in the kidney.
o Aldosterone
- - Secretion is increased by aldosterone.
- - This is explained by the effect of aldosterone on the principal cells.
o Tubular flow rate
- Secretion is increased when the tubular flow rate is increased.
- This is because the rapid flow of tubular fluid maintains low potassium
concentration in the lumen (i.e. maintains the chemical gradient for K+
secretion).
o Sodium concentration in the tubular fluid
- High sodium concentration [Na+] in the tubular fluid increases potassium
secretion. This can be explained by the high tubular flow rate when [Na +]
is high and by the facilitation of K+ secretion by Na+ reabsorption (read
mechanism of K secretion).
o pH
- Secretion is increased in alkalosis and decreased in acidosis.
- This is explained by the competition between H+ & K+ for exchange with
sodium in the tubular fluid. In acidosis H+ is secreted more than potassium
& in alkalosis K+ is secreted more than H+.
o Diuretics
- Most types of diuretics increase potassium secretion (read about
diuretics below). This occurs either directly (by inhibiting the 1Na+, 1K+ &
2Cl- pump) or indirectly (by increasing the tubular flow rate).

GLUCOSE REABSORPTION
- The amount filtered depends on the concentration of glucose in plasma
(filtered load= [glucose] in plasma x GFR).
- The amount reabsorbed has an upper limit.
- This limit is never reached normally; however, when glucose level is very
high, the limit is exceeded and glucose appears in urine.
- Reabsorption occurs almost totally in the PCT by:
o Secondary active transport on the luminal membrane (Co-transport
with Na+ to allow entry of glucose into PCT cells)
o Then glucose enters the interstitium by facilitated diffusion on the
- The carriers for the co-transport are: Sodium- Glucose transporters 2
(SGLT 2)
- The carriers for facilitated diffusion: Glucose transporters 2 (GLUT 2).
Fig 9.16: Glucose transporters

Remember that:
- Glucose transporters are also found in the intestine.
- In rats, SGLT-1 & GLUT-1 are also found in the terminal portions of the
PCT.
- Among the 7 types of glucose transporters in humans (from 1 to 7), only
GLUT-4 responds to insulin and allow entry of glucose in insulin sensitive
cells (e.g. muscle and fat cells).
- The transport of glucose can be inhibited by phlorhizin (a plant sugar that
competes with glucose for the transporters).
The tubular transport maximum for glucose (TmG)

- TmG is the maximum rate of glucose that can be transported by carriers
in the PCT per unit time.
= 375 mg/min in males or =300 mg/min in females.
- This value is never reached when glucose concentration is normal.
- For example, the normal glucose level in plasma = 80 mg/dL and its rate
of transport at the PCT = GFR x [glucose]; = 125 ml/min x 80 mg/100ml; =
125 ml/min x 0.80 mg/ml; = 100 mg/min (i.e. less than T max for glucose).
Calculation of Tmax for glucose
- The T max can be calculated by substracting the excretion from the
filtered load. Tmax = Filtered load - Excretion
Example:
Calculate Tmax for glucose in a patient whose GFR= 125 ml/min,
[glucose] in plasma= 360mg/dL, urine flow rate= 1ml/min and
[glucose] in urine= 50 mg/ml
Answer:
Tmax= (360 mg/100 ml x 125 ml/min) – (1 ml/min x 50 mg/ml)
= 450 mg/min – 50 mg/min = 400 mg/min

The renal threshold for glucose
- The level of glucose in the plasma at which all glucose carriers in the
PCT are saturated (= 180 mg/dL in veins or 200 mg/dL in arteries).
- At this level the filtered load of glucose is equivalent to the TmG (the
upper limit of transport) and above this level glucose appears in urine.
- However, when calculating the actual level of glucose in plasma, which
gives a filtered load that equals the TmG, it is found to be higher than
180mg/dL:
Filtered load = GFR x Plasma concentration
Plasma concentration = Filtered load (or TmG at this case) / GFR
Plasma concentration = 375 mg/min / 125 ml/min
Plasma concentration = 3 mg/ml = 300 mg/dL
- The difference between the calculated renal threshold & the true one is
related to the avidity with which the glucose transporters bind glucose
(some nephrons reabsorb small amount of glucoe whereas others can
reabsorb large amount. Tmax represents the average reabsorptive
capacity of all nephrons).
TUBULAR SECRETION
- Certain substances are lost from the body by secretion in the renal
tubules (leaves the blood to enter the lumen through the tubular cells in
the kidney).
- Examples include:
–Potassium
–Hydrogen
–Ammonia
–Phosphate

–Uric acid
–PAH
–Creatinine
–Penicillin
–5-hydroxyindolacetic acid
–Sulfonphthalein dyes
DIURETICS
- Include chemical substances and drugs that block sodium (and therefore
water) reabsorption to increase urine volume.
- Types include:
o Loop diuretics:
- Inhibit the (1Na+, 1K+ & 2Cl- co-transporters) in the thick ascending limb
of the loop of Henle. Example: Frusemide “Lasix”.
o Thiazide diuretics:
- Inhibit sodium reabsorption at the early portion of the DCT (inhibit the
Na+/Cl- co-transporter at this site”. Example: Chlorothiazide.
o Potassium sparing diuretics:
- Antagonize the action of aldosterone (e.g. spironolactone); or inhibit the
ENaCs (e.g. amiloride).
o Carbonic anhydrase inhibitors:
- Inhibit carbonic anhydrase enzyme. This decreases bicarbonate
formation and reabsorption and therefore decreases sodium reabsorption
and hydrogen secretion. Example: Acetazolamide “Diamox”.
o Osmotic diuretics:
- Un-reabsorbed substances in the renal tubules exert an osmotic effect to
trap water. This decreases Na+ concentration in the filtrate and thus

decreases its reabsorption. Examples: Manitol, excess glucose and
excess urea.
o Other diuretics:
 Water: excess water expands plasma volume & decreases osmolarity;
therefore inhibits ADH causing water diuresis.
 Alcohol (e.g. ethanol): inhibits ADH.
 Caffeine: increases GFR & decreases sodium reabsorption.
 Acidifying salts (Calcium chloride “CaCl2” & Ammonium chloride
“NH4Cl"): Acidify ECF and urine. The anion (Cl-) binds Na+ in urine
preventing its Reabsorption. This causes mild dieresis. They are used
to promote excretion of ionizable drugs & poisons.
CONCENTRATION OF URINE
- Depends on the action of ADH, which is responsible for the final
adjustment of urine volume and osmolarity at the collecting ducts.
- At the absence of ADH: about 87% of filtered water is reabsorbed but
urine volume is still high (about 23 L/day) and its osmolarity is very low
(about 30 mosm/L).
- At the presence of excess ADH: urine volume is very low (about 0.5
L/day) and its osmolarity is very high (may reach 1400 mosm/day).
- As mentioned above, the filtrate, which reaches the collecting ducts, is
hypotonic. At the absence of ADH, the filtrate is excreted as hypotonic
whereas at its presence, the filtrate is concentrated by osmosis
(movement of water from area of lower concentration to area of higher
concentration). This means that the action of ADH depends on presence
of hypertonic medulla.
- There is a gradient of increasing osmolarity along the medullary pyramids
(starting from 300 mosm/L at the cortex to 1400 mosm/L at the deepest

parts of the medulla in humans; or even more than 2000 mosm/L in some
animals).
- Hypertonicity in the medulla is created and maintained by many factors;
without these factors, urine can never be concentrated. In summary:
Together with ADH, these factors are responsible for excretion of
concentrated urine.
- The factors include:
1- The counter current system
- Counter current transfer is the passive transfer of a substance from a
fluid to another through a semi permeable membrane. It occurs when an
inflow of fluid runs parallel to, counter to and in close proximity to an
outflow.
- It is found at many sites in the body:
o The legs
- Between arteries and veins; to control core body temperature in cold
weather.
- Heat is transferred from the descending arteries to the ascending veins;
to keep the body warm and the feet cold.
o The testes
- Between arteries and veins in the pampiniform plexus; to supply the
testes with high amount of testosterone & to conserve the low temperature
at the scrotum.
- Testosterone, which is synthesized within the testes, diffuses from the
draining veins to the supplying arteries.
o The kidney
- Here the counter current system plays an important role in concentration
of urine.
- The counter current system is found at two sites:

a- The loop of Henle (the counter current multiplier): Creates
hypertonicity
b- The vasa recta (the counter current exchanger): Maintains
hypertonicity
a- The loop of Henle (the counter current multiplier):
- The counter current system is formed by the descending and the
ascending limbs of the loop of Henle.
- The thin descending limb is permeable to water not to solute.
- The thin ascending & the thick ascending limbs are not permeable to
water. However, they multiply solutes in the medulla (passively and
actively).
- Therefore they create hypertonicity of the medulla.
Fig 9.17: The counter current multiplier

b- The vasa recta (the counter current exchanger):
- The counter current system is formed by the descending and the
ascending limbs of the vasa recta.
- The descending limb allows passive influx of solutes and efflux of water.
- The ascending limb (which is fenestrated) allows passive efflux of solutes
and influx of water.
- By this exchange, water is diverted a way from the deepest parts of the
medulla (so as not to wash out the solutes); whereas the solutes recycle
between the interstitium of the medulla and the vasa recta (to maintain
hypertonicity).
Fig 9.18: The counter current exchanger
2- The low blood flow to the medulla

- The medulla receives only 10% of the whole renal blood flow.
- This is important to maintain hypertonicity of the medulla because the
high blood flow may wash out the solutes.

3- Urea recycling between the medulla and the tubules
- A high protein diet increases the ability of the kidney to concentrate urine
for a limited time.
- That is because urea (an end product of protein metabolism) recycles
between the tubules and the interstitium of the medulla for some time
before complete excretion.
- About 50% of the filtered urea is reabsorbed in the PCT & about 10% is
excreted in urine. The remaining 40% is reabsorbed in the collecting ducts
(at the presence of ADH) to the interstitium of the medulla and then
diffuses passively through the thin ascending limb of the loop of Henle into
the tubular lumen to recycle again; part of this is excreted and the
remainder is reabsorbed to repeat the circulation until all the amount is
excreted. Therefore, urea circulation between the interstitium and the
tubules increases hypertonicity of the medulla.
Fig 9.19: Urea recycling between the interstitium & the tubules

THE MICTURITION REFLEX
- It is a visceral reflex; integrated in the spinal cord and influenced by the
higher centers. Components of the reflex are:
a- Receptors
- These are stretch receptors situated on the smooth muscle in the wall of
the bladder. They are stimulated by stretch when urine volume reaches
400 ml (however, the first urge to void is felt at a volume of about 150 ml).
- At lower volumes the receptors are not stimulated because the pressure
inside the urinary bladder “intravesical pressure” is maintained constant by
relaxation (or plasticity) of the wall of the bladder.
- The relaxation increases the diameter and therefore decreases the
intravesical pressure (according to the Laplace law: Pressure α 1/radius).
b- Afferent
- Sensory neurons in the parasympathetic nerves (pelvic nerves).
c- Center
- The center is found at the sacral segments (S2, S3 & S4).
d- Efferent
- Motor neurons in the parasympathetic nerves (pelvic nerves).
e- Effectors
- The smooth muscle in the wall of the bladder “detrusor muscle” (which
contracts) & the smooth muscle of the internal sphincter (which relaxes).
Remember that: Although the sympathetic supplies the detrusor muscle

and the internal sphincter, it does not participate in the micturition reflex.
- Relaxation of muscles of the pelvic floor facilitates micturition.
- The reflex of micturition can be initiated even before complete filling of
the bladder by contraction of the abdominal muscles voluntarily to raise
the intra-abdominal pressure.

Effect of the higher centers:
- Descending tracts from the brain may facilitate or inhibit micturition.
- Facilitatory areas are found in the pons and posterior hypothalamus
whereas an inhibitory area is found in the midbrain.
- Voluntary orders from the cerebral cortex acting on the external sphincter
(skeletal muscle guarding the bladder neck) allow or inhibit micturition.
- In suitable conditions the subject relaxes the external sphincter
voluntarily to allow micturition whereas in unsuitable conditions he
contracts it to inhibit micturition.
- The voluntary orders from the higher centers leave the sacral segments
to reach the external sphincter through the pudendal nerve (S2, S3 & S4).
Fig 9.20: The micturition reflex

Abnormalities of micturition:
o Automatic bladder
–When the full bladder empties involuntarily (no voluntary control).
–Occurs due to spinal cord damage above S2 resulting in interruption of
the descending tracts from the brain. This causes loss of the voluntary
control.
–The micturition reflex is intact (because all components are present).
Therefore bladder filling is followed immediately (automatically) by reflex
emptying.
–Patients can be trained to induce micturition (before the automatic
emptying) by scratching the inner aspect of the thigh. In these patients the
afferent impulses irradiate in the whole sacral segments causing
micturition (through a mass reflex).
o Atonic bladder
–When the full bladder does not contract (atonic). This occurs due to
damage to the parasympathetic nerves or the sacral segments.
–The micturition reflex is lost. Therefore filling is not followed by emptying
(no contraction in the bladder wall).
–In this form of urine retention, the high pressure within the bladder may
force some droplets of urine to pass out (a condition known as overflow
incontinence).
o Enuresis (or bed wetting)

–Most children remain dry at night by the age of three to five years.
However, unintentional discharge of urine during sleep may occur in
children who cannot keep the external sphincter closed during sleep (but
the micturition reflex is intact).

–The cause of this may be unknown (primary enuresis) or may be
associated with problems like diabetes mellitus, diabetes insipidus,
epilepsy and urinary tract infection (secondary enuresis). Emotional stress
was reported in some cases.
- Most affected children retain the ability to control the sphincter at older
age.
ABNORMALITIES ASSOCIATED WITH RENAL DISEASES

1- Proteinuria (in glomerulonephritis & nephrotic syndrome)
- Loss of albumin in urine due to glomerular damage or loss of the
negative charges in the glomerular basement membrane.
2- Decreased GFR with increased urine volume (in renal failure)
- GFR is decreased due to loss of acting glomeruli whereas urine volume
is increased due to defective reabsorption of salts; the salts cause osmotic
diuresis.
3- Loss of concentrating & diluting power of the kidney (in renal failure)
- Due to loss of functioning nephrons & loss of hypertonicity of the medulla
that results from defective counter current multiplier and exchanger.
4- Uremia (in renal failure)
- Rise in blood urea due to failure in its excretion. The high urea causes
(nausea, vomiting, mental confusion, convulsions & coma).
- It should be treated by dialysis (hemodialysis or peritoneal dialysis).
5- Activation of the renin-angiotensin-aldosterone system (in renal failure)
- Renal is released due to renal ischemia or hyponatremia.
6- Hypertension (in renal failure)
- Due to activation of the renin-angiotensin-aldosterone system.
7- Hypocalcemia (in renal failure)
- Due to failure of the kidney to activate vitamin D.

- Hypocalcemia results in secondary stimulation of the parathyroid
hormone (PTH) from the parathyroid gland.
- PTH causes abnormalities in bone (= renal osteodystrophy).
8- Anemia (in renal failure) or polycythemia (in renal tumors)
- Due to abnormal synthesis of erythropoietin hormone by the kidney.
- The anemia is "Normocytic normochromic anemia".
9- Acidosis (in renal failure)
- Due to failure of the kidney to secrete hydrogen ions, reabsorb
bicarbonate and synthesize ammonia.
10- Hematuria (due to stones or tumors)
- Presence of blood in urine.
11- Pyuria (in urinary tract infections "U.T.I.")
- Presence of pus in urine.
- Diagnosed when there are 10 or more neutrophils, detected by high
power field microscopy, in midstream urine.

ACID BASE BALANCE
Normal pH
- pH = - log [H] = 7.4 ± 0.05.
- [H+] = 40 nmol/L or 0.00004 mmol/L (in arterial blood).
- pH less than 7.35 = Acidosis & more than 7.45 = Alkalosis.
- pH above 7.7 or below 7.0 is incompatible with life
Sources of acid in the body
- The body produces large amount of H+ every day. Sources of H+ include:
1- Carbon dioxide (Volatile acid)
- From metabolism of fats, proteins & carbohydrates.
- Co2 produces about 12,500 mmol of H+/day.
2- Fixed acids (H2SO4 , H3PO4)
- From metabolism of phospholipids and amino acids containing sulphur
(methionine, cystine) or phosphorus (phosphoserine).
- Produce 50-100 mmol of H+/day.
3- Organic acids (acetoacetic acid, lactic acid,...)
- From metabolism of fats & carbohydrates
- Give Small amount of H+. However, in abnormal conditions (e.g. diabetic
ketoacidosis & exercise) large amount of hydrogen ions are produced.
4- Ingestion of acidifying salts (NH4Cl, CaCl2)
- The anions of these salts react with water to give acids; thus adding
small amount of acid to the body.
5- Failure of diseased kidneys to excrete normal amount of acid
- Renal failure is a known cause of acidosis.
Sources of alkali
1- Loss of gastric acid
- After vomiting or naso-gastric tube suction of gastric contents, parietal
cells of the stomach increase secretion of HCL into the gastric lumen.

- For each H+ secreted to gastric lumen, HCO3- is secreted to the blood;
that is why alkalosis follows loss of gastric acid.
2- Ingestion of alkali
- Ingestion of alkalinizing salts (e.g. sodium bicarbonate “NaHCO3”).
- Ingestion of fruits (rich source of NaHCO3 and KHCO3).
CONTROL OF pH
- Control of ECF pH is important for:
 Normal enzyme function
 Normal neuronal function
- Mechanisms for control of pH include:
 Buffers (act immediately for very rapid control)
 The respiratory system (acts in seconds to minutes for less rapid
control)
 The renal system (acts in hours to days for long term control)
The buffers
- A buffer is defined as a chemical substance that has the ability to bind or
release H+ in solution, thus keeping the pH of the solution relatively
constant despite the addition of considerable quantities of acid or base.
- Or it can be defined as a chemical substance formed of weak acid &
alkali, acts to resist changes in pH.
Examples of Buffers in body fluids
 In the blood
–Bicarbonate
–Proteins
–Hemoglobin
 In the interstitium
–Bicarbonate
 In the cells
–Proteins
–Phosphate
 In urine
–Bicarbonate
–Ammonia
–Phosphate
Henderson-Hasselbalch Equation (= the equation of buffers)

pH = pK + log [base]/[acid]
- This equation is obtained as follows:

o From the general equation for a buffer system: HA = H+ + A-
(Where HA is un-dissociated acid & A- is any anion or base)
o By the law of mass action:
Equation constant = Concentration of products / reactants
K= [H] [A] / [HA] (Where K is the equation constant)
o By taking - log: - log K = - log [H] [A] / [HA]
- log K = - log [H] - log [A] / [HA]
- log [H] = - log K + log [A] / [HA]
pH = pK + log [base] / [acid]
- From the equation, the most effective buffer is expected to have equal
concentrations of base and acid.
- This means that [A] / [HA] = 1
- Since log 1 = zero, the equation will be (pK = pH).
- Therefore a buffer system is regarded to be effective when:
o Its pK is near to pH.
o Its concentration is high.

Bicarbonate buffer
- H2CO3 = H+ + HCO3-
- From H-H equation: pH = pK’ + log [HCO3-] / [H2CO3]
- pK = 6.1 & H2CO3 is found at equilibrium with CO2
- Therefore: pH = 6.1 + log [HCO3-] / [CO2]
- The solubility of CO2 = 0.0301 mmol/L/mmHg
- Therefore: pH = 6.1 + log [HCO3-] / 0.03 x Pco2
Example:
Calculate pH of a patient whose PaCO2= 10 mmHg and plasma [HCO3-]=
12 mmol/L
Answer:
pH= 6.1 + log 12/ 0.03x10= 6.1 + log 40= 6.1 + 1.6= 7.7
Remember that: pK of bicarbonate = 6.1 (not near to pH). In spite of this,

the bicarbonate buffer is an important buffer in ECF because:
1- Concentration in plasma is high.
2- The acid "CO2" can be controlled by respiration & the base "HCO3-"
can be controlled by the kidney.
 CO2 produced daily by metabolism is not buffered by "HCO 3-". It
diffuses inside RBCs where it reacts to give H+ that is buffered by Hb.
- The bicarbonate buffer acts by shifting this reaction (H2CO3 = H+ +

HCO3) to the right or left; e.g. addition of acid (H+) causes left shift with
formation of H2CO3 and this gives H2O + CO2 ; then CO2 is excreted by
the lung to keep pH constant.
- On the other hand, addition of alkali (HCO3-) causes consumption of (H+),
this causes right shift with dissociation of H2CO3 to more H+ & HCO3- . The
HCO3- is excreted in urine by the kidney to keep pH constant.

Protein buffer
- Proteins have two dissociated groups that act as buffers:
o Carboxyl group (RCOOH = RCOO- + H+)
o Amino group (RNH3 = RNH2 + H +)
- But these contribute little to the buffering capacity in the blood.
Hemoglobin buffer
- In addition to the two ionizable groups in its protein part “globin,”
hemoglobin has another ionizable group (imidazole group) that is found in
the amino acid histidine.
- There are 38 residues of histidine in each molecule of Hb. In addition,
concentration of Hb is high. That is why Hb has 6 times the buffering
capacity of proteins.
Remember about the Hb buffer: Deoxyhemoglobin as a buffer is better
than oxyhemoglobin. That is because the imidazole group in deoxyHb
dissociates less than in oxyHb; making deoxyHb a weaker acid &
therefore a better buffer.
Phosphate buffer
- Dihydrophsphate is a week acid that dissociates as follows:
H2 PO4- = H+ + HPO4-2
- The buffer equation for dihydrophoshate is as follows:
pH = pK + log [HPO4-2] / [H2 PO4-]
- pK = 6.8
- It is more important in ICF than ECF (because its concentration is higher
in ICF).
- It is also important in urine where it buffers hydrogen ions secreted
excessively in cases of acidosis.

The respiratory system
- Acts within seconds to minutes.
- There are 2 types of chemoreceptors:
o Peripheral: Stimulated by low Po2, high P co2 & low pH (in plasma)
o Central: Stimulated by high Pco2 & low pH (in CSF)
- Stimulation of the chemoreceptors (e.g. by the low pH) results in
stimulation of the respiratory center which causes hyperventilation. This
results in washout of CO2 and correction of the low pH.
- On the other hand, high pH decreases stimulation of the chemoreceptors
and this eventually causes hypoventilation resulting in accumulation of
CO2 and correction of the high pH.
The renal system

- The kidney participates in acid base balance by:
1- Reabsorption of HCO3-
2- Synthesis of new HCO3-
3- Secretion of H+
1- Reabsorption of HCO3-
- Filtered HCO3- reacts with secreted H+ at the brush border of the PCT as
follows: HCO3- + H+ ↔ H2CO3 ↔ H2O + CO2
- Then CO2 diffuses inside PCT cells.
- This reversible reaction between water and carbon dioxide proceeds at
the presence of carbonic anhydrase enzyme.
- In addition to the kidney, carbonic anhydrase enzyme is also found in
RBCs, saliva, parietal cells, lung, pancreas and other sites.
- Inhibition of this enzyme by certain drugs like sulphonamides (e.g.
acetazolamide) has a mild diuretic effect.

- Inside the PCT cells:
CO2 reacts with water (again at the presence of carbonic anhydrase
enzyme) as follows:
CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3-
- H+ is secreted to the lumen (antiported with Na+ ).
- HCO3- enters the interstitium (co-transported with Na+).
- At the collecting ducts, HCO3- is exchanged with Cl- through the
Remember that: reabsorption of HCO3- is almost 100% when the pH of
urine is < 6.5
Fig 9.21: Reabsorption of HCO3-
2- Synthesis of new HCO3-

- Inside PCT cells, bicarbonate is formed from the reaction between CO 2 &
water (here CO2 is produced by metabolism within the cells). Bicarbonate
is also formed from the amino acid glutamine during ammonia formation:
glutaminase
Glutamine+ water alpha ketoglutaric acid+ NH3 decarboxylation HCO3-

Remember that:
- Ammonia is an important buffer in urine. It is formed in the kidney (PCT)
from the amino acid glutamine, which is synthesized in the liver. It is also
formed by de-amination of glutamic acid & other amino acids.
- It is converted to ammonium ion (NH4+) and excreted as ammonium
chloride (NH4Cl) in urine.
3- Secretion of hydrogen
- In the PCT, hydrogen secretion occurs by the following mechanisms:
a- Antiported with Na+
b- H+ - ATPase pump (less important)
- In the collecting ducts (intercalated cells) hydrogen secretion occurs by:
a- H+ ATPase pump
b- Antiported with K+
- Cells cannot secrete hydrogen ions if pH of urine < 4.5 (the limiting pH).
- Therefore, there are buffers in urine that prevent decrease of urine pH to
less than 4.5; these include:
o Phosphate buffer (HPO4-2 + H+ ↔ H2 PO4-)___________pK = 6.8
o Ammonia (NH3 + H+ ↔ NH4+ )___________________pK = 9.0
- Acid buffered by phosphate in ueine is known as “titratable acid (TA)”.
- TA is defined as the amount of NaOH that must be added to urine to
raise its pH back to that od plasma.
- Net acid excretion per day equals (TA - NH4+ - HCO3-) x urine flow rate
ACID BASE DISTURBANCES

- Low pH (acidosis) is caused by:
o High CO2 (Due to a respiratory problem)
o Low HCO3- (Due to a metabolic cause)

- High pH (alkalosis) is caused by:
o Low CO2 (Due to a respiratory problem)
o High HCO3- (Due to a metabolic problem)
- Therefore there are 4 types of acid base disturbances:
a- Metabolic acidosis (due to low HCO3-)
b- Metabolic alkalosis (due to high HCO3-)
c- Respiratory acidosis (due to high CO2)
d- Respiratory alkalosis (due to low CO2)
- Uncompensated versus compensated acid base disturbance
- On acute presentation, the acid base problem is usually uncompensated
(i.e. the compensatory mechanisms are not fully activated).
- On chronic presentation (after a few days), the compensatory
mechanisms are fully activated.
- Generally, respiratory acidosis and alkalosis require renal compensation
whereas metabolic acidosis and alkalosis require both renal and
respiratory compensation (unless the cause of the metabolic problem is
renal failure).
- The renal compensation:
 As mentioned above, in acidosis there is increased:
1- Reabsorption of bicarbonate
2- Synthesis of new bicarbonate
3- Secretion of hydrogen ions
4- Synthesis of ammonia from glutamine & excretion of ammonium
chloride in urine
5- Lower ratio of HPO4-2 to H2 PO4- in urine (because the secreted
hydrogen ions convert HPO4-2 to H2 PO4- thus increasing the H2 PO4- and
decreasing the ratio).
 In alkalosis, all the above compensatory mechanisms are inhibited.

- The respiratory compensation:
- As mentioned above, there is hyperventilation in acidosis (resulting in
lower PCO2) and hypoventilation in alkalosis (resulting in higher PCO2).
1- Metabolic acidosis
- Causes:
o Failure to excrete acids (renal failure)
o Formation of high amounts of acids (diabetic ketoacidosis, lactic
acidosis)
o Loss of base (diarrhea)
- Characterized by:
o Low pH & low bicarbonate
- Compensation:
o Buffers
o Respiratory system (hyperventilation)= low PCO2
o Renal system (see the renal compensation above)
2- Metabolic alkalosis
- Causes:
o Loss of gastric acid: (vomiting or naso-gastric tube suction)
o Ingestion of alkali
o Diuretics
- Characterized by:
o High pH & high bicarbonate
- Compensation:
o Buffers
o Respiratory system (hypoventilation)= high PCO2
o Renal system

3- Respiratory acidosis
- Causes:
o Respiratory center depression by drugs or trauma
o Paralysis of respiratory muscles
o Diseases of the lung
- Characterized by:
o Low pH & high PCO2
- Compensation:
o Buffers & renal system (the respiratory system is the cause)
4- Respiratory alkalosis
- Causes:
o Hysteria (hyperventilation)
- Characterized by:
o High pH & low PCO2
- Compensation:
o Buffers & renal system (the respiratory system is the cause)
Fig 9.22: Compensation of acid base disturbances

EVALUATION OF ACID BASE STATUS
[1] Measurement of the following in the plasma:
o pH
o PCO2
o HCO3-
- These give idea about the type of acid base disturbance and state of
compensation.
[2] Measurement of the anion gap
o The anion gap is the difference between the sum of anions and cations
in ECF.
Anion gap = ([Na+] + [K+]) - ([Cl-] + [HCO3-])
o Note that Na & K = 95% of cations whereas Cl- & HCO3- = 86% of
anions.
o Therefore, the gap represents the unmeasured anions like phosphate,
sulphate and organic acids (e.g. lactate and ketones).
o Normal value = 8-16 mmol/L (average= 12 mmol/L).
o The anion gap is used to differentiate between the causes of metabolic
acidosis.
o When it is high, specific causes can be considered; and those, which
cause normal or low anion gap, can be excluded.
o Causes of high anion gap:
 Diabetic ketoacidosis "DKA"
 Severe exercise (lactic acidosis)
 Alcohol toxicity
 Aspirin toxicity
o Causes of normal anion gap:
 Carbonic anhydrase inhibition (acetazolamide)
 Ingestion of ammonium chloride

 Diarrhoea (loss of bicarbonate)
 Renal loss of bicarbonate (renal tubular acidosis)
o Causes of low anion gap:
 Rare but may occur when there is high positively charged
proteins (e.g. in multiple myeloma).
[3] The base excess

- Refers to the amount of cid or base required to restore the pH of one liter
of blood to normal at a PCO2 of 40 mmHg.
- The base is positive "excess" in alkalosis and negative "deficit" in
acidosis.
- Normal range from -2 to +2 meq/L.
- Examples:
 A base excess of -10 meq/L indicates severe metabolic acidosis
 A base excess of + 10 meq/L indicates severe metabolic
alkalosis.
- The term and concept were first introduced by Astrup and Siggaard
Andersen in 1958.

1. Water reabsorption occurs primarily in the:
a. Proximal convoluted tubules
b. Thin ascending loop of Henle
c. Thin descending loop of Henle
d. Collecting ducts
e. Distal convoluted tubules
2. The glomerular filtration rate is:
a. Increased by sympathetic stimulation
b. Higher in females than males
c. Measured by PAH clearance
d. Directly proportional to renal blood flow
e. About 23 L/day in patients with diabetes insipidus
3. Oxygen consumption by the kidney:
a. Is greater in the medulla than the cortex
b. Is inversely proportional to renal blood flow
c. Increases with afferent arteriolar constriction
d. Reflects active transport of solutes
e. Is controlled by ADH
4. Glucose transport across the luminal membrane in the PCT:
a. Is insulin dependent
b. Is antiported with hydrogen
c. Depends on GLUT type 2
d. Is decreased in diabetes mellitus
e. Is co transported with sodium
5. A patient with high anion gap is likely to have high plasma
concentration of:
a. Sodium
b. Chloride
c. Potassium
d. Bicarbonate
e. Lactate
6. Use the following data to calculate Tmax for glucose:
GFR= 125 ml/min
Plasma glucose= 400 mg/dL
Glucose excretion= 100 mg/min
a. 300 mg/min
b. 400 mg/min
c. 500 mg/min
d. 375 mg/min
e. 275 mg/min
7. The plasma concentration at which a substance starts to appear in the
urine is known as the:
a. Excretion fraction
b. Filtration fraction

c. Effective plasma flow
d. Transport maximum (Tmax)
e. Renal threshold
8. Most of hydrogen secreted in the PCT is buffered by:
a. Ammonia
b. Monohydrophosphate
c. Dihydrophosphate
d. Filtered protein
e. Bicarbonate
9. Under the effect of ADH, the filtrate becomes isotonic in the:
a. Descending limb of the loop of Henle
b. Ascending limb of the loop of Henle
c. Cortical collecting ducts
d. Medullary collecting ducts
e. Renal pelvis
10. Calculate renal clearance of a substance if its plasma concentration=
0.5 mg/dL, its urine concentration= 35 mg/dL and urine volume=
1ml/min.
a. 5 ml/min
b. 7 ml/min
c. 30 ml/min
d. 35.5 ml/min
e. 70 ml/min
11. The PCT in the kidney reabsorbs almost all of the filtered:
a. Sodium
b. Potassium
c. Chloride
d. Glucose
e. Water
12. Transport of sodium through basolateral membranes of thick ascending
limbs of Henle loops occurs mainly by:
a. 1Na+-1K+-2Cl- cotransport pump
b. Na+-K+ pumps
c. Solvent drag
d. Simple diffusion
e. Na+-H+ antiport
13. The "counter-current multiplier" in the kidney is:
a. Responsible for maintenance of hypertoncity of renal medulla
b. Formed by the juxtaglomerular apparatus
c. Found in other parts of the body
d. Dependent on slow blood flow through the vasa recta
e. Found in less than 20% of all nephrons in the kidney
14. Titratable acidity in urine is:
a. Equal to the amount of base that raises its pH to 7.0
b. Equal to amount of acid that reduces its pH to 1.0
c. Buffered by ammonia

d. Buffered by phosphate
e. Equal to net acid excretion
15. Clearance of which of the following measures the GFR:
a. Urea
b. Uric acid
c. Inulin
d. PAH
e. Cotinine
16. In a patient with chronic renal failure there is reduction in:
a. Anion gap
b. Acid excretion
c. Fractional excretion of sodium
d. Free water clearance
e. Calcium concentration in plasma
17. In absence of ADH, sodium concentration is lowest at the:
a. Proximal convoluted tubule
b. Distal convoluted tubule
c. Cortical collecting duct
d. Thick ascending limb of loop of Henle
e. Medullary collecting duct
18. The GFR is increased by:
a. Contraction of mesangial cells
b. Stimulation of renal nerves
c. Efferent arteriolar constriction
d. Compression of renal capsule
e. Activation of juxta-glomerular apparatus
19. Secretion of H+ in the PCT is primarily associated with reabsorption of:
a. Potassium
b. Bicarbonate
c. Chloride
d. Glucose
e. Calcium
20. Clearance of a substance that appears in the renal artery but not the
renal vein equals:
a. Renal blood flow
b. Glomerular filtration rate
c. Glucose clearance
d. Renal plasma flow
e. Free water clearance
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
a d d e e b e e c e d
12. 13. 14. 15. 16. 17. 18. 19. 20.
b e d c d e c b d

21. Ammonia (NH3) in the kidney:
a. Is synthesized in the collecting ducts
b. Reduces bicarbonate concentration in filtrate
c. Decreases urine pH
d. Is classified as titratable acid
e. Is increased in response to respiratory acidosis
22. The renal blood flow is:
a. Measured by creatinine clearance
b. Increased by Antidiuretic hormone
c. Increased by parasympathetic stimulation
d. Greater in the renal cortex than the renal medulla
e. Increased by chronic use of use of aspirin
23. The following substance is secreted by the renal tubules:
a. Uric acid
b. Calcium
c. Inulin
d. Ammonium
e. Glucose
24. Secretion of potassium in the distal tubules is increased by:
a. Anti-diuretic hormone
b. Acidosis
c. Hypokalaemia
d. Loop diuretics
e. Slow fluid tubular flow rate
25. As plasma glucose concentration rises from 100 to 160 mg/dL, its:
a. Filtered load increases
b. Transport maximum increases
c. Clearance increases
d. Excretion increases
e. Renal transporters decrease
26. Concentration of this substance at the beginning of the PCT is almost
equal to its concentration at the end of the PCT:
a. Inulin
b. Creatinine
c. Bicarbonate
d. Sodium
e. Phosphate
27. In presence of ADH, the tubular fluid leaving the:
a. PCT is hypotonic
b. Ascending loop of Henle is hyperotonic
c. DCT is isotonic
d. Collecting duct is hypertonic
e. Descending loop of Henle is hypotonic
28. Hypokalaemia is associated with:
a. Renal failure
b. Hypoventilation

c. Aldosterone excess
d. Diabetes mellitus
e. Graves’ disease
29. Which of the following is reabsorbed actively in the proximal
convoluted tubules:
a. Water
b. Hydrogen ions
c. Sodium ions
d. Creatinine
e. Carbon dioxide
30. Which of these statements about micturition reflex is correct; it is:
a. Facilitated by sympathetic activation
b. Never initiated unless urine volume reaches 400 ml
c. Present in paraplegic patients
d. Absent in children
e. Mediated by both sympathetic and parasympathetic neurons
31. Excretion of concentrated urine is more likely when:
a. 1Na+-1K+-2Cl- co-transport pump in the loop of Henle is inhibited
b. Na+-K+ pump in the loop of Henle is activated
c. Tubular flow rate in the loop of Henle is increased
d. The glomerular filtration rate is increased
e. ADH receptors in the collecting ducts are blocked
32. When blood glucose concentration is 300 mg/dl, the following is most
likely to be higher than normal
a. pH of the blood
b. Inulin clearance
c. Urine flow rate
d. Renal threshold for glucose
e. Sodium concentration in plasma
33. Atrial natriuretic peptide decreases sodium reabsorption at the:
a. Proximal convoluted tubule
b. Loop of Henle
c. Distal convoluted tubule
d. Cortical collecting duct
e. Medullary collecting duct
34. Metabolic acidosis with hypokalemia is likely to develop due to:
a. Vomiting
b. Hyperventilation
c. Diabetes insipidus
d. Diarrhoea
e. Renal failure
35. In a patient with compensated metabolic acidosis, which of the
following is most likely to be correct:
a. Bicarbonate concentration in plasma= 24 mmol/L
b. Partial pressure of carbon dioxide in arterial blood= 20 mmol/L
c. pH of urine is=6.5

d. pH of the plasma= 7.4
e. Ratio of HPO4-- to H2PO4- = 10
36. In chronic compensated Respiratory acidosis:
a. Urine pH becomes less than 4.0
b. Plasma pH becomes more than 7.4
c. The partial pressure of carbon dioxide in the arterial blood is
decreased
d. Ammonia production by the kidney is increased
e. Potassium secretion by the kidney is increased
37. Which of the following statements about principal cells in the kidney is
correct:
a. Found in the loop of Henle
b. Secrete ammonia
c. Secrete hydrogen ions
d. Secrete potassium ions
e. Have 1Na-1K -2Cl co transporters
38. Aldosterone:
a. Causees water retention through aquaporin 2 in the distal nephron
b. Activates H+ ATPase pumps in the proximal convoluted tubules
c. Excess causes edema due to sodium retention followed by water
d. Increases secretion of renin enzyme by the juxtaglomerular cells
e. Activates the Na/K ATPase pumps of principal cells
39. Which of the following has the highest renal clearance:
a. Calcium
b. Glucose
c. Sodium
d. Potassium
e. Creatinine
40. Which of the following is an important buffer in the interstitial fluid:
a. Proteins
b. Bicarbonate
c. Hemoglobin
d. Phosphate
e. Ammonia
21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31.
e d a d a d d c c c b
32. 33. 34. 35. 36. 37. 38. 39. 40.
c e d b d d e d b

CHAPTER (10)
THE ENDOCRINE SYSTEM
INTRODUCTION
The Endocrine glands
- The endocrine glands are ductless glands that release hormones directly
into the blood to act on target cells. Examples are mentioned in this figure:
Fig 10.1: The endocrine glands
Endocrine glands essential for life

- Some of the endocrine glands are essential for life because deficiency of
their hormones causes death in a short time. These include:
 The anterior lobe of the pituitary gland (releases adreno-
corticotrophic hormone “ACTH”)
 The adrenal cortex (releases “cortisol”)
 The parathyroid gland (releases parathyroid hormone “PTH”)
Organs with endocrine function
- Certain organs contain endocrine cells that synthesize and release
hormones, thus adding an endocrine function to these organs. Examples:
 The hypothalamus (see below)
 The kidney (releases erythropoietin)
 The heart (releases atrial natriuretic peptide “ANP”)
 The GIT (releases gastrin, secretin, CCK …)
 The skin (releases vitamin D)
 The adipose tissue (releases leptin)
 The liver (releases insulin like growth factors “IGF”)
 The placenta (releases estrogens, progesterone, hCG, hCS …)
Hormones
- Hormones are chemical substances released by endocrine glands or
organs to act on specific target cells. After release in tissue fluid, they act
through one or more of these types of signaling:
 Enter blood to act on distant target cells (endocrine action)
 Act on neighbouring cells (paracrine action)
 Act on the same cell that produced it (autocrine action)
Fig 10.2: Patterns of hormonal signaling

Chemical structure of hormones
- Generally, hormones are either derived from amino acids (= water-
soluble) or from cholesterol (lipid-soluble).
 Examples for hormones derived from amino acids:
o One amino acid: Catecholamines & melatonin
o Two aminoacids: thyroid hormones
o Eight amino acids: Angiotensin II
o Nine amino acids: ADH & oxytocin
o Polypeptides & proteins: GIT hormones, pancreatic hormones,
all hypothalamic releasing hormones, PTH, calcitonin, growth
hormone, prolactin, ACTH, hCS, ANP, leptin ...
o Glycoproteins: LH, FSH, TSH & hCG
 Examples for hormones derived from cholesterol:
o Steroid hormones (containing the steroid nucleus “4 rings”): the
hormones, which are released by the adrenal cortex & the
gonads (Aldosterone, cortisol, adrenal androgens, testosterone,
estrogens & progesterone).
o Secosteroid hormone (containing the steroid nucleus but one
ring is open): Vitamin D.
- Remember that: Local hormones like prostaglandins are lipid soluble but
derived from fatty acids “arachidonic acid” not cholesterol.
Transport of hormones in plasma
- Lipid soluble hormones like thyroid & steroid hormones circulate in
plasma in two forms:
 Free form (usually conjugated in case of steroid hormones to be water
soluble)
 Protein bound (to albumin or globulin “α”)
- The free form is the active form of the hormone.

- The protein-bound form is inactive; it acts as a storage form (not excreted
in urine).
- The protein-bound form is not filtered through the glomeruli in the kidney;
that is why it stays for longer time in the circulation.
Sites of catabolism
- The principal sites of hormonal destruction are:
 The liver
 The kidney
 Other tissues (e.g. adipose tissue)
- Generally, steroid hormones are destroyed mainly in the liver (and to a
lesser extent in the kidney) whereas peptide hormones are destroyed
mainly in the kidney.
- The products of hormonal catabolism (the metabolites) are excreted in
urine & bile.
Half-life
- The time required for half of a hormone to be metabolized or eliminated
by the body.
- Generally, the half-life of peptide hormones is less than steroid & thyroid
hormones (with a few exceptions).
- Glycoprotein hormones have longer half-life than other peptide
hormones. This is because the carbohydrate groups in the glycoproteins
decrease their rate of metabolism.
- A higher percentage of protein bound fraction of a hormone indicates a
longer half-life.
Receptors
- The receptors for hormones are proteins, located either on:
 The cell membrane
 Inside the cell (the nucleus or the cytoplasm)

- Generally, receptors for the peptide hormones are attached to the cell
membrane (= cell membrane associated receptors) whereas receptors for
the steroid hormones are found in the cytoplasm or the nucleus (=
intracellular receptors).
- Exception to this general rule: The thyroid hormones (which are
synthesized from the amino acid tyrosine) have intracellular receptors.
- Cell membrane receptors are integral proteins; they have three regions
“or domains”:
 Extracellular domains: the residues which are exposed to the
outside of the cell (= the N-terminal of the protein).
- These bind the hormone.
 Transmembrane domains: the hydrophobic parts of the protein;
serve to anchor the receptor in the membrane.
- May be simple or complex (e.g., the protein which binds GTP
or GDP “i.e. the G-protein” spans the cell membrane 7 times).
 Cytoplasmic or intracellular domains: the tails or loops of the
receptor that are within the cytoplasm (The C-terminal of the
protein). These lead to formation of second messengers (see
below).
Mechanism of hormonal action
o Peptide hormones: Binding of a hormone to its cell membrane receptor
initiates a series of events, which lead to generation of “second
messengers” within the cell. The second messengers then trigger a
series of reactions that alter the physiologic state of the cell.
o Steroid hormones: Act by binding of a hormone to a cytoplasmic
receptor. Then the hormone/receptor complex enters the nucleus and
binds to specific sites at the DNA. It acts as a transcription factor that
modulates gene expression.

Fig 10.3: Mechanism of action of steroid hormones
Functions
- Most hormones regulate metabolic processes; however, they have
additional effects on various organs of the body.
- Generally, the name of each hormone indicates one of its major functions
(e.g. growth hormone, anti-diuretic hormone, angiotensin II, prolactin,
thyroid-stimulating hormone …)
Control
- Many endocrine glands (e.g. the thyroid, the adrenal cortex & the
gonads) are controlled by the master gland in the body (the pituitary
gland). Release of hormones from these glands is stimulated or inhibited
by other hormones released from the pituitary. However, hormones of the
pituitary are also controlled by other hormones released by the brain
structure which is found immediately above the pituitary gland,” the
hypothalamus.” This is known as “the hypothalamo-pituitary axis.”
- Certain factors (environmental, nutritional, ions …) act directly on the
hypothalamus to stimulate or inhibit its hormones.

- Similar factors act on the other glands, which are not controlled by the
hypothalamo-pituitary axis (like the parathyroid gland, the pancreas and
the adrenal medulla) to activate or suppress their secretions.
- Most hormones in the body are controlled by “a negative feedback
mechanism.” (When a system’s output acts on the system input, resulting
in its attenuation). Here a hormone (e.g. secreted from the thyroid) acts on
the hormone that stimulates its release (secreted from the pituitary) &
inhibits further release of that hormone & therefore, its own release.
- Few hormones are controlled by “a positive feedback mechanism.”
(When a system’s output acts on the system input, resulting in its
amplification). Here the hormone stimulates its own release.
- Examples of positive feedback mechanism include oxytocin, angiotensin
II & LH in females (just before ovulation).
The second messengers of peptide hormones

- The second messengers are components of the signal transduction
cascades. Here a hormonal signal results in series of biochemical
reactions within the cell carried by enzymes. These enzymes are activated
by the second messengers, which include:
 cAMP “cyclic adenosine monophosphate”
- For ADH, LH, FSH, TSH, ACTH, PTH, calcitonin, glucagon,
catecholamines …
- The hormone binding activates a G-protein (GDP or GTP-bound protein).
- The protein activates the enzyme adenylate cyclase.
- This enzyme catalyzes formation of cAMP from ATP.
- cAMP activates certain proteins within the cell (e.g. protein kinase A).
- This phosphorylates other proteins (enzymes) to exert the effect of the
hormone.

 Tyrosine kinase
- For oxytocin, growth hormone, prolactin, insulin & erythropoietin.
- The hormone binding causes conformational changes in the receptor.
- The intracellular domain of the receptor, which becomes a tyrosine
kinase, phosphorylates itself or other proteins to exert effects.
- Fig 10.4: The second messengers of peptide hormones
 Inositol-triphosphate (IP3), diacylglycerol (DAG) & calcium

- For GnRH, TRH, catecholamines, angiotesin II and ADH.
- The hormone binding activates a G-protein (GDP or GTP-bound protein).
- The protein activates the enzyme phospholipase C.

- This results in hydrolysis of phosphatidyl-inositol-4,5-diphosphate (PIP2)
into two second messengers:
o inositol-1,4,5-triphosphate (IP3) & diacyl-glycerol (DAG).
- IP3 triggers release of calcium from the sarcoplasmic reticulum.
- Calcium ions bind to a calcium modulatory protein, calmodulin, which
binds to and activates the calmodulin-dependent kinase.
- DAG acts through activation of protein kinase C.
 cGMP “cyclic guanosine monophosphate”
- For atrial natriuretic peptide “ANP” (also for local signals like nitric oxide)
- The hormone binding causes conformational changes in the receptor.
- This activates guanylyl cyclase & results in formation of cGMP.
- cGMP activates the cGMP-dependent protein kinase (also protein kinase
A) to exert effects.
THE PITUITARY GLAND

- Small gland (1g) situated in the hypophyseal fossa “sella turcica” at the
base of the skull, below the brain.
- Consists of two lobes: anterior and posterior lobes (in animals there is an
additional intermediate lobe).
- The anterior lobe synthesizes and releases hormones whereas the
posterior lobe does not synthesize hormones. It stores hormones that
have been synthesized in the hypothalamus.
The neuro-endocrine relationship
- The endocrine system acts in close relation with the nervous system to
control the metabolic functions of the body. There are many examples
describing this relationship. One of these is the direct anatomical and
physiological connection between the hypothalamus (= neural structure)
and the pituitary (= endocrine gland).

- Through this connection, the hypothalamus controls the activity of the
pituitary gland (by releasing and inhibitory hormones); and the pituitary
controls the activity of many other endocrine glands in the body (by trophic
“or tropic” hormones).
- The hypothalamus is connected to the pituitary gland in two ways.
 Neural connection: between the hypothalamus and the posterior
pituitary. Here hormones from the hypothalamus are transmitted
through axons of neurons to be stored in the posterior pituitary gland.
 Vascular connection: between the hypothalamus and the anterior
pituitary. Here releasing and inhibitory hormones from the
hypothalamus are sent through portal blood vessels to control activity
of the anterior pituitary gland.
Fig 10.5: The hypothalamic-pituitary connections
Note:
- The intermediate lobe in animals secretes melanocyte stimulating
hormone (MSH). This lobe (and therefore its hormone) are not found in
humans. However, ACTH acts as a melanocyte stimulating hormone. This
is because it has a similar chemical structure to MSH since it comes from
the same large precursor molecule “pro-opiomelanocortin”.

- Acidophils in the anterior lobe secrete GH and PRL; basophils secrete
FSH, LH, TSH and ACTH whereas chromophobes are inactive.
- Some of the anterior pituitary hormones are tropic hormones since they
act on other endocrine glands to increase cellularity, vascularity and
secretion of these glands. These are:
 TSH (acts on the thyroid gland; also known as thyrotropin).
 ACTH (acts on the adrenal cortex; also known as corticotropin).
 FSH and LH (act on the gonads; also known as gonadotropins).
- In addition, GH can also be regarded as a tropic hormone because it
exerts comparable effects on the liver (see below).
- Look at these differences between the two lobes of the pituitary gland:
Table 10.1: Differences between the anterior and posterior lobes
Difference Anterior lobe Posterior lobe
Embryological From roof of pharynx “Rathke’s From floor of third
origin pouch” (i.e. glandular in origin) ventricle (i.e. neural
in origin)
Types of cells Acidophils (40%), basophils Modified astrocytes
(10%) and chromophobes (50%) (pituicytes) and
nerve endings
Hypothalamic Vascular: (Hypothalamo- Neural: (H-h neural
connection hypophyseal portal vessels) tracts)
Function Synthesizes hormones Stores hormones
Hormones 1- Growth hormone (GH) 1- Anti-diuretic
2- Prolactin (PRL) hormone (ADH)
3- Adrenocorticotrophic hormone 2- Oxytocin
4- Thyroid stimulating hormone
5- Follicle stimulating hormone
6- Luteinizing hormone

HORMONES OF THE ANTERIOR PITUITARY
GROWTH HORMONE (GH)
Characteristics of human growth hormone (hGH)
- Peptide hormone (191 amino acids) in a single chain.
- Molecular weight: 22,000 (22 k)
- Species specific (i.e. human growth hormone (hGH) differs from GH of
other species).
- Half life: (about 20 min).
- About 50% of the hormone is bound to a plasma protein (the protein is a
large fragment of GH receptor).
Control
 From the hypothalamus by:
o Growth hormone releasing hormone (GHRH)
o Growth hormone inhibitory hormone (GHIH); also known as
somatostatin.
 Negative feedback mechanism by GH itself or by somatomedins (see
below).
 GH stimuli:
o Hypoglycemia, fasting, starvation
o 2-Deoxyglucose (blocks catabolism of glucose 6 phosphate
causing intracellular glucose deficiency)
o Sleep (Non REM)
o Stress
o Exercise
o Protein intake (increase in circulating levels of certain amino
acids like arginine)
o Glucagon, estrogens and androgens
o L-Dopa, α adrenergics and their agonists

 GH inhibitors:
o REM sleep
o Free fatty acids
o I.V. glucose
o Cortisol
o Growth hormone
o Medroxyprogesterone
Somatomedins:
- These are insulin like growth factors “IGF” produced by the liver and
other tissues in response to GH. The principal somatomedins in humans
are:
o Insulin-like growth factor-I (IGF-I, or somatomedin C)
o Insulin-like growth factor II (IGF-II)
- They mediate the effects of GH on skeletal tissues (stimulate growth of
bone & cartilage), stimulate protein synthesis & exert some insulin like
activity.
Fig 10.6: Control of GH

- Effects of GH
 Promotion of growth:
- GH promotes growth directly in most tissues and indirectly in skeletal
tissues (through somatomedins).
 Metabolism of protein:
- GH is an anabolic hormone. It stimulates protein synthesis (i.e. exerts
+ve nitrogen and phosphorus balance). Therefore, it decreases the
level of blood urea and amino acids.
 Metabolism of fat:
- GH causes lipolysis (mobilization of adipose tissue). This increases
free fatty acids (FFAs) in the plasma.
 Metabolism of CHO:
- GH causes hyperglycemia by increasing hepatic glucose output
(gluconeogenesis & glycogenolysis) and antagonizing actions of insulin
in muscles and adipose tissues. Therefore, it has both diabetogenic
effect (by increasing the level of glucose in plasma) and ketogenic
effect (by increasing the level of FFAs in plasma).
- Remember that GH increases both glucose and FFAs in plasma;
however, it prevents utilization of glucose by antagonizing the effects of
insulin. Therefore, it shifts the metabolism towards utilization of FFAs
and sparing glucose as a source of energy for the brain.
 Metabolism of electrolytes:
- GH increases absorption of calcium & phosphate in the intestine
(through activation of vitamin D) and decreases excretion of sodium
and potassium by the kidney; because these electrolytes are needed
by the growing tissues.
 Lactogenic effect:
- Because it is similar in chemical structure to prolactin.

Remember that:
The polypeptide hormone “ghrelin,” which is produced by the
hypothalamus and the stomach to stimulate appetite, has marked growth
hormone stimulating activity.
Abnormalities
 GH excess before puberty = gigantism
- Excess GH before puberty causes gigantism. Here the size of viscera
and the length of bones are increased. Patients have tall stature because
the abnormality occurred before closure of the epiphyseal plates (which
occurs at puberty due to estrogens).
 GH excess after puberty = acromegaly
- Excess GH after puberty causes acromegaly. Here the size of viscera is
increased but the length of bones is not increased because the
abnormality occurred after closure of the epiphyseal plates. However,
bones at the acral “peripheral” parts of the body are increased in size.
These include bones of hands and feet. In addition, soft bones in the face
like the malar and frontal bones are increased in size. The size of the
lower jaw is also increased (= prognathism). These changes produce the
characteristic acromegalic facies.
Remember about GH excess:
- It is caused by pituitary adenomas (tumors secreting GH).
- It is associated with increased lean body mass (increased protein) and
decreased body fat.
- It is associated with increased excretion of hydroxyproline in urine, which
indicates either high collagen destruction or synthesis (here it indicates
increased collagen synthesis).
- May be associated with diabetes mellitus resistant to insulin treatment.

 GH deficiency before puberty = dwarfism
- Deficiency of GH before puberty causes dwarfism (characterized by short
stature with intact mental function) whereas deficiency of GH after puberty
causes minor metabolic abnormalities and increased sensitivity to insulin.
- Causes of GH deficiency include:
o Pituitary tumors
o Deficiency of GH releasing hormone or IGF-I
o GH receptor defect (Laron syndrome); here the level of GH in
plasma is not low.
Other causes of short stature
- Short stature is also caused by:
 Hormonal causes (before puberty):
o Deficiency of insulin during childhood (diabetes mellitus- type I).
o Deficiency of thyroid hormones during childhood (cretinism; associated
with mental retardation).
o Excess estrogens during childhood causing early closure of epiphyses
(precocious puberty).
 Non-hormonal causes:
o Chromosomal abnormalities (e.g. Turner’s syndrome)
- Lack of one X chromosome (XO pattern); characterized by female
appearance, short stature & ovarian agenesis
o Gene defects (e.g. achondroplasia)
- Common cause of short stature; inherited as autosomal dominant
- Characterized by short limbs & normal trunk
o Other causes
- Constitutional
- Malnutrition
- Psychological causes

PROLACTIN (PRL)
Characteristics
- Peptide hormone (199 amino acids) in a single folded chain.
- Similar in structure to growth hormone and human chorionic
somatomammotropin (hCS).
- Half life: (20 min).
- In addition to the anterior pituitary, it is also secreted by the endometrium
& the placenta.
Control
 From the hypothalamus by:
o Prolactin releasing hormone (PRLRH)
o Prolactin inhibitory hormone (PRLIH); also known as dopamine.
Note: PRLIH is more dominant than PRLRH. That is why cutting the
pituitary stalk increases release of PRL while decreasing release of other
anterior pituitary hormones.
 Negative feedback mechanism by PRL.
 Stimuli of PRL:
- Pregnancy (& estrogens)
- Suckling “stimulation of the nipple”; (Note: lactation without
nursing is a stimulus)
- Sleep
- Stress (& hypoglycemia)
- Exercise
- Thyroid releasing hormone “TRH” (& hypothyroidism)
- Dopamine antagonists (e.g. phenothiazines)
 Inhibitors of PRL:
- L-dopa
- Dopamine agonists (e.g. bromocriptine)

Fig 10.7: Control of PRL
Effects of PRL
 Growth of mammary glands (During pregnancy, together with estrogen
& progesterone)
 Production of milk (Starts after delivery. This action is inhibited during
pregnancy by estrogen & progesterone).
 Inhibition of gonadotrophins (resulting in loss of menstrual cycle during
lactation)
Abnormalities
 PRL excess:
- Caused by pituitary tumors (chromophobes adenoma).
- Characterized by:
o Infertility in both males and females due to inhibition of
gonadotropin effects.
o Amenorrhoea in females (absence of the menstrual cycle).
o Impotence & loss of lipido in males.
o Osteoporosis in females (due to low estrogens resulting from the
inhibition of gonadotropins).
o Galactorrhoea (milk production).

ADRENO-CORTICOTROPHIC HORMONE (ACTH)
Characteristics
- A single chain polypeptide (39 amino acids); synthesized from pro-
opiomelanocortin in the anterior pituitary.
- Half life: (5-15 min); with “unknown” site of catabolism.
Control
 From the hypothalamus by corticotrophin releasing hormone (CRH).
 Negative feedback mechanism by ACTH itself and cortisol from the
adrenal cortex.
 Diurnal (or circadian) rhythm: Increases in the morning and decreases
at night.
Remember that:
About 75% of ACTH secretion during the day occurs in the morning. This
is regulated by the suprachiasmatic nuclei of the hypothalamus (= the
biological clock).
 Stimuli = all types of stress: (physical stress “exercise”, emotional
stress “fear”, hypoglycemia, cold exposure and pain.
- The above stimuli activate the median eminence of the hypothalamus to
increase CRH by the neurons of the paraventricular nucleus; then CRH
stimulates ACTH secretion.
Effects of ACTH
 Trophic effect on the adrenal cortex: Increases cellularity, vascularity
and secretion of cortisol from the adrenal cortex.
 Increases the responsiveness of the adrenal cortex to subsequent
doses of ACTH. Therefore patients with hypopituitarism or those on
chronic treatment with cortisol-like drugs “e.g. prednisolone” (both are
not secreting cortisol) fail to respond immediately to ACTH injections or
re-secretion after stopping the treatment.

 Pigmentation of the skin (The melanocyte stimulating hormone “MSH”
is not found in humans; however, ACTH takes over its action and
stimulates the melanocytes to increase melanin production (This is
because ACTH is synthesized from the same large precursor molecule
of MSH in animals “pro-opiomelanocortin”).
Fig 10.8: Control of cortisol and ACTH
Abnormalities
 Excess ACTH:
- Caused by:
o Pituitary tumors that secrete ACTH (= cortisol excess of secondary
Cushing’s syndrome)
o Lung tumors that secrete ACTH (= cortisol excess of ectopic
Cushing’s syndrome)
o Adrenal problems causing cortisol deficiency due to loss of the
negative feedback on the pituitary (= Primary Addison’s disease)

 Deficiency of ACTH:
- Caused by:
o Pituitary tumors, which destroy the cells that secrete ACTH (=
decreased cortisol secretion from the adrenal cortex = secondary
Addison’s disease)
o Diseases of the adrenal cortex that cause excessive cortisol secretion
(= primary Cushing’s disease) are associated with low ACTH due to the
negative feedback mechanism.
THYROID STIMULATING HORMONE (TSH)

Characteristics
- Glycoprotein (211 amino acids) consisting of two subunits: alpha & beta.
- Other glycoprotein hormones that have similar alpha subunits but differ in
the beta ones are FSH, LH and hCG (see the reproductive system).
- Half life: (60 min), catabolized mainly in the kidney and to a lesser extent
in the liver.
Control
 From the hypothalamus by thyroid releasing hormone (TRH).
 Negative feedback mechanism by TSH itself (short loop –ve feedback)
& by the thyroid hormones from the thyroid gland (long loop –ve
feedback).
o Stimuli: Cold
o Inhibitors: Heat and stress
- Glucocorticoids, dopamine and somatostatin also inhibit TSH secretion.
However, they are not involved in its physiological control.
Effects
 Trophic effect on the thyroid gland: Increases cellularity, vascularity
and secretion of thyroid hormones from the thyroid gland.

Abnormalities
 TSH excess
- Caused by:
o Pituitary tumors that secrete TSH (= high T3 & T4 = secondary
hyperthyroidism)
o Thyroid diseases that decrease T3 & T4 secretion (= primary
hypothyroidism)
 TSH deficiency
- Caused by:
o Pituitary tumors that decrease T3 & T4 secretion (= secondary
hypothyroidism)
o Thyroid diseases that increase T3 & T4 secretion (= primary
hyperthyroidism)
FOLLICLE STIMULATING HORMONE (FSH) &

LEUTINIZING HORMONE (LH)
Characteristics
- Known as gonadotrophins “or gonadotropins” because of their trophic
effects on the gonads.
- They are glycoproteins. Each consists of 2 subunits: alpha & beta
(similar to TSH & hCG).
- Half life: FSH= 3 hours and LH= 1 hour.
Control
 From the hypothalamus by the gonadotrophin releasing hormone
(GnRH).
 Negative feedback mechanism by FSH and LH and by the sex
hormones that are released from the gonads in response to them
(estrogens, progesterone and testosterone).

 Release of GnRH starts at puberty (after maturation of the CNS) and
then the release of FSH and LH starts following that (see the
reproductive system). Therefore FSH & LH are almost absent before
puberty.
 Inhibitors: Stress and Prolactin (possibly inhibits their effects at the
level of the ovary)
Actions
 Trophic effect on the gonads: Increase vascularity, cellularity and
secretion of sex hormones from the gonads in both males and females.
 Control of gonadal functions: production of sperms in males and the
menstrual cycle including ovulation in females (see the reproductive
system).
Abnormalities
o Gonadotrophin excess
- Results in "precocious puberty" if occurred before puberty.
o Gonadotrophin deficiency
- Delays onset of puberty (if occurred before puberty) & results in infertility
(if occurred after puberty).
PITUITARY INSUFFICIENCY (PAN-HYPOPITUITARISM)

Causes:
 Tumors (e.g. craniopharyngioma or pituitary tumors)
 Surgical removal of the pituitary (for eradication of a tumor)
 Sheehan’s syndrome (pituitary infarction following postpartum
hemorrhage, due to severe vasoconstriction as a body response to
shock)
 Infiltration of the pituitary (e.g. by iron as in hemochromatosis)
 Infections (e.g. tuberculosis or meningitis)

Features:
- (Combined features of hupothyroidism, Addison’s disease,
hypogonadism & low GH)
 Skin pallor due to loss of the melanocyte stimulating activity of ACTH
 Intolerance to cold due to decreased rate of metabolism caused by low
TSH GH & ACTH
 Loss of menstrual cycle in females due to low LH & FSH
 Failure of lactation due to low prolactin
 Hypoglycemia & increased sensitivity to insulin (due to low GH & ACTH
which antagonize insulin). Hypopituitarism improves diabetes mellitus.
 Increased sensitivity to stress (due to low ACTH)
 Atrophy of some endocrine glands (e.g. gonads & adrenal cortex (zona
fasciculata & zona reticularis, but not zona glomerulosa)
 Polyuria due to absence of ADH; However, this is not very severe
because the decreased metabolism is associated with decrease in the
osmotic load that should be excreted
Remember that:
- The following are not features of pituitary insufficiency:
 Salt & water depletion (hypovolemia shock); because aldosterone
secretion is maintained
 Fatal hypoglycemia
 Loss of weight
Treatment:
- Hormone replacement as follows:
 Glucocorticoids (in form of hydrocortisone) & thyroid hormones.
 Sex hormones (testosterone in males & estrogen in females).
 Growth hormone (for children).

HORMONES OF THE POSTERIOR PITUITARY
ANTIDIURETIC HORMONE (ADH)
Characteristics
- Also known as vasopressin (or arginine-vasopressin “AVP” to
differentiate it from lysine- vasopressin of pigs).
- Nona-peptide (9 amino acids)
- Half life: 18 min
- Synthesized in hypothalamus in the:
o Supra-optic nucleus (SON): the main site of ADH synthesis
o Paraventricular nucleus (PVN): synthesis occurs to a lesser
extent
- Transmitted through axons in the hypothalamo-hypophseal neural tracts
(bound to neurophysin II) to be stored in the posterior pituitary.
- Synthesized also in other locations like the gonads and the adrenal
cortex (but the function & the significance of this secretion are unknown).
Control
- Release of this hormone is stimulated by:
 Hyperosmolarity
- Detected by osmoreceptors located at the hypothalamus and connected
to the cell bodies of the SON & PVN through dendrites.
- The osmoreceptors contain isotonic fluid; when the osmolarity of ECF is
increased, the osmoreceptors shrink due to osmosis; this pulls the
dendrites causing mechanical stimulation for the release of ADH.
 Hypovolemia
- The volume of ECF is detected by volume receptors located at the great
veins near the heart (the lower pressure side of the circulation); these
send tonic inhibitory discharge through the vagus to inhibit release of
ADH.

- Hypovolemia results in less stretch of the volume receptors and therefore
less inhibition of ADH release.
 Hypotension
- The blood pressure is detected by baroreceptors located at the aortic
arch and the carotid bifurcation (high-pressure side of the circulation).
These receptors respond to elevation in blood pressure by sending
inhibitory discharge to the cardiovascular centers in the medulla (to control
blood pressure) and to the hypothalamus (to inhibit release of ADH).
- Hypotension causes less stimulation of the receptors & therefore less
inhibition of ADH.
 Angiotensin II
- This octa-peptide (8 amino acids) hormone is synthesized in the blood
from angiotensinogen, a plasma protein synthesized in the liver, following
release of renin from the Juxta-glomerular apparatus in the kidney (see
the section of adrenal cortex). Angiotensin II stimulates release of ADH.
 Drugs
- Include: barbiturates, clofibrate, nicotine and morphine.
- Inhibitors of ADH include:
 Hypo-osmolarity
 Hypertension
 Hypervolemia
 Alcohol
Receptors
- Vasopressin has two types of cell membrane receptors:
o V1 receptors (V1A & V1B):
o V1A (in the blood vessels, liver & brain)
o V1B (in the anterior pituitary)
o Both act through Ca++ as a second messenger

o V2 receptors:
o In the collecting ducts (& distal part of the DCTs)
o Act through cAMP as a second messenger
Effects
 Water retention:
- ADH acts on V2 receptors in the distal part of the distal convoluted
tubules “DCT” and the collecting ducts “CDs” in the kidney causing
water retention (through insertion of aquaporin II on the luminal
membrane, see the renal system).
- It facilitates reabsorption of 7-13% of the filtrate in the kidney.
 Vasoconstriction:
- ADH does not cause vasoconstriction when it is present in normal
level in the circulation except in the vasa recta. However, in high levels
(e.g. in response to hemorrhage) it causes vasoconstriction (through V1
receptors) resulting in elevation of the B.P.
 Other effects
- Glycogenolysis in the liver (through V1a receptors)
- Neurotransmitter in the brain and spinal cord (through V1a receptors)
- Release of ACTH from the anterior pituitary (through V1B receptors)
Abnormalities
 ADH deficiency: “diabetes insipidus”
- Results in polyuria and excessive thirst (urine volume may reach up
to 23 L/day).
- The condition is known as diabetes insipidus (DI).
- It may result from a problem in the hypothalamus (neurogenic DI) or a
problem in the kidney (nephrogenic DI).

- The neurogenic type is caused by trauma, tumors or diseases
affecting the hypothalamus. It can be treated by synthetic ADH
(desmopressin “DDAVP”) given by nasal inhalation.
- The nephrogenic type can be inherited (sex-linked for defective V2
receptors or autosomal for abnormal aquaporin II) or can be caused by
drugs (e.g. demeclocycline & lithium).
 Excessive ADH secretion: “SIADH”
- Excessive ADH causes abnormal water retention.
- This results in oliguria (reduction in urine volume), hypertension, and
edema. The condition is known as syndrome of inappropriate ADH
secretion (SIADH).
- It is caused by head trauma, pneumonia, lung tumors, pancreatitis,
and drugs like chlorpropamide, cyclophosphamide & carbamazepine.
- It can be treated by drugs that decrease the sensitivity of the renal
receptors to ADH (e.g. demeclocycline).
Notice that: Polyuria in diabetes insipidus is decreased by removal of the
anterior pituitary; because the rate of metabolism (induced by TSH, ACTH
& GH) is decreased. This decreases the metabolic products and therefore
the osmotic load that should be excreted in urine.
OXYTOCIN
Characteristics
- Nona-peptide (9 amino acids); half-life: (1-4 min).
- Synthesized in hypothalamus mainly in the paraventricular nucleus
(PVN) and to a lesser extent in the supra-optic nucleus (SON) & stored in
the posterior pituitary (it is transmitted bound to neurophysin I through the
neural tracts).
- It is synthesized in other locations like the gonads and adrenal cortex.

Control
 Positive feedback mechanism through neuro-endocrine reflexes
stimulated by:
o Suckling (stimulation of touch receptors around the nipple with the
mouth of the baby during suckling results in discharge of impulses that
activate the PVN & the SON in the hypothalamus, this stimulates
release of stored oxytocin in the posterior pituitary. Oxytocin causes
ejection of milk & the baby sucks the milk, and at the same time,
causes more stimulation and therefore more release of oxytocin)
o Labor (towards the end of pregnancy, the fetal head descends into the
pelvis and starts to stimulate touch receptors at the cervix of the uterus,
afferent impulses ascend to stimulate release of oxytocin. Oxytocin
causes contraction of the uterus, the fetus descends more, his head
dilates the uterine cervix, and at the same time, causes more
stimulation of receptors and more release of oxytocin until delivery)
 Other stimuli: Stress & coitus (genital stimulation)
 Inhibitors: Alcohol
Effects
 Milk ejection: Acts on myoepithelial cells in the breast tissue causing
ejection of milk.
 Contraction of the uterus: Contracts the smooth muscle in the uterus
during labor. This effect is facilitated by estrogens and inhibited by
progesterone.
 Other minor effects (when stimulated by coitus):
- Helps in contraction of the uterus to facilitate movement of sperms
- Helps in contraction of the vas deferens to facilitate ejaculation
Clinical points: Clinical abnormalities related to oxytocin are not known. A
synthetic oxytocin (Syntocinon®) is used clinically to initiate labor.

1- The following hormone is not released by the hypothalamus:
a. Growth hormone
b. Adrenocorticotrophic hormone
c. Dopamine
d. Thyroxin
e. Insulinotropic hormone
2- Which of the following hormones induces milk synthesis?
a. Oxytocin
b. Prolactin
c. Thyroxin
d. FSH
e. ACTH
3- Growth hormone:
a. Stimulates lipogenesis
b. Secretion is lowered during fasting
c. Secretion is increased during sleep
d. Is a steroid hormone
e. Is released from basophils of the pituitary
4- Deficiency of which of the following hormones results in short stature
with mental retardation?
a. Insulin
b. Growth hormone
c. Prolactin
d. Thyroid hormones
e. Vasopressin
5- Acromegaly is a condition produced by:
a. Arginine vasopressin deficiency
b. Excess growth hormone
c. Excess secretion of oxytocin
d. Destruction of the adrenal gland
e. Deficiency of somatomedin C
6- ACTH is released:
a. During REM sleep
b. After trauma
c. After food intake
d. During corticosteroid therapy
e. From acidophil cells of anterior pituitary
7- Prolactin:
a. Is not found in males
b. Is secreted by acidophils of the white blood cells
c. Antagonizes eefects of gonadotropins
d. Is increased in sheehan’s syndrome
e. Inhibits secretion of estrogen during pregnancy

8- Growth hormone is:
a. Catabolic
b. Hypoglycemic
c. Anti-ketogenic
d. Lipogenic
e. Lactogenic
9- Hormones synthesized in acidophils of the pituitary include:
a. Prolactin releasing hormone
b. Growth hormone
c. Follicle stimulating hormone
d. Adrenocorticotrophic hormone
e. Thyroid releasing hormone
10- In cases of deficiency, replacement of the hormone secreted by this
gland is essential for life:
a. Thyroid
b. Pituitary
c. Adrenal cortex
d. Testes
e. Pancreas
11- Secretion of anti diuretic hormone (ADH) is inhibited by:
a. Standing
b. Hyperosmolarity
c. Hypotension
d. Hypovolemia
e. Alcohol
12- Physiological effects of ADH include:
a. Raising peripheral resistance
b. Increasing blood viscosity
c. Skin vasoconstriction
d. Increasing urine osmolarity
e. Decreasing rate of sweating
13- Growth hormone:
a. Receptors are cytoplasmic
b. Synthesis is from cholesterol
c. Effects on bone are indirect
d. Secretion is increased during REM sleep
e. Inhibition is by dopamine
14- Growth hormone differs from prolactin in that, it is:
a. A protein hormone
b. Released from acidophils of the anterior pituitary
c. Stimulated by stress
d. Inhibited by dopamine
e. Not increased during pregnancy
15- Following transection of the pituitary stalk, plasma concentration of this
hormone remains constant:
a. GH

b. TRH
c. FSH
d. ADH
e. Cortisol
16- Excessive production of growth hormone in a 9-year old boy results in:
a. Acromegaly
b. Paget’s disease of bone
c. Short stature
d. Increased glucose tolerance
e. Positive nitrogen balance
17- A pituitary adenoma in a 45-year-old man, that excessively secretes
prolactin, may result in:
a. Infertility
b. Diabetes mellitus
c. Renal stones
d. Female hair distribution
e. Goiter
18- Cutting the connection between the pituitary and the hypothalamus
increases secretion of:
a. Oxytocin
b. Insulin
c. Growth hormone
d. Prolactin
e. ACTH
19- Which of the following statements about hormones is correct?
a. Neuro-hormones are released by glands to act on neurons
b. Autocrine hormones act on cells of the autonomic nerves system
c. All hormones act through second messengers
d. All hormones have both endocrine and paracrine effects
e. Effects include synthesis of specific proteins in the target cell
20- The anterior pituitary:
a. Is neural in origin
b. Is derived as down-growth from floor of 3rd ventricle
c. Is connected to hypothalamus by neural tracts
d. Hormones are regulated by neuro-hormones secreted from hypothalamus
e. Hormones are released during stress
21- ACTH:
a. Decreases the conversion of cholesterol to pregnenolone in adrenal
cortex
b. Stimulates glucocorticoid secretion
c. Is released in response to hyperglycaemia
d. Is secreted continuously throughout the day
e. Level is decreased in adrenalectomized animal
22- The basophilic cells of the adenohypophysis secrete:
a. TSH
b. Somatostatin

c. Oxytocin
d. Gonadotrophins relating hormone
e. Growth hormone
23- Growth hormone:
a. Decreases somatomedin formation in the liver
b. Stimulates glucose entry into cells
c. Increases free fatty acids in the blood
d. Decreases the level of ketone bodies in the blood
e. Stimulates the growth of bones in the fetus
24- The action of trophic hormones released by the anterior pituitary on
their target glands include:
a. Reducing the blood flow
b. Decreasing the size of the gland
c. Increasing the synthesis of specific hormone
d. Reducing antibody formation against specific hormone
e. Decreasing cyclic AMP production
25- In an adult with a pituitary tumor producing excessive amounts of
ACTH:
a. Production of adrenal androgens is decreased due to consumption of
cholesterol
b. Blood pressure is increased due to increased secretion of aldosterone
c. Blood sugar is decreased due to increased secretion of insulin
d. Total body weight is decreased due to higher rate of metabolism
e. Glomerular filtration rate is decreased due to higher secretion of cortisol
26- Which of the following hormones is not a glycoprotein:
a. TSH
b. CRH
c. FSH
d. LH
e. HCG
27- Oxytocin is:
a. Synthesized in the posterior pituitary
b. Regulated by positive feed back mechanism
c. A known cause of galactorrhoea
d. Synthesized from cholesterol
e. Antagonized by progesterone
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
c b c d b b c e b c e
12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
d c e d e a d e d b a
23. 24. 25. 26. 27.
c c b b e

THE THYROID GLAND
Structure of the thyroid gland
- The thyroid gland is the largest endocrine gland in the body; weighing
about (20-25g). It lies on the trachea at the anterior aspect of the neck and
moves with swallowing.
- In the embryo, at the 3rd or 4th week of pregnancy, the thyroid originates
from the floor of the pharynx at the base of the tongue, at a point latter
indicated by the foramen cecum. Subsequently the thyroid descends to its
position through the thyroglossal cyst.
- It consists of two lobes that are connected by the thyroid isthmus. In
addition, an extra pyramidal lobe may be found sometimes.
- Concerning its histology, it is made up of multiple acini (or follicles). Each
follicle is surrounded by a single layer of cells and filled with a protein
material (known as the colloid).
- The type of protein in the colloid is known as the thyroglobulin.
- The activity of the gland is indicated by:
• The amount of colloid (abundant when the gland is inactive, small
amount when it is active)
• The shape of follicular cells (flat when the gland is inactive,
columnar when it is active)
Fig 10.9: The thyroid gland

- The thyroid gland synthesizes the following hormones:
 Thyroid hormones “T3 and T4” (by the follicular cells- see below)
 Calcitonin (by the parafollicular cells “clear cells” - see control of Ca++)
THYROID HORMONES
Characteristics
- The thyroid hormones are two types:
a- T3 (Tri-iodothyronine)
b- T4 (tetra-iodothronine or thyroxine)
- T3 is about 3 to 5 times more active than T4.
- Each hormone is synthesized from two molecules of tyrosine and 3 or 4
atoms of iodide.
Steps of thyroid hormone synthesis

1. Iodide trapping by the follicular cells:
–The “I-/Na+ symporters” pump iodide into thyroid cells against electrical &
chemical gradients; co-transported with Na+ (these symporters are
stimulated by TSH).
–Iodide trapping also occurs in other tissues including: (salivary glands,
gastric mucosa, placenta, ciliary body of the eye, choroid plexus &
mammary glands). However, the physiological significance is unknown.
–To maintain normal thyroid function, the minimum daily requirement of
iodine intake is about 150 µg/day.
2. Oxidation of iodide into iodine inside the follicular cells:
–Iodide (I-) is converted to iodine (I2).
–This is catalyzed by the enzyme thyroid peroxidase.
–Then iodine diffuses to the colloid down its chemical and electrical
gradients.
3. Synthesis of thyroglobulin by the follicular cells
–Glycoprotein made up of two subunits (MWt= 660,000).
–Each molecule contains 123 tyrosine residues (but only 4-8 are involved
in synthesis of Hs).
–It is secreted into the colloid by exocytosis.
4. Iodination
–Iodine is added to the tyrosine residues in thyroglobulin (to carbon
number 3 &/or 5). This gives either mono-iodo-tyrosine “MIT” &/or di-iodo-
tyrosine “DIT” residues.
–Iodination occurs as the iodine & thyroglobulin are transported through
the cell membrane towards the colloid and it is catalyzed by the enzyme
thyroid peroxidase.
5. Coupling (Condensation) inside the colloid
–Coupling of the iodinated tyrosine residues within the thyroglobulin.
–Also catalyzed by the enzyme thyroid peroxidase.
–Tyrosine + tyrosine = “thyronine”; and the iodine molecules are also
summated as follows:
 MIT + DIT = T3 (= 7%)
 DIT + DIT = T4 (= 35%)
 DIT + MIT = reverse T3 “RT3” (= trace)
 Uncoupled residues “MIT & DIT” (= 56%).
6. Release of thyroid hormones
–The colloid is ingested by the follicular cells by the process of
endocytosis. The iodinated residues are detached from thyroglobulin by
the lysosomal enzymes: (proteases); giving T3, T4, RT3, MIT & DIT.
–T3, T4 & RT3 are released to the blood as well as the rest of the
thyroglobulin.

–Iodine in MIT & DIT is extracted by iodotyrosine deiodinase enzyme for
re-utilization in thyroid hormone synthesis.
–This de-iodination is an important source of iodine; therefore deficiency of
the enzyme iodotyrosine de-iodinase results in loss of the iodine in MIT &
DIT in urine.
Fig 10.10: The thyroid hormones
7. Peripheral conversion of T4 into T3

–About one third of T4 (thyroxine) is converted to T3 by de-iodinase
enzymes found in peripheral tissues including the liver, kidney and brain.
–Note that the thyroid gland secretes only 13% of the circulating T 3. The
rest is formed by peripheral de-iodination. Similarly, most of RT3 in the
plasma is formed by peripheral de-iodination.
–Certain conditions may cause fluctuation in de-iodination, resulting in rise
of RT3 and depression in T3. They include selenium deficiency (because
the de-iodinase enzymes are selenium dependent), hypercatabolic states
(burn, trauma, advanced cancer, liver cirrhosis, renal failure & myocardial
infarction) and the fasting states.
–Remember that: in the above states the low T3 guards against rapid loss
of calories and protein.
Thyroid hormones in the plasma
- The average normal level in the plasma:
 [T3] = 2.3 nmol/L
 [T4] “thyroxine”= 103 nmol/L
- Both hormones are found in the circulation in the two forms:
 Free form (the active form that carries out the functions).
 Protein bound form (inactive form not filtered in the kidney, acts as
storage form).
- About 99.98% of T4 is bound to proteins whereas about 99.8% of T3 is
bound to proteins.
- The binding proteins are:
1- Thyroxine binding globulin (TBG)
- Has the highest affinity to bind thyroxine
- It carries about 67% of all T4 and 46% of all T3 in plasma
2- Thyroxine binding albumin (TBA)
- Has the highest capacity “available sites” to bind thyroid
hormones
3- Thyroxine binding pre albumin (TBPA or Transthyretin)
Note:
- Albumin has the highest concentration in the plasma and it stays for
longer time in the circulation (Half-life for TBA = 13 days, TBG = 5 days
and TBPA = 2 days).

- Alterations in the level of the binding proteins (e.g. TBG) result in
changes in the level of total hormone (the free + the protein bound
fractions); however, plasma TSH and the free hormone are normal; and
the patient remains euthyroid.
- E.g. Elevation in TBG level causes reduction in the free fraction; resulting
in elevation of TSH (due to loss of the –ve feedback mechanism). TSH
stimulates secretion of more thyroid hormones. Therefore a new
equilibrium is reached where TSH and thyroid hormone secretion return to
normal (euthyroid) but the total hormone is increased.
Remember that: in hypo or hyperthyroidism, plasma TSH and the free
hormone level are abnormal.
- Factors that increase TBG (= increase total hormone) include:
 Pregnancy
 Contraceptive pills (containing estrogen)
 Certain drugs (clofibrate, tranquilizers …)
- Factors that decrease TBG (= decrease total hormone) include:
 Androgens
 Glucocorticoids
- Drugs that inhibit binding of TBG to thyroid hormones (= decrease total
hormone) include:
 Aspirin
 Phenytoin
- The half-life of each hormone:
 T3= 1.5 days (It is less bound to proteins and more active than T4)
 T4= 6-7 days (It is more bound to proteins and less active than T3)
- Sites of metabolism:
 Liver (conjugated and excreted in bile)
 Kidney (and other tissues).

Control of thyroid hormones
 By the hypothalamo-pituitary axis
- The hypothalamus secretes thyroid releasing hormone (TRH); the
anterior pituitary responds by secreting thyroid stimulating hormone (TSH);
then the thyroid gland secretes thyroid hormones (see TSH in the section
of the pituitary gland).
 The thyroid hormones exert a negative feedback effect on the pituitary
and hypothalamus.
 TRH is stimulated by cold exposure and inhibited by hot exposure and
stress.
Fig 10.11: Control of thyroid hormones
Mechanism of thyroid hormone action

- Receptors for thyroid hormones are intracellular DNA-binding proteins
that function as transcription factors, very similar to the receptors for
steroid hormones.
- The hormone enters target cells through membrane transporter proteins
(facilitated diffusion).

- In the cytoplasm, T4 is converted to T3 by the enzyme 5’ de-iodinase.
- Once inside the nucleus, T3 binds its receptor.
- The hormone-receptor complex interacts with specific sequences of DNA
to modulate gene expression, either by stimulating or inhibiting
transcription of specific genes.
- Thyroxine (T4) has not been shown to alter gene transcription although it
can bind to the nuclear receptor with much less affinity than
triiodothyronine.
- Therefore, it is likely that it serves as a pro-hormone with essentially all
actions of thyroid hormone at the transcriptional level caused by
triiodothyronine.
Fig 10.12: Mechanism of thyroid hormone action

Effects of thyroid hormones
1- Calorigenic action:
- Thyroid hormones increase oxygen consumption of most tissues in
the body. This is because they increase the rate of metabolism and the
activity of Na+-K+ ATPase pump. Exceptions include adult brain,
anterior pituitary, testes, uterus, and lymph nodes.
Note: oxygen and glucose uptake by the brain are normal in hypo and
hyperthyroidism.
2- Effect on metabolism:
Protein:
- Thyroid hormones increase both protein catabolism (in high levels)
and increase protein anabolism (in low to moderate levels).
- The increased protein catabolism may partly explain the proximal
myopathy (muscle weakness) seen in thyrotoxicosis.
- In hypothyroidism, a variety of proteins and polysaccharides
accumulate in the skin producing the characteristic puffiness of the skin
(= myxedema). However, it is also associated with myopathy.
Fat:
- Thyroid hormones increase mobilization of fat & decrease cholesterol
level in plasma.
- They decrease cholesterol because they increase formation of LDL
receptors in the liver cells; thus increasing hepatic uptake of
cholesterol to be excreted in bile.
CHO:
- Increase absorption of carbohydrates in the GIT.
- In hyperthyroidism, the plasma glucose level rises and then descends
rapidly following ingestion of a carbohydrate meal (= lag storage curve
in glucose tolerance test “GTT”). It also increases degradation of

insulin & potentiates the glycogenolytic effects of catecholamines; thus
making diabetes worse.
Vitamins:
- Because of their effects on metabolism, they increase the need for
vitamins.
- They convert carotene to vitamin A in the liver.
- In hypothyroidism, carotene accumulates in plasma (carotenemia)
causing yellowish coloration of the skin but not the scleras (this
differentiates it from jaundice).
3- Growth:
- Thyroid hormones are needed for normal growth and skeletal
maturation. In addition, they potentiate the effects of growth hormone
on tissues.
- Hypothyroidism in children results in stunted growth.
4- CVS:
- Thyroid hormones have the following effects on the cardiovascular
system:
 Increase heart rate (because they increase number & affinity of β1
receptors to catecholamines. They also increase α myosin heavy
chains, G proteins, Na+-K+ ATPase pump and some K+ channels).
Note: α myosin heavy chains have more ATPase activity and
therefore higher speed of contraction than β myosin heavy chains.
 Increase stroke volume (because they increase contractility of the
heart by increasing number & affinity of β1 receptors to
catecholamines. They also increase α myosin heavy chains, G
proteins, Na+-K+ ATPase pump and some K+ channels).
 Increase the cardiac output (because they increase the heart rate &
the stroke volume).

 Increase the systolic blood pressure (because they increase the
cardiac output).
 Vasodilatation (because they increase the metabolic rate and
therefore heat production).
 Decrease the diastolic blood pressure (because they cause skin
vasodilatation and therefore decrease the peripheral resistance).
 Increase the pulse pressure (because they increase the systolic &
decrease the diastolic).
5- GIT:
- Increase appetite and increase intestinal motility.
- Hypothyroid patients suffer from constipation whereas hyperthyroid
patients suffer from diarrhea.
6- CNS:
- Increase development of the brain in children (especially the cerebral
cortex, basal ganglia and cochlea). That is why hypothyroidism in
children causes mental retardation, motor rigidity, and deafness.
- Increase mentation in adults (partly due to increased responsiveness
to catecholamines).
- Thyroid hormones are needed for normal reaction time in stretch
reflexes.
7- Other effects:
- Increase milk synthesis.
- Essential for normal menstruation and fertility; therefore hypo and
hyperthyroidism are associated with abnormal menstruation.
Abnormalities
Hyperthyroidism (or thyrotoxicosis)
- Primary hyperthyroidism is caused by toxic tumors, inflammation, drugs,
or autoantibodies that activate the thyroid.
- When the cause is “long acting thyroid stimulating antibodies” (LATS
antibodies), acting on TSH receptors of the thyroid gland (i.e. thyroid
stimulating antibodies), hyperthyroidism is called “Graves’ disease”. Unlike
other causes of hyperthyroidism, Graves’ disease is characterized by eye
signs (see below).
- Secondary hyperthyroidism is caused by pituitary tumors that increase
production of TSH.
- Features of hyperthyroidism (see effects of thyroid hormones) include:
 Increased metabolism = increased heat production = intolerance to hot
 Increased heart rate, SV, COP, systolic B.P. and pulse pressure.
Decreased diastolic B.P.
 Irritability and nervousness
 Increased appetite (hyperphagia)
 Diarrhea and weight loss
 Fine tremor
 Warm, soft skin and sweating
 Eye signs (only in Graves’ disease which is the commonest cause of
thyrotoxicosis):
o Lid retraction (= retraction of the upper eyelid; allowing appearance
of the whitish sclera above the cornea. Normally, the upper sclera
cannot be seen).
o Lid lag (= delay in movement of the upper eyelid when looking to an
object descending from above to downwards. This sign is seen only
during clinical examination).
o Exophthalmos (= protrusion of the eye globe forward due to
inflammation and edema of the tissues in the orbit. The
inflammation is caused by cytokines produced by fibroblasts in the
orbit that respond to the autoantibodies.

Fig 10.13: Lid retraction and exophthalmos in Graves'disease
Hypothyroidism (or myxedema)

- Primary hypothyroidism is caused by thyroid problems (common)
whereas secondary hypothyroidism is caused by pituitary or hypothalamic
problems (rare).
- Thyroid problems include:
 Congenital deficiency of the enzymes involved in thyroid hormone
synthesis
 Severe iodine deficiency or excess.
(Iodine excess inhibits thyroid function (Wolff-Chaikoff effect) by the
following mechanisms: inhibition of iodination, inhibition of proteolysis
of thyroglobulin and reduction of cAMP rise in response to TSH)
 Tumors
 Inflammation
 Surgical removal
 Autoantibodies that destroy the thyroid (Hashimoto’s thyroiditis)
 Antithyroid drugs (interfere with iodide trapping “perchlorate, nitrate
and thiocynate” or block iodination and coupling “propylthiouracil and
methimazole”)

- Features of hypothyroidism:
 Low metabolism = decreased heat production = intolerance to cold
 Hair changes (becomes coarse and sparse); loss of the outer eyebrow
 Skin becomes dry and yellow (carotenemia)
 Voice becomes characteristically husky and slow
 CNS symptoms (sleepy, slow mentation and poor memory “myxedema
madness”)
 Bradycardia
 Constipation
 High cholesterol level in plasma
Cretinism
- Congenital hypothyroidism is caused by:
 Maternal iodine or thyroid hormone deficiency
 Maternal antithyroid antibodies that cross the placenta
 Congenital absence of the thyroid gland
 Congenital absence of enzymes involved in thyroid hormone synthesis
- In addition to the above features of hypothyrodism, cretinism is
associated with: Mental retardation, short stature, large protruded tongue
and umbilical hernia.
Remember that: early diagnosis and treatment of cretinism can prevent
mental retardation.
Fig 10.14: Congenital hypothyroidism (= Cretinism)

Goiter
- Swelling of the thyroid gland caused by high TSH.
- High TSH (& therefore goiter) is caused by:
 Iodine deficiency (endemic goiter)
 Graves’ disease (due to the effect of long acting thyroid stimulating
antibodies)
 Anti-thyroid drugs (see above)
 Goitrogens (chemical substances found in vegetables, converted in the
intestine to an antithyroid agent that causes goiter “goitrin”)
 Some causes of congenital hypothyroidism (peroxidase or de-iodinase
deficiency)
Fig 10.15: Endemic goiter
Tests assessing thyroid function

1- Total & free T3 & T4
- Direct measurement of the total & free fractions of thyroid hormones is
now available by radioimmunoassay. In the past, the thyroid function used
to be assessed indirectly, by measurement of the basal metabolic rate.

2- TSH
- Measurement of TSH by radioimmunoassay differentiates between
primary and secondary thyroid hormone abnormalities.
- Examples:
 TSH is low in primary hyperthyroidism (due to the -ve feedback effect
of T3 on TSH).
 TSH is high in primary hypothyroidism (due to loss of the –ve feedback
mechanism).
 TSH is low in secondary hypothyroidism. However, to differentiate
between a pituitary and a hypothalamic cause, the response to an I.V.
dose of TRH should be assessed. A good response (rise in TSH after
I.V. TRH) indicates a hypothalamic cause of the hypothyroidism.
3- Radioactive iodine uptake
- A test dose of radioactive isotope of iodine (123I) is given orally and then
its uptake by the thyroid gland is measured by a gamma camera.
- The degree of uptake acts as an index of the thyroid function (high in
hyperthyroidism and low in hypothyroidism).
- The use of radioactive iodine uptake as a diagnostic tool is now rare
because of the availability of radioimmunoassay of the hormones.
However, it is still used in treatment of some cases of hyperthyroidism and
thyroid cancer (because the radioactive iodine, in large doses, destroys
the thyroid cells).

THE ADRENAL GLAND
- The adrenal gland consists of two endocrine glands:
1- Adrenal cortex:
 Essential for life.
 Secretes the following steroid hormones synthesized from cholesterol:
o Glucocorticoids (cortisol)
o Mineralocorticoids (aldosterone)
o Sex Hormones (androgens)
2- Adrenal medulla:
 A sympathetic ganglion that lost its postganglionic axons and became
modified into secretory cells.
 Not essential for life but prepares the body for emergencies.
 Secretes the catecholamines: (epinephrine, norepinephrine &
dopamine).
Fig 10.16: The adrenal gland
Anatomy of the adrenal gland

The adrenal cortex:
- Cells of the adrenal cortex contain abundant lipid, mitochondria and
smooth endoplasmic reticulum involved in steroid biosynthesis.

- The cortex is divided into 3 zones:
 Zona glomerulosa (The outer zone. = 15% of the adrenal gland.
Secretes aldosterone. Also responsible for formation of new cells to
replace the lost ones, even from the other zones).
 Zona fasciculata (The inner zone. = 50% of the gland. Secretes
glucocorticoids).
 Zona reticularis (The innermost zone. = 7% of the gland. Secretes
sex hormones).
Remember that: corticosterone is secreted by the 3 zones, glucocorticoids
are secreted by the two inner zones but mainly by zona fasciculate, sex
hormones are also secreted by the two inner zones but mainly by zona
reticularis; whereas secretion of aldosterone is confined to zona
glomerulosa.
- The two inner zones (fasciculate and reticularis) respond to ACTH from
the pituitary gland. They undergo hypertrophy in ACTH excess and
atrophy in ACTH deficiency.
- In fetal life, the whole adrenal cortex is under pituitary control. It is
involved in synthesis of androgens which are converted to estrogens in the
placenta (the feto-placental unit). However, most of the fetal adrenal cells
degenerate at birth.
The adrenal medulla:
- The adrenal medulla constitutes about 28% of the adrenal gland. It
consists of densely innervated granulated cells; 90% of these are
epinephrine-secreting cells and 10% are norepinephrine secreting cells
(the dopamine secreting cells are unknown).
Biosynthesis of the adreno-cortical hormones
- The adrenocortical hormones are synthesized from cholesterol; so they
contain the steroid nucleus (cyclopentanoperhydrophenanthrene nucleus).

- Cholesterol contains 27 carbons whereas the adrenocortical hormones
contain 21 or 19 carbons (C21 or C19 steroids).
- Most of the C19 steroids are 17-ketosteroids (contain keto group at
position 17) and have androgenic activity.
- Most of the C21 steroids are 17-hydroxycorticosteroids (contain hydroxyl
group at position 17) and have mineralocorticoid &/or glucocorticoid
activity.
- By the action of specific enzymes (most of which are members of the
cytochrome P450 superfamily), cholesterol is converted first to
pregnenolone and then to one of the adrenocortical hormones.
Fig 10.17: Synthesis of adrenocortical hormones

Important notes about adrenocortical hormone biosynthesis:
- Pregnenolone is formed in the mitochondria, androgens are formed in
the smooth endoplasmic reticulum, and the last step in glucocorticoid
formation occurs in the mitochondria.
- Androgens and glucocorticoids are formed in the cells of zona reticularis
and zona fasciculata because these cells contain the enzymes 11β-
Hydroxylase and 17α-Hydroxylase.
- These 2 enzymes are not present in zona glomerulosa; that is why it can
not form cortisol and androgens. However, it contains an enzyme similar to
11β-Hydroxylase known as aldosterone synthase. This catalyzes
formation of aldosterone.
- Zona fasciculata has higher 3β-Hydroxysteroid dehydrogenase activity
than zona reticularis that is why it is more active in formation of
glucocorticoids; on the other hand, zona reticularis has higher 17α-
Hydroxylase activity that is why it is more active in formation of androgens.
- Congenital deficiency of these enzymes causes the adrenogenital
syndrome in females:
 21β-Hydroxylase (common)
 11β-Hydroxylase (rare)
- The adrenogenital syndrome (one of the syndromes of congenital
adrenal hyperplasia) is characterized by:
o Decreased synthesis of cortisol.
o High ACTH (this causes the adrenal hyperplasia).
o Increased synthesis of androgens causing:
 Virilization in females (= female pseudo-hermaphroditism)
 Precocious pseudo-puberty in males
o Hypotension (due to absent mineralocorticoids & Na+ loss in 21β-
Hydroxylase deficiency; “salt losing type”).

o Hypertension (due to the mineralocorticoid effects of 11-
Deoxycortisol & 11-Deoxycorticosterone in 11β-Hydroxylase
deficiency “hypertensive form”).
- Other syndromes of congenital adrenal hyperplasia may be caused by:
 Absence of the protein that transports cholesterol to the
mitochondria.
 3β-Hydroxysteroid dehydrogenase deficiency (= excess
androgens).
 17α-Hydroxylase deficiency (= no androgens).
Glucocorticoids
- These are the adrenocortrical hormones with predominant effects on
glucose and protein metabolism.
- They include: cortisol (the dominant glucocorticoid in humans) and
corticosterone (the dominant glucocorticoid in some animals).
- Synthetic steroids with high cortisol activity and with longer half-life:
 Prednisolone (4 times cortisol activity and minimal aldosterone activity)
 Dexamethasone (25 times cortisol activity and no aldosterone activity)
 9α fluorocortisol (10 times cortisol activity and appreciable aldosterone
activity)
CORTISOL
Characteristics
- Cortisol is the most dominant glucocorticoid in humans.
- It is essential for life.
- Half life of cortisol= 60-90 min; with the liver as the main site of
catabolism.
- Some of the metabolites (e.g. ketosteroids) are excreted in urine after
hepatic conjugation.
- Most of the hormone is bound in the plasma to α globulin (transcortin or
corticosteroid binding globulin “CBG”), plus minor binding to albumin.
- As in the case of thyroid hormone binding globulin, CBG level fluctuates
during pregnancy.
Control of cortisol
- Hypothalamo-pituitary axis: The hypothalamus releases CRF in response
to stress. The anterior pituitary releases ACTH. The adrenal cortex
releases cortisol.
- Feedback mechanism
- Circadian rhythm (high in the morning and low at night)
- The main stimulus: stress
Fig 10.18: Control of cortisol
Effects of cortisol
 Metabolism of CHO:
- Cortisol causes hyperglycemia by anti-insulin action on the peripheral
tissues and by increasing hepatic gluconeogensis; however it causes
glycogenesis in the liver by activating the enzyme glycogen synthase.
 Metabolism of protein:
- Cortisol increases protein catabolism in skin & bone.

 Metabolism of lipid:
- Cortisol increases mobilization of fat and stimulates formation of ketone
bodies.
 Metabolism of water:
- Cortisol increases the GFR and facilitates excretion of water load.
- Patients with adrenal insufficiency may easily get into water intoxication.
 Permissive effect for catecholamines and glucagon:
- At least small amount of cortisol is essential for the effects of glucagon
(e.g. lipolysis) and the effects of catecholamines (e.g. vasoconstriction &
bronchodilation).
 Blood cells:
- Cortisol increases RBCs, platelets, neutrophils and monocytes. It
decreases lymphocytes, basophils and eosinophils.
 The nervous system:
- The effects of cortisol on the nervous system can be studied from the
abnormal symptoms and signs that appear in patients with cortisol
deficiency.
- These include abnormal slowing of the EEG activity and personality
changes (irritability apprehension and failure to concentrate).
 Mineralocorticoid effect:
- Cortisol has a minor mineralocorticoid effect. It increases Na+
reabsorption & K+ secretion in the distal convoluted tubules and collecting
ducts in the kidney.
 Anti-inflammatory effect:
- Excess cortisol (e.g. when treating patients with high doses of
prednisolone or hydrocortisone) decreases signs of inflammation
(redness, hotness, pain and swelling); and inhibits the subsequent
formation of fibrous tissue. This is achieved by inhibiting the enzyme

phospholipase A2 thus preventing formation of the inflammatory mediators:
prostaglandins and leukotrienes.
- Prevention of fibrous tissue formation is beneficial in patients with
corneal ulcers. However, it may allow spread of bacteria in patients with
active tuberculosis or pneumonia (unless antibiotics are administered at
the same time).
 Anti-allergic effect
- Excess cortisol decreases allergic signs by inhibiting release of histamine
by mast cells.
 Anti-immunity effect
- Excess cortisol decreases number of lymphocytes and release of
lymphokines like IL-2 resulting in reduced proliferation of lymphocytes. It
also decreases the size of lymphatic organs. These effects are needed in
patients with transplanted organs to minimize the chance of rejection; that
is why they are treated with high doses of prednisolone.
 Anti-stress effect
- Cortisol is essential for survival. It guards against stress; but the
mechanism is unknown.
 Other effects:
- Cortisol accelerates surfactant production during fetal life. For this
reason, prednisolone is administered to pregnant women suffering from
contractions of premature labor.
- Excess cortisol decreases growth hormone and TSH secretion.
Abnormalities
Cortisol excess = Cushing’s syndrome
- It is caused by either: ACTH independent or ACTH dependent causes.
- ACTH independent causes (characterized by low ACTH) include:
 Adrenal tumor secreting cortisol (primary Cushing’s).

 Prolonged use of drugs with cortisol activity (e.g. prednisolone in
asthma).
- ACTH dependent causes (characterized by high ACTH) include:
 Pituitary tumor secreting ACTH (secondary Cushing’s or Cushing’s
disease).
 Lung tumor secreting ACTH or CRH (ectopic Cushing’s).
- Features of Cushing’s syndrome include:
o Thin skin and weak muscles (due to protein depletion) resulting in
poor healing of wounds and easy bruising and ecchymoses.
o Striae (appear in the skin of the abdomen because it is thin and
stretched by the fat deposition).
o Central obesity, moon face and thin limbs (due to redistribution of
fat).
o Buffalo hump (due to accumulation of fat at the upper trunk).
o Plethora.
o Hypertension (due to:
 Salt and water retention by cortisol or
deoxycorticosterone, which is also elevated
 The permissive effect of cortisol on blood vessels
 Increased secretion of angiotensinogen
o Hypokalemia (contributes to muscle weakness).
o Diabetes mellitus (hyperglycemia, hyperlipemia and ketosis).
o Osteoporosis (loss of bone mass) and fractures.
o Increased facial hair and acne (due to associated androgen
secretion).
Remember that: facial hair in females is known as “hirsutism”.
o CNS changes and personality changes (rapid EEG rhythm,
increased appetite, insomnia, euphoria, or frank psychosis).

Fig 10.19: Cushing's syndrome
Cortisol deficiency = Addison's disease

- Primary adrenal insufficiency “Addison's disease” is caused by
destruction of the adrenal cortex (by tuberculosis or autoantibodies).
- Secondary adrenal insufficiency is caused by pituitary disorders
(decrease ACTH release).
- Tertiary adrenal insufficiency is caused by hypothalamic disorders
(decrease CRH release).
- Adrenal insufficiency is characterized by:
o Hyponatremia
o Hypotension
o Hyperkalemia
o Hyperpigmentation (only in the primary type due to high ACTH)
o Acidosis
o Weight loss
o Muscle weakness (due to hyperkalemia)

o Small heart (because the low after load “the hypotension”
decreases work of the heart).
o Risk of death due:
 Addisonian crisis (caused by stress and characterized by
circulatory collapse)
 Fasting (causes fatal hypoglycemia)
 Water intoxication (failure to excrete water).
MINERALOCORTICOIDS
- These are the adrenocortrical hormones with predominant effects on Na +
& K+ excretion.
- They include:
 Aldosterone (strong mineralocorticoid)
 Deoxycorticosterone (has only 3% of aldosterone activity).
ALDOSTERONE
Characteristics
= The main mineralocorticoid; formed only in the zona glomerulosa of the
adrenal cortex.
- Unlike cortisol, only small fraction is bound to plasma protein.
- Half life= 20 min; with the liver and kidney as the main sites of
metabolism.
Control of aldosterone
- Normal regulation of aldosterone secretion is not under the control of the
hypothalamo-pituitary axis.
- High ACTH can stimulate aldosterone secretion; whereas normal level of
ACTH has no effect on zona glomerulosa of the adrenal cortex.
- The direct stimuli of aldosterone include:

1- Hyperkalemia
- Directly stimulates aldosterone release from the adrenal cortex (activates
conversion of cholesterol to pregnenolone and conversion of
corticosterone to aldosterone).
2- High level of ACTH
- The (ACTH) is released by the anterior pituitary gland to stimulate
secretion of cortisol by the adrenal cortex. In high levels (levels higher
than that which stimulate maximal cortisol secretion) ACTH can also
stimulate aldosterone secretion.
3- The renin-angiotensin-aldosterone system
- In this system, renin enzyme, which is produced by the Juxta-glomerular
apparatus in the kidney, converts the plasma protein “angiotensinogen” to
“angiotensin I.” Then the angiotensin converting enzyme in the pulmonary
circulation converts “angiotensin I” to “angiotensin II”. Angiotensin-II
directly stimulates aldosterone secretion from the adrenal cortex (activates
conversion of cholesterol to pregnenolone and conversion of
corticosterone to aldosterone).
Remember that: The stimuli that activate the Juxta-glomerular apparatus
to release renin are regarded as indirect stimuli of aldosterone secretion.
These include:
o Hyponatremia
o Renal ischemia (caused by hypotension, standing, hypovolemia or
renal artery stenosis)
o Sympathetic stimulation (associated with stressful stimuli like trauma,
pain, surgery and hemorrhage; here cortisol secretion is also
stimulated).
- ANP decreases aldosterone secretion by inhibiting renin secretion and
decreasing the effects of angiotensin II on zona glomerulosa.

Effects of aldosterone
- Reabsorption of Na+ & secretion of K+ at the following sites: The DCT
and CDs in the kidneys, the GIT (salivary ducts and colon) & the sweat
glands.
Remeber that: in the kidney, the reabsorption of Na+ is coupled to K+
secretion (or H+ secretion).
Abnormalities
Aldosterone excess
Primary hyperaldosteronism = Conn’s syndrome
- Caused by a tumor in the adrenal gland secreting aldosterone; here renin
is inhibited and its level in plasma becomes very low.
- Characterized by:
o High blood pressure (due to salt and water retention)
o Low [K+] (due to K+ secretion)
o Alkalosis (due to hypokalemia and secretion of H+ in urine)
o Muscle weakness (due to low K+)
o Tetany (due to low Ca++ ions secondary to the alkalosis)
- Edema does not develop due to “aldosterone escape phenomenon”
caused by ANP.
- Here ANP prevents salt and water retention above certain point (before
development of edema) by antagonizing the effects of aldosterone and
increasing excretion of sodium in urine (this causes polyuria).
Secondary hyperaldosteronism
- Unlike the primary type, secondary hyperaldosteronism is associated
with high renin secretion and characterized by development of edema.
- It is associated with congestive heart failure, liver cirrhosis and
nephrosis.

Aldosterone deficiency
- Hyporeninemic hypoaldosteronism occurs rarely due to impaired renin
secretion by the diseased kidney whereas pseudo-hypoaldosteronism
occurs due receptor defects.
- These disorders are characterized by salt loss, hypotension,
hyperkalemia and acidosis.

1. Hypothyroidism is characterized by:
a. Increased heart rate
b. Increased temperature
c. Diarrhea
d. Irritability
e. Weight gain
2. The following is a feature of Graves’ disease:
a. Drop of the upper eyelid
b. High level of TSH
c. Iintolerance to cold
d. High systolic blood pressure
e. Constipation
3. Primary hyperaldosteronism (Conn's syndrome) is characterized by:
a. Oedema
b. High plasma potassium
c. Hyperglycemia
d. High renin level in blood
e. High plasma bicarbonate
4. Aldosterone is directly stimulated by:
a. Hyponatremia
b. Hyperkalemia
c. Hyovolemia
d. ADH
e. Renin
5. Hyperglycemia and hypertension may occur in:
a. Addison’s disease
b. Diabetes mellitus
c. Acromegaly
d. Rickets
e. Conn's syndrome

6. Hypothalamic TRH is released in response to:
a. Stress
b. Neural signals
c. Feedback from TSH
d. Cold
e. Sleep
7. The physiological effects of cortisol include:
a. Lipogenesis
b. Lymphocytosis
c. Water retention
d. Increased glucose utilization
e. Gluconeogenesis
8. Aldosterone exerts its effects on which of the following cells:
a. Parietal cells
b. Podocytes
c. Juxtaglomerular cells
d. Intercalated cells
e. Principal cells
9. This hormone is synthesized in zona fasciculata of the adrenal cortex:
a. Aldosterone
b. Cortisol
c. Glucagon
d. Adrenaline
e. Androstenedione
10. Hyperthyroidism is characterized by:
a. Hyperglycemia
b. Bradycardia
c. Fever with rigors
d. Increased intestinal motility
e. Mask face
11. High dietary intake of sodium every day is expected to:
a. Increase plasma renin activity
b. Lower rate of daily sodium excretion
c. Decrease plasma ANP level
d. Increase plasma vasopressin level
e. Keep constant plasma aldosterone level
12. Cushing's disease is characterized by:
a. Anemia
b. Hypoglycemia
c. Hypopigmentation
d. Alkalosis
e. Leucopenia
13. The following effect is caused only by high level of plasma cortisol:
a. Feedback effect on ACTH
b. Potentiates effects of norepinephrine on blood vessels
c. Inhibition of inflammation

d. Gluconeogenesis
e. Increases GFR
14. Excessive secretion of one of these hormones is unlikely to increase
normal rate of linear growth in children:
a. Insulin
b. Testosterone
c. Growth hormone
d. Thyroid hormones
e. Vitamin D
15. In the following, a hormone and an abnormality are paired correctly:
a. ADH & diabetes mellitus
b. Prolactin & infertility
c. Vitamin D & renal stones
d. Aldosterone & Horner’s syndrome
e. Cortisol & Conn's syndrome
16. Aldosterone effects on target cells include all the following except:
a. Insertion of ENaC (epithelial sodium channels) on cell membrane
b. Activation of sodium-potassium pumps
c. Binding to nuclear receptors
d. Kaliuresis
e. Has both rapid and long term effects
17. Aldosterone, but not cortisol, is increased during:
a. Surgery
b. Anxiety
c. Hypovolemic shock
d. Standing
e. Physical trauma
18. Which of the following corticosteroids has the highest glucocorticoid
activity and the lowest mineralocorticoid activity:
a. Cortisol
b. 9α-Fluorocortisol
c. Prednisolone
d. Dexamethasone
e. Corticosterone
19. Steroid hormones are produced by which of the following glands:
a. Adrenal cortex and pancreas
b. Anterior Pituitary and thyroid
c. Gonads and pineal gland
d. Parathyroid glands and pancreas
e. Gonads and adrenal cortex
20. Following slow intravenous infusion in humans, which of the following
is increased by epinephrine but decreased by norepinephrine:
a. Systolic blood pressure
b. Total peripheral resistance
c. Mean arterial pressure
d. Blood glucose level

e. Cardiac output
21. It is known that secretion of noreadrenaline is higher than adrenaline
during rest; the reverse occurs during:
a. Standing from sitting position
b. Exercise (mild, moderate or severe)
c. Hypoglycemia
d. After surgery
e. Pheochromocytoma
22. Hypokalemia is associated with:
a. Insulin deficiency
b. Aldosterone antagonists
c. Use of diuretics
d. Acidosis
e. Addison's disease
23. Regarding thyroid hormones, which of the following is correct:
a. They are soluble in water
b. Secretion of TSH is regulated by level of T3 in blood
c. They are stored in intracellular rather than extracellular sites
d. They increase metabolic activity of the brain
e. The enzyme D3 thyroid deiodinase converts T4 to T3
24. The principal steroid hormone secreted by adrenal gland of the fetus is:
a. Cortisol
b. Dehydroepiandrosterone
c. Progesterone
d. Aldosterone
e. Corticosterone
25. In myxedema, there is:
a. Increased rate of metabolism
b. Reduction of body weight
c. Increased sweating
d. Elevation of cholesterol level
e. Pitting edema
26. Addison’s disease is characterized by:
a. Hypokalemia
b. Hypernatremia
c. Hypochloremia
d. Hyperglycemia
e. Hyperosmolarity
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

e d e b C d e e b d d d c
14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26.
e b c d D e e c c b b d c

THE PANCREAS
Structure
- The pancreas has both: an endocrine part (Islets of Langerhans = (2% of
the pancreas)) & an exocrine part (with no ducts = (80% of the pancreas)).
- The islets of Langerhans are collections of cells scattered throughout the
pancreas.
- They contain the following types of cells (according to morphology and
staining properties):
 Type A cells (or α): = 20% of all cells; secrete glucagon
 Type B cells (or β): = 60-75% of all cells; secrete insulin
 Type D cells (or δ): secrete somatostatin
 Type F cells: secrete pancreatic poly peptide
- The B cells are located at the center of the islets surrounded by the other
cells.
- All the hormones are polypeptides. They control glucose concentration in
the blood.
INSULIN
Characteristics & synthesis
- Polypeptide hormone. Consists of 2 chains (A & B) connected by 2
disulfide bridges.
- It is synthesized in the rough endoplasmic reticulum of the beta cells
(from mRNA synthesized by a gene on chromosome 11) and then packed
into secretory granules in the Golgi apparatus as follows:
 Preproinsulin (Straight molecule; contains signal peptide (of 23
amino acids), A chain (of 21 amino acids), B chain (of 30 amino
acids) & C chain (of 31 amino acids)).
 Proinsulin (Folded by the 2 disulfide bridges; contains A chain, B
chain and C chain; the signal peptides is removed).

 Insulin (Folded by the 2 disulfide bridges; contains A chain and B
chain; the C chain is detached but still remains in the secretory
granules).
- The preproinsulin loses the signal peptide to give proinsulin. The
proinsulin loses the C peptide to give insulin.
- The C peptide is released with insulin in the blood. Its presence in blood
indicates endogenous release of insulin.
- Unlike the growth hormone, insulin is not species specific. There are
minor differences between human insulin & insulin of other species (e.g.
beef and pork insulin).
- This allows their use in humans for treatment of diabetes mellitus.
However, the minor differences, although not sufficient to affect activity,
are sufficient to induce antigenicity (i.e. antibody formation against the
injected insulin).
- Human insulin produced in bacteria by recombinant DNA technology is
now available to avoid antibody formation.
- Half life of insulin is about 5 minutes.
Fig 10.20: Structure of insulin

Control of insulin secretion
- Not by the hypothalamo-pituitary axis. It is stimulated by:
 Glucose (see the mechanism described below).
 Amino acids (leucine, arginine …) and ketoacids.
 GIT hormones including glucagon, gastrin, secretin, CCK…(which
increase cAMP) and more important: GIP & glucagon like polypeptide
“GLP-1” (which increase Ca++ influx through voltage gated channels).
 Acetylcholine and parasympathetic stimulation (or stimulation of the Rt
vagus). Acts on M4 receptors to increase ICF calcium for exocytosis.
 Drugs (sulfonylureas, theophylline, β adrenergic agonists …).
Mechanism of insulin release by glucose
 Glucose enters the beta cells via GLUT-2; then it is phosphorylated by
glucokinase and converted to pyruvate in the cytoplasm
 Pyruvate enters the mitochondria to give ATP via the citric acid cycle
 ATP in the cytoplasm inhibits ATP-sensitive K+ channels
 This reduces K+ efflux and depolarizes the beta cells resulting in
opening of voltage gated calcium channels
 Calcium enters beta cells and facilitate exocytosis of insulin granules
 On the other hand, some pyruvate in the citric acid cycle gives
glutamate; glutamate also facilitates exocytosis of insulin granules.
Fig 10.21: Mechanism of insulin release

- Insulin secretion is inhibited by:
 2- Deoxyglucose.
 Somatostatin, catecholamines, galanin & insulin.
 Drugs (α adrenergic agonists, β adrenenrgic blockers, diazoxide,
thiazide diuretics, phenytoin, alloxan …).
 Potassium depletion.
 Galanin (polypeptide released by some autonomic neurons; activates
the ATP sensitive potassium channels to inhibit insulin release).
Remember that: The basal rate of insulin secretion is about 1 unit per
hour; however, this increases to 5-10 units following a meal.
- Therefore the average insulin secretion per day is about 40 units.
Effects of insulin
- Insulin is a true anabolic and growth promoting hormone. It acts on cell
membrane receptors. Its effects can be divided into rapid, intermediate
and delayed effects:
Rapid effects (within seconds):
- Increases entry of the following inside insulin sensitive cells (e.g. muscle,
fat, liver cells …):
 Glucose
 Amino acids
 Potassium
- Insulin increases glucose entry by increasing number of the glucose
transporters 4 (GLUT-4) in the muscle and fat cells.
- In the liver cells, which are permeable to glucose, insulin stimulates
glucokinase; this decreases the free glucose intracellularly and therefore
facilitates glucose entry inside the liver cells.

- The cells which do not need insulin to facilitate uptake of glucose are the
cells of the:
 Brain
 Kidney
 Intestine
 Red blood cells
- Insulin increases potassium entry by unknown mechanism (may be by
increasing the activity of the Na+-K+ ATPase pump).
Intermediate effects (within minutes):
- Increases synthesis & inhibits catabolism of glycogen, fat and protein.
- Inhibits gluconeogenesis.
- Activates lipoprotein lipase & inhibits hormone-sensitive lipase.
Delayed effects (within hours):
- Increases mRNAs for the enzymes involved in anabolism (= increases
growth).
Remember that: Insulin (with glucose infusion) is used clinically for rapid
reduction of high plasma potassium
- This is a life saving treatment in patients with hyperkalemia due to renal
failure; waiting for dialysis. (They are given insulin with glucose infusion)
Insulin receptors
- Insulin receptors are tetramer made up of two α and two β glycoprotein
subunits; connected together by disulfide bridges.
- They are synthesized by a gene on chromosome 19; their molecular
weight is about 340,000.
- The α subunits are located extracellularly whereas the β subunits span
the cell membrane; with a tyrosine kinase activity in their intracellular
portions.

- The mechanism of insulin action can be summarized in the following
steps:
 Insulin is attached to its binding site in the α subunits
 The tyrosine kinase activity in the β subunits is triggered producing
autophosphorylation of the β subunits.
 The autophosphorylation allows phosphorylation of some proteins
and dephosphorylation of others.
 The proteins mediate insulin effects.
Abnormalities
o Insulin excess: Hypoglycemia
- It may be caused by insulinoma, insulin injections or hypoglycemic drugs.
- Insulin secretion is totally inhibited when glucose level in plasma is about
80 mg/dL (= normal level).
- Further reduction of glucose stimulates the counter-regulatory hormones:
glucagon, epinephrine, growth hormone and then cortisol (all these are
hyperglycemic). Then symptoms of hypoglycemia start to develop with any
further reduction in glucose level.
- Symptoms in order of appearance, as glucose decreases, include:
 Symptoms of autonomic discharge (sweating, palpitations, tremors
& irritability).
 Neuroglycopenic symptoms (hunger and confusion).
 Lethargy & coma.
 Convulsions
 Permanent brain damage & death
- Diabetic patients are usually a ware of the symptoms of autonomic
discharge (sweating, palpitations, tremors & irritability) as indications of
hypoglycemia. However, some patients with long-term diabetes may
develop hypoglycemic coma without having these symptoms.

o Insulin deficiency: Diabetes Mellitus (DM).
- DM is a state of hyperglycemia and abnormal protein and fat metabolism
resulting from absolute or relative insulin deficiency.
Diabetes mellitus is divided into 2 main types:
 IDDM: insulin dependent DM or type 1; appears early in life due to
absolute insulin deficiency caused by autoimmune destruction of the
beta cells. It is treated by insulin.
 NIDDM: Non insulin dependent DM or type 2; appears later in life,
usually after the age of 40 years, due to relative insulin deficiency
caused by insulin resistance (associated with obesity) and beta cell
exhaustion. It is treated by oral hypoglycemic drugs.
- Both types (especially type 2 DM) usually occur in a genetically
susceptible individuals.
- Other clinical types of D.M. include:
 Secondary D.M. (secondary to acomegaly, pheochromocytoma,
Cushing’s syndrome, chronic pancreatitis, pancreatectomy and drugs
like diazoxide and thiazide diuretics).
 Gestational D.M. (D.M. occurring during pregnancy).
The metabolic abnormalities in diabetes include:

 CHO: Hyperglycemia due to decreased entry of glucose in cells and
increased output of glucose from the liver. Glucose output from the
liver is high due to increased glycogenolysis and gluconeogenesis
(resulting from not only the low insulin but also a high glucagon level in
diabetes).
 Protein: Decreased entry of amino acids in cells; decreased synthesis
of protein, increased their catablism and increased conversion of
amino acids into glucose in the liver (negative nitrogen balance).

 Fat: Increased level of free fatty acids, triglycerides and cholesterol in
plasma due to:
o Increased mobilization from adipose tissue (because the
hormone-sensitive lipase is not inhibited by insulin)
o Decreased deposition in adipose tissue (because the lipoprotein
lipase is not activated by insulin)
o Decreased lipogenesis with increased lipolysis in the liver
(resulting in excessive acetyl-Co A production).
o Decreased removal of VLDL and LDL from the circulation by the
liver.
 Ketosis: The excess acetyl-Co A is converted to ketone bodies
(acetoacetic acid “which gives acetone” and beta-hydroxybutyric acid).
- The ketone bodies are important source of energy in diabetes and
also in the normal fasting state.
- However, in diabetes they cause acidosis and consequently coma (=
coma of diabetic keto-acidosis “DKA”).
 Water and electrolytes: Dehydration and decreased total body Na+ &
K+ occur due to polyuria and loss of Na+ & K+ in urine with the anions
of ketone bodies.
- Plasma Na+ is low when Na+ is lost in excess of water; however,
plasma K+ is usually normal (because K+ moves out from cells in
acidosis), except after treatment with insulin when K + returns back to
the cells.
Symptoms and signs of DM include:
 Fatigue (due to low entry of glucose in muscle and depletion of its
glycogen stores).
 Polyuria (large urine volume due to loss of glucose in urine “osmotic
diuresis”).

 Polydipsia (excessive thirst due to hypovolemia and hyperosmolarity
caused by the polyuria).
 Hyperphagia (increased appetite due to decreased utilization of
glucose by the cells of the ventromedial nuclei of the hypothalamus
“satiety center”; thus allowing the appetite area to work without
inhibition).
 Weight loss (due to loss of the energy substrate “glucose” in urine and
its failure to enter the cells; the cells use protein and fat as alternative
sources of energy).
 Kussmaul breathing (rapid deep respiration due to acidosis as in DKA).
 Coma (occurs due to many causes: diabetic keto-acidosis, non ketotic
hyperosmolar coma, lactic acidosis and rarely brain edema).
Remember that: A diabetic patient may also present with hypoglycemic
coma due to wrong higher dose of insulin or increased exercise with low
food intake. This is usually fatal if not treated immediately.
Investigations show:
 Hyperglycemia (especially following meals due to decreased entry of
glucose in cells and increased output of glucose from the liver).
 Glycosuria (when glucose concentration exceeds the renal threshold
“180 mg/dL”).
 Ketosis & ketonuria (ketone bodies like acetone in plasma & urine;
when D.M. is complicated by diabetic ketoacidosis (DKA)).
 Acidosis (low plasma pH due to the ketone bodies; when D.M. is
complicated by diabetic ketoacidosis (DKA)).
 High Hb A1C (the glycated Hb is high; it is measured for follow up not
for diagnosis).
 Diabetic curve in the oral glucose tolerance test “GTT”.

Diagnosis of D.M. using the GTT:
 Diagnosis is sometimes achieved by the oral glucose tolerance test.
 Here a standard dose of glucose (75 g) is administered orally. The
concentration of glucose in venous blood is measured before
administration of glucose “fasting” and then 0.5, 1.0, 1.5 and 2.0 hours
after the dose (or just before the dose and then after 2.0 hours).
 A normal GTT curve is obtained when glucose in venous blood is:
o Less than 110 mg/dL in the fasting state, before the dose (= less
than 6.8 mmol/L).
o Less than 180 mg/dL after 0.5-1.5 hours following the dose (= less
than 10.0 mmol/L).
o Less than 140 mg/dL after 2.0 hours (= less than 7.8 mmol/L).
- Abnormal glucose tolerance curves include
 Diabetic curve: According to the latest WHO guidelines, a fasting
glucose level of more than or equals 126 mg/dL (≥ 7.0 mmol/L) or a
result of more than or equals 200 mg/dL after the 2.0 hours (≥ 11.1
mmol/L) indicates D.M.
 Impaired GTT: Defined as two-hour glucose levels of 140 mg to 199
mg/dL (or 7.8 to 11.0 mmol/L). It may precede type II diabetes mellitus
by many years & it is a known risk factor for cardiovascular ischemic
problems.
 Lag storage curve: Caused by partial gastrectomy & hyperthyroidism.
The blood sugar rises rapidly from a normal fasting value to more than
180 mg/100 ml (due to the rapid absorption) but returns to the fasting
value within 120 min & may overshoots to cause symptoms of
hypoglycemia two hours after the test.
 Curve of liver disease: This is a diabetic curve but the fasting plasma
glucose level is low.

Fig 10.22: Glucose tolerance test
Complications expected in diabetic patients include:

 Acute complications:
1- Diabetic ketoacidosis (DKA)
2- Hyperosmolar non-ketotic coma
 Long term complications:
1- Macro-vascular atherosclerosis (due to the high cholesterol;
results in increased risk of stroke and ischemic heart disease “MI”).
2- Micro-vascular disease (results in renal disease “diabetic
nephropathy” and blindness “diabetic retinopathy”).
4- Peripheral neuropathy and autonomic neuropathy.
5- Increased susceptibility to infections.
- For this reason, D.M. should be controlled tightly to avoid these
complications.

Treatment of D.M.
Medical treatment includes:
o Insulin injections: for type 1 D.M.; given daily as a combination of short
acting (e.g. regular insulin) and long acting insulin (e.g. lente insulin).
o Hypoglycemic drugs: for type 2 D.M.; these include:
 Sulfonylureas (e.g. glibenclamide, glipizide …): These inhibit
ATP sensitive K channels to stimulate insulin release.
 Biguanides (e.g. metformin): This decreases glucose output by
the liver by inhibiting gluconeogenesis.
Non-medical treatment includes:
o Diet control (high fiber diet, low in fat and refined sugars).
o Weight reduction (especially important in obese patients with the
metabolic syndrome “syndrome X”). The increased adipose tissue in
these patients is associated with high insulin resistance & weight loss
decreases insulin resistance.
o Regular exercise (facilitates entry of glucose into the cells by
stimulating insertion of GLUT-4 into their membranes).
Remember that: Features of “syndrome X” include: Obesity, insulin
resistance (hyperinsulinemia), dyslipidemia (high triglycerides and low
HDL) and atherosclerosis.
Fig 10.2 : Consequences of hypoglycemia:
No. ICF hypoglycemia results in: ECF hyperglycemia results in:
1- Increased catabolism of fat and Glycosuria
protein
2- Ketone body formation Osmotic diuresis = polyuria
3- Hyperphagia Dehydraion
4- Depletion of glycogen stores Polydipsia
5- Weight loss Increased Hb A1C

GLUCAGON
Characteristics
- Polypeptide hormone of 29 amino acids in a single chain (molecular
weight = 3485).
- Produced by A cells of the pancreas, L cells of the upper GIT and the
brain.
- The preproglucagon at these sites gives glucagon plus other fragements;
for example:
o Glicentin (polypeptide with glucagon activity; released from upper GIT).
o GLP-1 & 2 (glucagon like polypeptides; of these, GLP-1 is a potent
stimulus for insulin release (more potent than GIP) & GLP-2 is a
neurotransmitter. Both are produced in upper GIT and the brain).
o Half life = 5–10 min.
o Metabolism mainly in the liver; that is why its level is higher in patients
with cirrhosis.
Effects of glucagon
- Glucagon is a hyperglycemis and a lipolytic hormone. It exerts the
following effects:
 Glycogenolysis (in the liver but not in muscle).
 Gluconeogenesis.
 Lipolysis.
 Ketogenesis.
 Increased metabolic rate (= calorigenic effect). This is due to both
hyperglycemia and increased hepatic deamination of amino acids.
 Positive inotropic effect on the heart (= increased contractility of the
heart; but only when injected in large doses).
 Stimulates secretion of some hormones (growth hormone, insulin &
somatostatin).

Mechanism of action
- Glucagon acts on cell membrance receptors, with cAMP as a second
messenger; however, it also acts through Ca++ (note that both are
activated through G-protein, see the introduction).
- cAMP, through protein kinase A, activates phosphorylase A (the enzyme
responsible for release of glucose-1-phosphate from glycogen in the liver).
Remember that: the enzyme “phosphorylase A” is not present in muscle
cells, that is why glucagon cannot cause glycogenolysis in muscles.
Control of glucagon
- Glucagon is stimulated by:
o Amino acids (especially alanine, glycine, serine, cysteine &
threonine).
o GIT hormones (gastrin, CCK …).
o Other hormones (cortisol, catecholamines …)
o Sympathetic and stresses (emotions, exercise, infections …).
o Parasympathetic (right vagus) and acetylcholine.
o Drugs (β adrenergic agonists, theophilline …)
o Fasting and starvation (glucagon increases and reaches a peak
on the 3rd day (= day of maximum gluconeogensis); then it
declines).
- Glucagon is inhibited by:
o Glucose
o Free fatty acids
o Ketones
o Hormones (insulin, somatostatin, secretin …).
o GABA
o Drugs (phenytoin, α adrenergic agonists …).

Remember that: Insulin and glucagon have opposite effects; that is why
when the concentration of one hormone rises in plasma, the other
declines.
- For example the insulin-glucagon molar ratio is high in some situations
(e.g. following a carbohydrate meal, a protein meal or glucose infusion);
and low in others (e.g. during starvation “especially the 3rd day”).
Abnormalities of glucagon
Glucagonoma:
- Glycogen excess, caused by a pancreatic tumor secreting glucagon,
results in hyperglycemia & other clinical manifestations due to glucagon
excess.
- Its treatment includes administration of a somatostatin analogue (e.g.
octreotide).
SOMATOSTATIN
Characteristics & effects
- Peptide hormone found in two forms (14 and 28 amino acids); produced
by many sites in the body:
 The brain: acting as a neurotransmitter.
 The hypothalamus: acting as a growth hormone inhibitory hormone.
 The GIT: acting as inhibitory hormone to other GIT hormones and to
HCL secretion.
 The pancreas: acting as inhibitory hormone to insulin, glucagon &
pancreatic polypeptide.
Remember that: Hormones inhibited by somatostatin include insulin,
glucagon, pancreatic polypeptide, growth hormone, thyroid stimulating
hormone, VIP, GIP, secretin, CCK and gastrin.

Stimuli of somatostatin
- Include many stimuli of insulin (e.g. glucose, amino acids and CCK).
Abnormalities
- Pancreatic tumors secreting somatostatin result in hyperglycemia
(Diabetes mellitus).
PANCREATIC POLYPEPTIDE
- Polypeptide hormone (36 amino acids). Similar in structure to:
 Polypeptide YY (GIT hormone).
 Neuropeptide Y (found in the brain and autonomic nervous system).
- It is stimulated by parasympathetic, hypoglycemia, fasting, protein meal
and exercise and it is inhibited by atropine, somatostatin and intravenous
infusion of glucose.
- Pancreatic polypeptide slows the absorption of food in humans; however,
its exact function is unknown.
Effects of exercise and hormones on CHO metabolism
 Exercise increases entry of glucose into skeletal muscle cells (by
increasing GLUT-4 on cell membranes).
 Catecholamines cause an initial glycogenolysis followed by glycogen
synthesis (initially they cause glycogenolysis in the liver but in the
muscles glucose is converted to pyruvate and this is converted to
lactate which diffuses to the circulation. When it reaches the liver, it is
converted back to pyruvate and then to glycogen).
 Other effects of catecholamines (increase FFAs, decrease peripheral
utilization of glucose and increase metabolic rate (increase lactate
oxidation = calorigenic effect).
 Thyroid hormones increase intestinal absorption of glucose and
potentiate the glycogenolytic effects of catecholamines. The hormones

also increase degradation of insulin. All these effects aggravate
hyperglycemia in diabetics.
 Cortisol cause hyperglycemia and diabetes by antagonizing the
peripheral effects of insulin (inhibits glucose phosphorylation),
increases protein breakdown & increases gluconeogensis (by glucagon
permissive effect). It also increases glycogenesis and ketogenesis.
 Growth hormone causes hyperglycemia and diabetes by anti-insulin
effects. It decreases uptake of glucose, increases mobilization of fat,
increases ketogenesis and increases hepatic release of glucose.
These effects are partially direct “due to GH” or indirect “due to IGF-1”.

REGULATION OF CALCIUM
INTRODUCTION
Calcium
Calcium in the body and its concentration in plasma
- Total body calcium in adults = 1100 grams (≈ 1kg). About 99% of this
amount is found in bone whereas 1% is found in soft tissues & plasma.
However, some calcium in bone is exchangeable with plasma.
- The level of calcium in plasma = 9-10.5 mg/dL or 2.1-2.6 mmol/L.
- About 53% (1.34 mmol/L) of plasma calcium is diffusible (i.e. ionized or
complexed to citrate & bicarbonate) whereas 47% (1.16 mmol/L) is non-
diffusible (i.e. bound to plasma proteins “albumin & globulin”).
- Calcium level in the plasma is affected by:
 Total amount of proteins
 Other electrolytes
 pH (affects the ionized calcium not the total calcium in plasma)
- At low pH (acidosis), hydrogen ions are buffered by protein; therefore
calcium binding to protein is decreased and the ionized calcium is
increased. The opposite occurs at high pH (alkalosis).
Calcium in diet and its absorption
- Dietary sources of calcium include milk, milk products, other animal
products & certain plants.
- Plants are not regarded as an important source of calcium since they
contain high amounts of phosphate & oxalate which decrease calcium
absorption.
- About 30-80% of ingested calcium is absorbed at the small intestine.
- Sites of absorption:
 Duodenum (most efficient part)
 Ileum (absorbs 60% of ingested calcium)

- Mechanisms of absorption:
 Active transport (regulated by vitamin D)
 Passive diffusion
- Factors that increase absorption:
 Vitamin D
 Protein diet
- Factors that decrease absorption:
 Phosphate, oxalate
 Caffeine
 Fats (e.g. due to decreased bile salts)
 High intestinal pH (e.g. due to gastrectomy)
Calcium excretion
- Calcium is excreted mainly in stool and some amount is excreted in
urine.
- The filtered load of calcium in the kidney is about 450 mmol/day whereas
the amount excreted is about 5 mmol/day indicating that 98-99% of filtered
calcium is reabsorbed in the renal tubules.
- Reabsorption occurs in the PCT (reabsorbs about 60%), loop of Henle
(ascending limb) and the DCT (here the amount reabsorbed is controlled
by the parathyroid hormone).
Functions of calcium
 Formation of bone & teeth
 Contraction of muscles
 Conduction in nerves (facilitates exocytosis of neurotransmitters at the
synapses)
 Intracellular second messenger
 Hemostasis (regarded as the clotting factor number 4). Many
anticoagulants act by binding Ca++ (e.g. citrate, phosphate, EDTA …)

Phosphate
Phosphate in the body & plasma
- Total phosphate in adults is about 500-800 g; most of this amount (85-
90%) is found in the skeleton.
- Concentration of phosphate in the plasma = 12 mg/dL.
- About two thirds of phosphate in plasma is organic phosphorus whereas
one third is inorganic.
- Phosphorus is found in the following compounds:
 ATP
 cAMP
 2,3 DPG
 Phosphoproteins
 phospholipids
Absorption of phosphate in the intestine
- Phosphate is absorbed in the duodenum. Mechanisms of absorption:
 Active transport (stimulated by vitamin D).
 Simple diffusion
Reabsorption of phosphate in the kidney
- About 85-90% of filtered phosphate is reabsorbed actively; mainly in the
PCT. PTH decreases reabsorption in the PCT.
Bone
Structure of bone
- Bone is a rigid structure that forms the skeleton. It is a type of connective
tissue consisting of bone cells and a hard matrix surrounding the cells.
- The matrix consists of organic substances (collagen, especially type 1)
and inorganic substances (salts of calcium and phosphate known as
“hydroxyapatites”).

- The bone cells are many types; two of these types participate in calcium
homeostasis:
 Osteoblasts (modified fibroblasts responsible for bone formation by
laying down osteoid (contains collagen) and releasing alkaline
phosphatase enzyme (involved in bone mineralizaion); resulting in
transfer of calcium from the plasma to the bone matrix. These cells are
activated by many hormones including vitamin D, growth hormone,
thyroid hormones and sex hormones (estrogens & androgens).
 Osteoclasts (these cells are derived from monocytes. They are
responsible for bone resorption. They beak down collagen and release
calcium from bone to the plasma). They are stimulated by PTH and
also by vitamin D; and they are inhibited by calcitonin and certain drugs
(e.g. biphosphonates).
Remember that: bone resorption (by osteoclasts) is followed by bone
formation (by osteoblasts) in repeated cycles known as bone remodeling.
These cycles continue throughout life.
- There are two types of bone:
 Compact bone (= the outer layer of most bones; also known as cortical
bone. It constitutes about 80% of the whole skeleton. Its cells receive
their nutrition through Haversian canals (which contain blood vessels).
 Spongy bone (= the inner layer of bones; also known as trabecular
bone. It constitutes about 20% of the whole skeleton but its surface
area is larger than that of the compact bone. Its cells receive their
nutrition by diffusion from the ECF).
Bone growth
- Most bones in the body are modeled in cartilage (during fetal life) which
then undergoes ossification to form bone (= endochondral ossification).

Exceptions include the clavicles, mandibles and certain bones in the skull;
these form bone directly (= intramembranous ossification).
- Linear bone growth (i.e. the increase in length) occurs during the growth
period as long as the epiphyseal plate lays down new bone on the shaft
side.
- The epiphyseal plate is the active cartilage that separates the end of a
long bone “epiphysis” from the shaft “diaphysis”.
- Linear bone growth stops after puberty by ossification of the epiphyseal
plate (= epiphyseal closure).
- This occurs due to estrogens (which are secreted by the ovaries in
females or formed in the adipose tissue from androgens in males).
- The width of bones continues to grow throughout life in response to
stress by muscles or weight. Remodeling also continues for renewal of
bone and repair of fractures.
- Bone growth is affected by many hormones especially the growth
hormone and IGF-1.
Functions of bone
- Functions of bone include:
 Protection of vital organs (e.g. the brain, the spinal cord and the
heart)
 Movement and support (provides attachments for muscles and
functions with the tendons, ligaments and joints to move the body)
 Production of blood cells (hematopoiesis by the bone marrow)
 Detoxification (stores some heavy metals to remove them from the
blood)
 Participation in hearing (can conduct sound waves “bone
conduction”)

Diseases of bone
1- Osteoporosis
=Loss of bone matrix (or decreased bone mineral density); resulting in
increased possibility of fractures.
- It develops when the rate of bone resorption exceeds the rate of
formation; as in hyperparathyroidism, Cushing’s syndrome and post-
menopausal period (decreased estrogen).
2- Osteopetrosis
=Excessive bone matrix (or increased bone mineral density); known as
“marble bone disease”. Also results in increased fractures
- It is a rare inherited disorder characterized by defective osteoclasts;
allowing the osteoblasts to lay down excessive amount of bone matrix.
3- Rickets and osteomalacia
- Rickets is softening and weakening of bones in children, leading to
deformities and fractures. Deformities appear in many sites including the
legs, ribs, wrists and skul.
- It is caused by severe and prolonged vitamin D deficiency or low Ca ++ in
diet; resulting in hypocalcemia and failure of bone mineralization.
- Osteomalacia is a similar condition in adults (= adult rickets).
4- Paget’s disease
- A chronic bone disorder characterized by bone deformities; described by
James Paget.
- It results from excessive bone resorption due to increased osteoclastic
activity.
- The osteoblastic activity is also increased as compensation; however,
bone formation is disorganized, resulting in the deformities.
- It is treated by inhibition of osteoclastic activity using biphosphonates or
calcitonin.

REGULATION OF CALCIUM
- Many hormones participate in calcium homeostasis; however, the most
important are:
 Parathyroid hormone (hypercalcemic; the most important, essential
for life).
 Vitamin D (hypercalcemic)
 Calcitonin (hypocalcemic)
THE PARATHYROID HORMONE “PTH”
The parathyroid glands
- These are four small glands or more; each one is (3 x 6 x 2 mm),
weighing about 20-50 mg.
- They lie in the posterior surface of the thyroid gland but their location
may vary considerably; for example, they may be found in the chest.
- They are discovered by a Swedish medical student in 1880.
- They contain two types of cells:
 Chief cells (or principal cells): The most abundant cells. They
secrete PTH.
 Oxyphil cells: Their function is unknown.
Fig 10.23: The parathyroid glands

Characteristics of the PTH
- PTH is a linear polypeptide (84 amino acids).
- Produced by chief cells in the parathyroid gland as prepro-parathyroid
hormone (115 aa); this gives pro-parathyroid hormone (90 aa) and then
parathyroid hormone (84 aa).
- The mature hormone is packed within the Golgi apparatus into secretory
vesicles & secreted into the blood by exocytosis.
- Half life is about 10 min; fragmented in the liver & excreted by the kidney.
Control of the PTH
 It is not controlled by the hypothalamo- pituitary axis. It is increased by:
o Hypocalcemia
o Hypomagnesemia
o Hyperphosphatemia (lowers plasma calcium and inhibits 1,25 (OH)2
D3).
o Stimulation of β 2 receptors
 It is decreased by:
o Hypercalcemia (-ve feedback)
o Hypermagnesemia
o Increased 1,25 dihydroxy-cholecalciferol
Mechanism of action
- PTH acts on cell membrane receptors bound to G-ptotein, with cAMP as
the main second messenger.
Effects of PTH
 PTH is essential for regulation of calcium & phosphate level in plasma:
o Increases calcium level (Hypercalcemic)
o Decreases phosphate level (Hypophosphatemic)
 It acts on the bone and kidneys (directly) and on the intestine
(indirectly) as follows:

o Bone:
- Stimulates osteoclasts to increase bone resorption and release
calcium
o Kidney:
- Stimulates calcium reabsorption (in the DCTs & CDs)
- Decreases phosphate reabsorption (in the PCTs)
- Activates vitamin D (by activating the enzyme 1-α hydroxylase to
add (OH) on carbon number 1)
o Intestine:
- Increases calcium absorption indirectly (by activating vitamin D).
Abnormalities
 Primary hyperparathyroidism
- Increased production of PTH due to:
o Tumor in the parathyroid gland (either alone or multiple endocrine
neoplasia ”MEN’)
o A tumor in other site secreting PTH (e.g. lung tumor)
- Patients develop hypercalcemia & hypophosphatemia.
- Symptoms & signs do not appear early (asymptomatic); however, later
patient may develop:
o Bone manifestations (due to removal of calcium from bone):
 Osteitis fibrosa cystica (subperiosteal resorption & bone cysts)
 Osteoporosis
 Fractures
o Manifestations of hypercalcemia
 Increased filtered load of calcium in the kidney & increased
excretion of calcium & phosphate (hypercalciuria &
hyperphosphaturia)

 Polyuria (osmotic diuresis)
 Renal stones (due to the hypercalciuria & hyperphosphaturia)
 Deposition of calcium in tissues (calcifications)
 Muscle weakness
 Impaired memory & mental confusion
 Coma
 Secondary hyperparathyroidism
- Increased production of PTH due to chronic hypocalcemia (as in chronic
renal failure, or rickets).
- The condition is associated with hypertrophy of the parathyroid glands,
and if the hypocalcemia persists for long time, the secondary
hyperparathyroidism may be complicated by autonomus release of PTH
causing tertiary hyperparathyroidism (with hypercalcemia).
 Hypoparathyroidism
- Decreased production of PTH due to damage to the parathyroid glands
by a tumor, auto-antibodies, or surgical removal.
- Features:
o Hypocalcemia
o Convulsions
o Neuro-muscular hyperexcitability (= tetany)
TETANY
= Neuromuscular hyper-excitability caused by hypocalcemia.
- Characterized by numbness or tingling sensation in the fingers, toes and
lips, carpal or carpopedal spasm, muscle cramps, and risk of death due to
laryngeal spasm.

- It is explained as follows:
 The leak channels of sodium are guarded by calcium ions
 In hypocalcemia, sodium ions enter the muscle and nerve cells,
thus elevating the resting membrane potential towards the
threshold and making these cells more excitable “= latent tetany”.
 When the resting membrane potential reaches the threshold (in
more severe hypocalcemia), the cells become excited and signs of
tetany appear “= overt tetany”).
- Therefore, two types of tetany can be described:
 Overt tetany
 Latent tetany
Overt tetany
o Signs of tetany (carpal spasm, muscle cramps and laryngeal spasm)
appear because the resting membrane potential reaches the threshold.
Latent tetany
o Signs of tetany (e.g. carpal spasm & muscle cramps) do not appear
because the resting membrane potential does not reach the threshold.
However, the signs can be demonstrated by:
 Chvosteck’s sign (tapping the facial nerve causes contraction of
facial muscles)
 Trousseau’s sign (arresting blood flow to the forearm by
sphygmomanometer causes carpal spasm)
Fig 10.24: Carpal spasm in tetany

- Causes of hypocalcemia that results in tetany include:
o Thyroidectomy (the parathyroids are also removed; symptoms develop
after 2 days or more).
o Respiratory alkalosis (hyperventilation)
o Metabolic alkalosis (vomiting, Cushing’s & Conn’s syndromes)
 Pseudohypoparathyroidism
- Due to receptor disease
- Characterized by the same signs & symptoms of hypoparathyroidism but
with normal or elevated level of PTH
PARATHYROID HORMONE RELATED PROTEIN “PTHRP”

- Polypeptide (140 aa); partially similar to PTH.
- Acts on the same receptors of PTH (some of the receptors).
- It is produced loclly “local hormone” by different tissues in the body
including: (Fetal cartilage, brain, breast, teeth, skin & smooth muscle).
Actions:
o Growth & development of cartilage in the fetus
o Inhibits excitotoxic damage to the developing neurons
o Involved in calcium transport in placenta
o Essential for teeth eruption
o A cause of hypercalcemia in some malignancies
SUMMARY TO THE CAUSES OF HYPERCALCEMIA

 Parathyroid hormone-related
o Primary hyperparathyroidism
o Tertiary hyperparathyroidism
 Vitamin D-related
o Vitamin D intoxication

o Granulomatous disease sarcoidosis, berylliosis, tuberculosis
o Hodgkin's lymphoma
 Malignancy
o Humoral hypercalcemia of malignancy (mediated by PTHrP)
o Local osteolysis by secondaries from brest, skin or gonads
(mediated by cytokines)
 Medications
o Thiazide diuretics (usually mild), Lithium …
o Milk-alkali syndrome (from calcium antacids)
 Other endocrine disorders
o Hyperthyroidism
o Adrenal insufficiency
o Acromegaly
o Pheochromocytoma
 Others
o Familial hypocalciuric hypercalcemia: mutated calcium-sensing
receptor which mediate the –ve feedback effect of Ca++ on PTH
o Immobilization, with high bone turnover
o Paget's disease
VITAMIN D
Characteristics, sources and activation
- Vitamin D is a group of fat soluble vitamins that includes vitamin D2
(ergocalciferol) and vitaminD3 (cholecalciferol).
- The vitamins in this group and their metabolites are secosteroids (i.e.
one of the rings in each steroid nucleus is open).
- Vitamin D2 is derived from plants and can substitute for Vitamin D 3 in
humans; however vitamin D3 is the major circulating form in the body.

- Vitamin D3 “cholecalciferol” is synthesized in the skin by the action of
sunlight on 7-dehydrocholesterol. It is also ingested with food.
- It is activated in the liver to form 25-hydroxycholecalciferol “25(OH) D3” or
“calcidiol” and then in the kidney (in the PCT cells) to form 1, 25-
dihydroxycholecalciferol “1, 25 (OH)2 D3” or “calcitriol”; which is the active
form. Activation in the kidney is catalyzed by the enzyme 1 α hydroxylase.
This enzyme is activated by PTH and other hormones (PTH, growth
hormone, prolactin, human chorionic somatomammotropin and calcitonin).
- The active form “1, 25 (OH)2 D3” is also formed in the following sites: the
placenta, the skin keratinocytes and the macrophages like the alveolar
macrophages (this explains the hypercalcemia in patients with
sarcoidosis).
- Vitamin D3 is transported in plasma bound to the globulin: “vitamin D
binding protein” & can be stored in the liver.
Control
 1,25 (OH)2 D3 formation (the active form of vitamin D) is increased by:
o Hypocalcemia
o Hypophosphatemia
o PTH, growth hormone, prolactin, human chorionic
somatomammotropin “hCS” and calcitonin (all these hormones
increase the activity of 1α-hydroxylase).
o Estrogens (increase the total not the free form “by increasing the
binding protein”).
 1,25 (OH)2 D3 is inhibited by:
o Hypercalcemia (here the kidneys form the inactive compound 24,25
(OH)2 D3)
o Hyperphosphatemia

o 1,25 (OH)2 D3 (exerts -ve feedback on its own formation “i.e. it
inhibits the enzyme 1α-hydroxylase”. It also exerts +ve feedback
effect on the formation of 24,25 (OH)2D3 and an inhibitory effect on
PTH production).
o Hyperparathyroidism (decreases the level of the hormone and
causes osteoporosis).
- Many factors affect vitamin D formation; these include the geographical
location, the season, the type of clothing and the color of the skin (melanin
in the dark skin decreases penetration of sun light and reduces formation
of vitamin D; that is why the whitish skin is more efficient in formation of
vitamin D than the dark skin).
- Vitamin D supplementation is especially needed for: Infants, pregnant
women, lactating women and old subjects.
Effects of vitamin D
 Regulation of calcium & phosphate level in plasma:
o Increases calcium level (Hypercalcemic)
o Increases phosphate level (Hyperphosphatemic)
 Sites of action:
o Intestine: Increases calcium absorption and phosphate absorption.
o Kidney: Increases calcium reabsorption and phosphate
reabsorption.
o Bone: Stimulates osteoblasts for bone calcification. Activation of the
osteoblasts causes secondary activation of osteoblasts.
- In summary vitamin D increases absorption, reabsorption and bone
formation (or calcification).
Remember that: Vitamin D acts on nuclear receptors. It increases
transcription of some mRNAs and inhibits transcription of others.

- Examples of mRNAs increased by vitamin D are those which form the
calcium binding protein “calbindin D” which facilitates calcium absorption
in the intestine.
- Other effects of vitamin D “under investigation”: It stimulates
differentiation of immune cells and skin keratinocytes and participates in
growth regulation.
Abnormalities
 Rickets:
- Occurs due to deficiency of vitamin D in children.
- It is characterized by hypocalcemia and failure of bone mineralization
resulting in weakness & bowing of bones (see above).
- Rarely, rickets may not respond to treatment with vitamin D (= vitamin D
resistant rickets). The possible causes include a gene defect involving the
enzyme 1α-hydroxylase (type I) or a gene defect involving formation of
vitamin D receptors (type II).
- Note that type I responds to treatment with 1,25 (OH)2 D3 whereas type II
does not.
 Osteomalacia:
- Deficiency of vitamin D in adults. It si known as adult rickets. It is
characterized by weak and easily fractured bones.
Fig 10.25: Rickets

CALCITONIN
Characteristics
- Polypeptide hormone (32 aa) that is produced by Clear (C) cells of the
thyroid gland. Its half life is less than 10 minutes.
Control
- It is stimulated by: Hypercalcemia, GIT hormones (gastrin, CCK, secretin,
glucagon) and β adrenergic agonists
Actions
- Lower calcium & phosphate levels in the blood (hypocalcemic and
hypophosphatemic)
- Inhibits bone resorption by inhibiting osteoclasts
- Increases calcium excretion in urine
Remember that: the physiological role of calcitonin is unknown. It may
offer protection against postprandial hypercalcemia (i.e. short-term effect
on calcium homeostasis; it has no long-term effect).
- It is used clinically for treatment of Paget’s disease (to inhibit the
increased osteoclastic activity) and for treatment of severe hypercalcemia.
Abnormalities
Calcitonin excess: Occurs in medullary carcinoma of the thyroid. It is not
associated with symptoms related to calcitonin.
Calcitonin deficiency: No reported syndrome.
OTHER HORMONES AFFECTING CALCIUM HOMEOSTASIS:
Positive balance:
- Growth hormone, androgens & IGF-1 (stimulate osteoblasts)
- Estrogen (inhibits osteoclasts and stimulates osteoblasts)
Negative balance:
- Glucocorticoids (inhibit osteoblasts)
- Thyroxine and vitamin A (stimulate osteoclasts)

1- Physiological effects of glucagon include:
a. Glycogenesis in liver
b. Lipolysis in adipose tissue
c. Glycogenolysis in muscle
d. Inotropic effect in the heart
e. Stimulation of hunger in hypothalamus
2- In this photo, the endocrine abnormality is
known as:
a. Gigantism
b. Acromegaly
c. Rickets
d. Diabetes mellitus
e. Cushing’s syndrome
3- The parathyroid hormone is stimulated by:
a. Low phosphate
b. High calcium
c. Low glucose
d. High chloride
e. Low magnesium
4- Calcitonin:
a. Is produced by chief cells of the parathyroid gland
b. Inhibits calcium mobilization from bone
c. Inactivates vitamin D in the kidney
d. Inhibits calcium absorption in the intestine
e. Excess causes hypocalcemia
5- Clinical features of diabetes mellitus include:
a. Oliguria
b. Hyperphagia
c. Insomnia
d. Hyperventilation
e. Weight gain
6- Physiological effects of parathyroid hormone include:
a. Reabsorption of phosphate
b. Deposition of calcium in tissues
c. Resorption of bone
d. Inhibition of vitamin D formation
e. Renal stone formation
7- Hypocalcaemia results in:
a. Increased membrane permeability to sodium
b. Enhanced transmitter release in the synapse
c. Decreased release of PTH
d. Increased stability in neurons
e. Increased formation of 24,25 D3 by the kidney

8- All these hormones activate 1-hydroxylase in the kidney EXCEPT:
a. Growth hormone
b. Prolactin
c. 1,25 (OH)2 cholecalciferol
d. Parathyroid hormone
e. Calcitonin
9- Abnormal total plasma calcium concentration is a recognized feature in:
a. Diabetes mellitus
b. Hyperthyroidism
c. Conn’s syndrome
d. Hyperventilatrion
e. Medullary carcinoma of the thyroid
10- Insulin production is best stimulated by:
a. GLP-2
b. Cholecystokinin
c. Somatostatin
d. Gastrin
e. GIP
11- In the absence of insulin, patients may suffer from:
a. Hypoglycemia
b. Hypertension
c. Hypercalcemia
d. Metabolic acidosis
e. Respiratory alkalosis
12- Regulation of plasma calcium in the short term depends on:
a. Release or suppression of parathyroid hormone
b. Secretion of calcitonin
c. Activation of vitamin D3
d. Renal reabsorption of calcium
e. Activation of osteoblasts
13- One of the physiological roles of calcitonin is to:
a. Stimulate bone growth in children
b. Stimulate bone resorption in old age
c. Safeguard against osteomalacia
d. Prevent postprandial hypercalcaemia
e. Recovery from hypocalcaemic tetany
14- Insulin:
a. Decreases amino acid entry into cells
b. Controls glucose absorption in the intestine
c. Decreases lipoprotein lipase activity in plasma
d. Increases glucose output from the liver
e. Requires calcium for secretion from the beta cells
15- Hypoglycemia results in secretion of all of the following EXCEPT:
a. Glucagon
b. Somatostatin
c. Adrenaline

d. Cortisol
e. Growth Hormone
16- This hormone increases calcium absorption:
a. Calcitonin
b. Calcitriol
c. PTH
d. Pancreatic Polypeptide
e. Corticotropin Releasing Factor (CRF)
17- Insulin increases the entry of glucose into:
a. All tissues
b. Renal tubules
c. The mucosa of the small intestine
d. Most neurons of the cerebral cortex
e. Skeletal muscle
18- Glucose increases plasma insulin by a process that involves:
a. GLUT1
b. GLUT2
c. GLUT3
d. SGLT1
e. GLUT4
19- The parathyroid hormone:
a. Is secreted by the thyroid para-follicular cells
b. Decreases the renal excretion of phosphates
c. If increased, it depresses the activity of the anterior pituitary
d. Secretion is stimulated when blood calcium increases
e. Mobilizes Ca++ mainly from the bone
20- Activation of hormone-sensitive lipase in adipocytes:
a. Depends on insulin
b. Is inhibited by cortisol
c. Requires cAMP-dependent protein kinase
d. Results in hydrolysis of cholesterol esters
e. Increases monoglycerides and diglycerides in adipocytes
21- Prolonged fasting (more than 3 days) is associated with:
a. Decreased lipolysis
b. Increased excretion of nitrogen in urine
c. Decreased gluconeogenesis
d. Increased secretion of insulin
e. Increased glucose utilization by the brain
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
b c e b b c a c b e d
12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
b d e b b e b e c c

CHAPTER (11)
HUMAN REPRODUCTION
INTRODUCTION
- The anatomical & physiological differences between males & females
primarily are due to:
 Presence or absence of the Y chromosome
 Presence of either the testes (if Y chromosome is present) or the
ovaries (if Y chromosome is absent)
- The testes produce androgens (sex hormones with masculinizing effects)
whereas the ovaries produce estrogens (sex hormones with feminizing
effects).
- The Y chromosome is essential for formation of the testes because it
contains a gene that produces a DNA regulatory protein known as the
“SRY” for “sex-determining region of the Y chromosome.” This protein acts
as a transcription factor to initiate formation of the testes.
Fig 11.1: Male and female chromosomes

Remember that: Each ovum produced by female gametogenesis contains
22 chromosomes + X chromosome; whereas ach sperm produced by male
gametogenesis contains 22 chromosomes + either X or Y chromosome.
- A genetic male (44, XY) results when a sperm containing Y chromosome
fertilizes an ovum containing X chromosome.
- A genetic female (44, XX) results when a sperm containing X
chromosome fertilizes an ovum containing X chromosome.
- Only one of the X chromosomes in females is active; the inactive one
appears as the “Barr body” within the nuclei of female cells or as a
“drumstick” in some of their polymorphonuclear leukocytes.
- The embryo in the 7th week of pregnancy has both:
 The male genital duct (Wolffian duct)
 The female genital duct (Mullerian duct)
- In the presence of Y chromosome the testes develop. They release:
1- Testosterone to increase development of the Wolffian duct into
epididymis & vas deferens. Testosterone is also converted to
dihydrotestosterone, which forms the external genitalia in males.
2- Mullerian inhibitory substance (MIS) to cause regression of the
Mullerian duct.
- In the absence of the Y chromosome the testes do not develop. The
ovaries are developed and the Mullerian duct persists. It gives the uterus
& the uterine tubes.
Fig 11.2: Drumstick chromosome

Abnormalities of sexual differentiation
- These are caused by two main types of abnormalities:
Chromosomal abnormalities & hormonal abnormalities
Chromosomal abnormalities:
- Occur due to non-disjunction (or failure of separation) of the sex
chromosomes during gametogenesis.
- This results in formation of abnormal gametes with 24 & 22
chromosomes rather than 23.
 Examples for abnormal sperm patterns: (22,XY) and (22,O)
 Examples for abnormal ovum patterns (22,XX) and (22,O)
- Fertilization that involves an abnormal sperm and/or an abnormal ovum
may cause one of the following syndromes:
Turner syndrome
- Also known as “ovarian agenesis” because the ovaries are not
developed (streaks). It occurs due to non-disjunction. E.g. when an
abnormal sperm (22,O) fertilizes a normal ovum (22,X); the developing
subject is a female with 45 chromosomes (44,XO).
- Features of Turner’s syndrome include:
 Female genitalia with absent ovaries
 Failure of maturation at puberty (no ovaries = no hormones= no
features of puberty)
 Primary amenorrhea
 Short stature
 Broad chest
 Poor breast development with wide separation of the nipples
 Webbing of the neck
 Cubitus valgus (turned-out elbows or increased carrying angle)
 Congenital anomalies (e.g. coarctation of the aorta)

Klinefelter’s syndrome
- Also known as “seminiferous tubule dysgenesis”.
- It occurs due to non-disjunction, for example when an abnormal sperm
(22,XY) fertilizes a normal ovum (22,X).
- The developing subject is a male with 47 chromosomes (44,XXY); i.e.
with additional X.
- Features of Klinefelter’s syndrome include:
 Male genitalia with small testicles
 Azospermia (low sperm count in semen) due to dysgenesis of
seminiferous tubules (= reduced fertility “sterility”)
 Tall stature
 Gynecomastia
 Higher incidence of mental retardation
True hermaphroditism
- It also occurs due to non-disjunction.
- The developing subject is a true hermaphrodite with XX / XY mosaicism.
- True hermaphrodite subject has both ovaries & testes
Fig 11.3: Chromosomal abnormalities of sexual differentiation

Remember that: The incidence of non-disjunction is increased as the
maternal age of the mother increases.
- Non-disjunction also occurs in chromosomes other than the sex
chromosomes as in chromosome 21. Here each cell contains three rather
than two copies of chromosome 21 (i.e. trisomy 21).
- Patients with trisomy 21 suffer from "Down syndrome" (characterized by
mental retardation and certain physical features: flat nasal bridge, low set
ears, protruding tongue, single palmar crease and a short neck).
- In addition to non-disjunction, chromosomal abnormalities may involve
transposition of some parts of a chromosome to another chromosome
(e.g. transposition of the short arm of chromosome Y to the X
chromosome of the father). Since the short arm of Y chromosome contains
the gene that produces the SRY, which forms the testis; the developing
embryo who takes the X from the father and an other X from the mother is
a male.
Fig 11.4: Chromosomal abnormalities

Hormonal abnormalities
- Hormones (usually androgens) result in two types of abnormal sexual
differentiation:
 Female pseudohermaphroditism
 Male pseudohermaphroditism
Female pseudohermaphroditism
- Genetic female (44,XX) but with external genitalia of males (and internal
genitalia of females).
- Due to exposure of the female embryo to androgens in intrauterine life
(during the 8th to 13th week of gestation).
- Sources of androgens:
 Mother taking androgens (e.g. athletes)
 Congenital adrenal hyperplasia
Male pseudohermaphroditism
- Genetic males (44,XY) but with external & internal genitalia of females.
- Occurs due to a defect in the testes during development, resulting in
failure to secrete androgens & MIS (therefore both the external and the
internal genitalia are of females).
- Other causes of Male pseudohermaphroditism:
 Testicular feminization syndrome
- This is one of the forms of male pseudohermaphroditism due to
“complete androgen resistance” caused by receptor defect.
- Androgens and MIS are secreted normally; however, because of the
receptor defect, androgens fail to form internal or external genitalia of
males.
- On the other hand, the MIS acts normally to prevent formation of female
internal genitalia. Therefore in this patient there is female external genitalia
but the vagina ends blindly because there is no internal genitalia.

 5 alpha reductase deficiency
- The enzyme that converts testosterone to dihydrotestosterone (see
below).
 17 alpha hydroxylase deficiency
- See the adrenal gland.
PUBERTY
Definition
- The period when the endocrine & gametogenic functions of the gonads
have first developed to attain reproductive capacity.
Onset
- Onset of puberty varies according to genetic and environmental factors.
- It is at the age range of (9-13 y) in females and (11-15 y) in males.
Mechanism of Onset
- Although the pituitaries of children contain gonadotrophins and their
hypothalami contain GnRHs; their release is inhibited by unkown neural
mechanism.
- What initiates the release of these hormones and starts puberty is still
unknown. However, it is thought to be some sort of CNS maturation.
- The CNS maturation initiates release of GnRH in a pulsatile pattern
from the hypothalamus.
- This results in release of gonadotrophins (FSH & LH) from the pituitary
gland.
- The gonadotrophins control functions of the gonads and release of the
sex hormones (testosterone in males; estrogen and progesterone in
females).
- The sex hormones result in appearance of the characteristic features of
puberty.

- The hormone leptin (the satiety-producing hormone produced by fat
cells) probably plays a role in control of puberty. That is why some young
females with loss of weight fail to menstruate unless they gain weight.
Features of puberty
- Growth spurt.
- Development of secondary sex characters.
- Enlargement of reproductive organs.
- Attainment of reproductive capacity.
- Note the following features in females:
 Thelarche: Development of the breast (an early feature of puberty in
females).
 Menarche: The first menstrual period.
 Pubarche: Development of axillary and pubic hair. Also occurs in
males; however, the pattern of hair distribution at the pubic area differs
between males and females.
 Adrenarche: Increased secretion of adrenal androgens (occurs in both
sexes).
The secondary sex characters
In males:
 Enlargement of internal genitalia (testes, ducts and glands; the glands
start secretion).
 Enlargement of external genitalia (penis and scrotum).
 Deep voice (due to enlargement of the larynx & thickening of the vocal
cords).
 Growth of hair in the:
o Face: beard & moustache; with receding of hairline on the scalp.
o Pubic area: in a triangular pattern, with its apex facing up.
o Other areas: axilla, chest, anus & other hair in the body.

 Emotional changes (more active, aggressive and interested in the
opposite sex).
 Conformational changes (enlargement of muscles and broadening of
shoulders).
 Secretion of sebaceous glands increases and thickens; predisposing to
acne.
In females:
 Enlargement of the internal genitalia (uterus and vagina).
 Enlargement of the external genitalia (labia majora, labia minora and
clitoris).
 Enlargement of the breasts.
 The voice remains high pitched (no enlargement of the larynx).
 Deposition of subcutaneous fat (especially in the breasts and
buttocks).
 Development of pubic and axillary hair:
o Due to adrenal androgens in both sexes (adrenarche)
o The female pattern of hair distribution at the pubic area is also
triangular, with its apex facing down (i.e. flat-topped pattern).
 Emotional changes & conformational changes (broad hips with narrow
shoulders).
Abnormalities of puberty
Precocious puberty:
= Early development of secondary sex characters, due to early release of
sex hormones (androgens in males & estrogens in females). The early
release of sex hormones may or may not be associated with
gonadotrophin release.
- When the gonadotrophins are also released, the child becomes capable
of gametogenesis.

- Therefore the precocious puberty is described as true precocious
puberty.
- When the gonadotrophins are not released, the child is not capable of
gametogenesis. Therefore, the precocious puberty is described as
pseudo-puberty.
- Causes of true precocious puberty:
 Constitutional (no apparent cause)
 Lesions in the posterior hypothalamus (tumor or infection)
 Congenital abnormality
- Causes of precocious pseudo-puberty:
 Congenital adrenal hyperplasia (in males)
 Adrenal tumors secreting androgens or estrogens
 Testicular tumors secreting androgens
 Ovarian tumors secreting estrogens
- Note: There is no single age that reliably separates normal from
abnormal. However, precocious puberty is clinically important because:
 It results in early closure of epiphyseal plates in bones (= short
stature).
 It may indicate presence of a tumor in the adrenals or gonads.
Delayed puberty
- Can be considered if features of puberty fail to develop by the age of 17
in females or 20 in males. The delay occurs due to failure of
gonadotrophin or sex hormone secretion.
- Causes of delayed puberty include:
 Pituitary disorder (e.g. panhypopituitarism)
 Chromosomal abnormality (e.g. Turner syndrome)
 Gonadal problems
 Unknown causes

THE MALE REPRODUCTIVE SYSTEM
STRUCTURE
- The male reproductive system consists of the following organs:
The testes
- The testes hang outside the abdominal cavity of the male & lie within the
scrotum.
- Each testis is composed of:
o Seminiferous tubules containing Germ cells (to produce sperms)
& Sertoli cells (to do many functions, see below).
o Interstitial cells “or Leydig cells” (to release testosterone).
- The testes begin their development in the abdominal cavity but descend
into the scrotal sacs later during pregnancy.
- This is required because the internal body temperature is too high for
sperm production.
Fig 11.5: The testes
The duct system:

Epididymis: The narrow, tightly coiled tube that connects the testes to the
vas deferens on each side. It stores sperms produced by the testes until
the time of ejaculation. These sperms are immature and not motile. They

become able to swim during their transit through the epididymis; however,
final maturation to acquire the ability for fertilization occurs within the
female genital tract (= Capacitation).
Vas deferns: The muscular duct that connects the epididymis on each
side to the ejaculatory ducts. Each tube is about 30 centimeters long. It is
part of the spermatic cord. It moves sperms by peristalsis.
Ejaculatory ducts: Two ducts, each one is 2 cm in length; formed by the
union of the seminal vesicle with the vas deferens. It evacuates semen
into the urethra.
Urethra: The narrow tube that connects the urinary bladder to the outside
of the body. In addition to its excretory function, it has a reproductive
function; it transports semen to the outside.
 Associated glands:
Seminal vesicles: Two glands, each one is about 5 cm long; found
postero-inferior to the urinary bladder and above the prostate. They
secrete about 70% of the seminal fluid. Their secretion contains proteins,
enzymes, fructose, mucus and prostaglandins. Fructose provides
nutritional energy for the sperms within the female genital tract. Its
secretion starts at puberty.
Prostate: The exocrine gland that surrounds the urethra just below the
urinary bladder. It secretes about 10-30% of the seminal fluid. Its secretion
contains prostate specific antigen (PSA), acid phosphatase and zinc. The
secretion is slightly alkaline to neutralize acidity in the female genital tract.
The PSA hydrolyses inhibitors of sperm motility in semen. Small amount of
PSA escapes into the plasma in normal conditions. High plasma level of
PSA is an important indicator of prostatic cancer.
Cowper’s glands: Also known as “the bulbourethral glands.” Two small
exocrine glands, homologous to Bartholin's glands in females. Their ducts

open into the urethra at the base of the penis. They produce a clear,
viscous fluid known as (pre-ejaculate). This fluid helps to flush the urethra
from any residual urine & to lubricate it for passage of sperms.
The penis
The penis is the copulatory organ of the males. It has a long shaft and
enlarged tip called the glans penis. It is made up of three columns of
erectile tissue: two corpora cavernosum (responsible for erection) and one
corpus spongiosum (contains the urethra).
Fig 11.6: The male reproductive organs
Functions of Sertoli cells:

- Sertoli cells are large, complex glycogen-containing cells. They line the
walls of the seminiferous tubules in the testes. They perform many
functions, for example:
 Formation of blood testes barrier "BTB"
- Formed by fusion of adjacent Sertoli cells by tight junctions near the
basal lamina of seminiferous tubules.

- The blood testes barrier prevents passage of large molecules from
the interstitium of the testes to the lumen of Seminiferous tubules,
where sperms are formed (i.e. protective function).
- Certain substances as testosterone (which is essential for
spermatogenesis) crosses this barrier easily.
 Physical support of germ cells
- The survival of germ cells requires direct contact with Sertoli cells.
 Maintenance of fluid composition in the lumen of seminiferous tubules
- The fluid in the lumen of seminiferous tubules differs from that of
plasma; it contains less protein & glucose but more androgens,
estrogens, K+, inositol & glutamate.
 Release of Mullerian inhibitory substance "MIS"
- The MIS causes regression of Mullerian duct in the male fetus.
 Release of androgen binding protein
- This protein is released by Sertoli cells in response to FSH.
- It binds testosterone within the lumen of seminiferous tubule to lower
its concentration. Therefore, testosterone continues to diffuse passively
from the interstitium to the lumen of the tubules.
 Release of inhibin
- A peptide hormone secreted by the gonads in both males and
females.
- In both sexes, it causes inhibition of FSH (as a negative feedback
mechanism).
 Conversion of androgens to estrogens
- The enzyme aromatase is found within Sertoli cells.
- It converts androgens into estrogens.
- Estrogens in males are also formed from androgens in the adipose
tissue.

Spermatogenesis
Definition:
- Spermatogenesis is the process of sperm production.
- It starts at puberty and continues throughout the life of males.
Stages:
 Germ cells or spermatogonia (46 chromosomes) divide to give
primary spermatocytes (46 chromosomes) by mitotic division.
 Primary spermatocytes (46 chromosomes) divide to give secondary
spermatocytes (23 chromosomes) and then spermatids (23
chromosomes) by the two steps of meiotic division.
 Finally, spermatids are transformed into spermatozoa (23
chromosomes).
Important points:
- The process takes 74 days.
- It needs temperature lower than the body (about 32 ◦c).
- This low temperature is achieved by:
 Location of the testes outside of the abdominal cavity.
 The countercurrent system between spermatic arteries and veins at
the pampiniform plexus.
(By the exchange between the supplying arteries and the draining veins,
this system not only maintains low temperature at the scrotum but also
maintains high concentration of testosterone within the testes).
- One spermatogonium gives about 512 spermatids.
- At first sperms are not fully motile.
- Motility increases with passage through the epididymis (this involves
activation of a protein in the tails of sperms "CatSper" that allows Ca ++
influx).

Fig 11.7: Spermatogenesis
Role of hormones in control of spermatogenesis:

 Testosterone (androgens): Needed for the last step only (conversion
of spermatids to spermatozoa). Previous steps are independent of
androgens.
 FSH: Acts on Sertoli cells to release androgen binding protein (and
inhibin). The androgen binding protein is needed to bind testosterone &
maintain it in high concentration within the seminiferous tubules. Inhibin
exerts a negative feedback effect on the pituitary to inhibit FSH.
 LH: Acts on Leydig cells to release testosterone. Testosterone exerts a
negative feedback effect on the pituitary to inhibit LH.
Fig 11.8: Control of spermatogenesis

Semen
- Fluid ejaculated by the male. Its volume is about 2.5 to 3.5 ml. It contains
sperms & secretions of the associated glands (seminal vesicles, prostate
& Cowper's glands). Count of sperms: 100 million/ml. Sperm count of less
than 20 million/ml indicates infertility.
- The rete testes (at the hilar part of the testes) contain concentrated
sperms. Damage or failure of concentration at this part produces diluted
semen and results in infertility.
Fig 11.9: Structure of human spermatozoon
Erection
- Erection is the increase in size and turgor of the penis.
- It occurs when the two erectile columns in the penis (the corpora
cavernosa) become engorged with venous blood. In addition, the third
erectile column (the corpus spongiosum), which contains the urethra, also
becomes slightly engorged with blood, but to a lesser extent.
- It is stimulated by erotic psychic stimuli or direct tactile stimulation of the
genitalia.
- Efferent impulses pass through the parasympathetic fibers in the pelvic
splanchnic nerves to dilate the arterioles of the penis.
- When the erectile tissue fills with blood, the draining veins are
compressed, this keeps blood within the penis causing its enlargement
and increasing its turgor (= erection).

- The neurotransmitters released by the neurons in the pelvic splanchnic
nerves include acetylcholine, vasoactive intestinal polypeptide “VIP” and
nitric oxide “NO”.
- “NO” plays a major role in erection; it acts intracellularly to activate the
enzyme guanylyl cyclase. This triggers production of cGMP (a potent
vasodilator) from GTP.
- cGMP is broken down by phosphodiesterases. For this reason, the
phosphodiesterase inhibitor, Sildenafil (or Viagra) is used for treatment of
erectile dysfunction (impotence) by preventing breakdown of cGMP.
Ejaculation
- Ejaculation is the ejecting of semen from the urethra, and is usually
accompanied by orgasm (sexual climax).
- It usually results from sexual stimulation, but it may occur spontaneously
during sleep.
- It occurs as a spinal reflex that involves two phases: emission and
ejaculation proper.
- The emission phase is under control of the sympathetic nervous sytem
(integrated in the lumbar segments and mediated through the hypogastric
nerves); whereas the ejaculatory phase is under control of somatic
nervous system (integrated in he lower abdominal and upper sacral
segments and mediated through the pudendal nerve).
- During emission, the vas deferens and the seminal vesicles contract to
propel semen from the epididymis to the urethra.
- During ejaculation proper, the semen is ejected through the urethra with
rhythmic contractions.
- These rhythmic contractions are part of the male orgasm. They are
generated by the bulbocavernosus muscle.

Testosterone
Characteristics
- Steroid hormone (C19) with masculinizing effects.
- Synthesized from cholesterol by Leydig cells in the testes.
- Also synthesized from androgens secreted by the adrenal cortex
(androstenedione and dehydroepiandrosterone).
- Activated to dihydrotestosterone (by the enzyme 5 α reductase).
- In the female, small amount of testosterone is secreted from the ovary
and the adrenal gland.
Control
- Testosterone secretion starts in the male fetus before birth (to stimulate
formation of the male genital organs), then the secretion increases during
the neonatal period for unknown reason and then stops until puberty.
- At and following puberty, the control of secretion is through the
hypothalamo-pituitary axis.
- The hypothalamus releases GnRH to the pituitary, which releases LH.
Then LH acts on Leydig cells in the testes to release testosterone.
- Testosterone, to control its plasma level, exerts a negative feedback
effect on LH.
- In old men, secretion of testosterone never stops; however, its plasma
level decreases.
- On the other hand, the plasma level of estrogens (formed from
androgens) increases in old men.
Transport in plasma
- Most of testosterone in plasma (98%) is bound to:
 Gonadal steroid-binding globulin "GBG": β globulin, binds 65% of
testosterone
 Albumin: binds 33% of testosterone

Metabolism
- Products of testosterone metabolism in the liver and peripheral tissues:
 17-Ketosteroids (e.g. androsterone, excreted in urine)
 Estrogen
Note: About two thirds of 17-ketosteroids in urine are metabolic products
of adreno-cortical hormones.
Effects of testosterone
 Formation of male genitalia (the internal genitalia is formed directly by
testosterone whereas the external genitalia is formed by its active form
"dihydrotestosterone").
 Spermatogenesis (assisted by FSH).
 Development of the secondary sex characters.
 Anabolic action (protein synthesis) = increases growth.
 Retention of water and electrolytes (secondary to increased growth).
 Negative feedback effect on LH at the anterior pituitary gland (it has no
effect on FSH except in very high level).
Important note: Testosterone injections inhibits (rather than stimulates)
spermatogenesis. This is because systemic testosterone is not enough for
spermatogenesis, whereas it is enough for inhibiting LH secretion by the
pituitary. This explains the importance of the countercurrent mechanism
that keeps high testosterone level within the testes.
Remember about dihydrotestosterone
- It is formed from testosterone by the action of 5-α reductase in the scalp,
genital skin and the prostate.
- It binds to the same intracellular receptors of testosterone before binding
DNA in the nucleus; however, its receptor-hormone complex is more
stable than that of testosterone. That is why it is more active than
testosterone although its plasma level is only 10% of that of testosterone).

- It is responsible for formation and enlargement of external genitalia,
enlargement of the prostate, and growth of facial hair, formation of acne
and receding of hairline on the scalp.
Remember that: 5-α reductase inhibitors (e.g. finasteride) are widely used
to treat benign prostatic hypertrophy; which is a common cause of urine
retention in old men.
Abnormalities
Deficiency of 5 α reductase enzyme
 = Deficiency of dihydrotestosterone.
 This results in absence of male external genitalia; the patient is
regarded as female (= male pseudohermaphroditism).
 However, at puberty, due to high production of testosterone, the patient
develops male configuration and libido, facial hair and increased size
of clitoris.
 Then investigations confirm that he is a male.
Other abnormalities related to the male reproductive system

Cryptorchidism "un-descended testes"
- The testes descend during fetal life from the abdominal cavity to its
normal position in the scrotum due to MIS and other factors.
- Un-descended testes at birth require treatment (by gonadotrophins or
better by surgery); because of:
o The higher incidence of malignancy
o The irreversible damage to the testes at puberty due to the high
temperature within the abdomen.
Male hypogonadism
- Develops either due to testicular disease or pituitary/hypothalamic
disorder. Accordingly, the plasma level of gonadotrpins is either:

 Increased (in testicular disease) causing hypergonadotropic
hypogonadism
 Decreased (pituitary/hypothalamic disorder) causing hypogonadotropic
hypogonadism
- Other important point is the development of the secondary sex
characters in these patients; this depends on the date of abnormality; e.g:
Congenital or childhood abnormality:
- Results in absence of male secondary sex characters. Patients have the
following features:
- Tall stature (due to delayed closure of epiphyseal plates in bones).
- Female features (eunuchoidism): narrow shoulders, small muscles, small
genitalia, high pitched voice, female contours and pattern of pubic hair.
- Example: Kallmann's syndrome (= hypogonadotropic hypogonadism due
to an inherited hypothalamic abnormality. It is characterized by congenital
anosmia, low GnRH and therefore low FSH, LH and sex hormones;
resulting in delayed puerty and infertility).
Remember that:
Pubic and axillary hairs are due to the androgens from the adrenal cortex.
Abnormality after puberty:
- Results in regression of the secondary sex characters. However, the
voice (which is due to enlargement of the larynx) remains deep.

THE FEMALE REPRODUCTIVE SYSTEM
STRUCTURE
- The female reproductive system consists of the following organs:
Ovaries
o The ovaries are two oval shaped female reproductive organs located in
the lateral wall of the pelvis. Each one measures approximately (3 x 1.5 x
1.5) cm.
o They contain the primordial follicles (also known as ovarian follicles);
each follicle contains an immature ovum “oocyte” and surrounded by two
types of cells (granulosa cells and thecal cells).
o The total count of these follicles decreases (due to degeneration) from
about 7 millions in the fetus to 2 millions at birth; however, one million of
these are normal, they start their first meiotic division and enter stage of
arrest in prophase. Of these, less than 300,000 follicles survive until
puberty.
o Following puberty (& until menopause) the ovarian follicles continue to
decrease in number because each month a few of them start to grow in
response to FSH and then become atretic except one follicle that reaches
maturation.
o The total count of follicles that reach maturation within the reproductive
life of a female that never gets pregnant is about 500 follicles ("12 follicles
per year" times "40 years").
o The mature ovarian follicle:

- Also known as Graafian follicle
- The ovum (in stage of primary oocyte) becomes surrounded by the
zona pellucida (a mucopolysaccharide layer) and some granulosa
cells (these form the cumulus oophorus following ovulation).

- The granulosa cells form several layers around the follicle and
contains fluid that fills the follicle (the antrum) and pushes the ovum to
one side.
- The theca cells become differentiated into two layers: Theca interna
(well vascularized) & theca externa (less vascularized)
- The primary oocyte completes its first meiotic division giving
secondary oocyte & first polar body (this occurs just before ovulation).
- The mature follicle is now ready for ovulation (usually 9 hours
following LH peak).
Fig 11.10: The mature ovarian follicle
Uterine tubes
o Also known as the “Fallopian tubes” or the “oviducts”.
o These are two tubes, attached to either side of the upper end of the
uterus, and each one is about 7-14 cm long, terminating near the ovary.
o There are four regions of the fallopian tube from the ovary to the
uterus: Infudibulum (contains the fimbria), ampulla (the site of
fertilization), isthmus & intramural oviduct (inside the uterine wall).

Uterus
o The uterus (or womb) is the major female reproductive organ.
o Its lower end (the cervix) opens into the vagina.
o Its upper part is connected on both sides to the Fallopian tubes.
o The uterus is the site that accepts the fertilized ovum and allows its
implantation.
o It provides nutrition for the developing embryo and fetus through the
placenta.
o The layers that form the wall of the uterus are as follows:
- The endometrium (the layer that lines the uterine cavity from inside)
- The myometrium (the smooth muscle that forms the wall of the uterus)
- The perimetrium
- The peritonium
Cervix
o The cervix (the uterine neck) is the lower, narrow portion of the uterus,
which provides passage between the uterine cavity and the vaginal cavity.
o It is about 4 cm long, with 2 cm projecting into the upper vaginal cavity.
o The cervical opening into the vagina is called the external os.
Vagina
o In humans, the vagina is about 9 cm long on average (with the anterior
wall slightly shorter than the posterior one).
o It is located in front of the rectum and behind the bladder.
o In most virgins, the external opening to the vagina is partially closed by
a thin fold of tissue known as the hymen.
External genitalia (or vulva)
o The parts of the female reproductive system, which lie external to the
vagina. They include the labia majora, mons pubis, labia minora, clitoris,
and glands within the vestibule (lesser and greater vestibular glands).

o The clitoris is an erectile organ that responds to sexual stimulation
(similar to the male penis).
o The two lesser vestibular glands (also known as Skene's glands,
periurethral glands and paraurethral glands) are equivalent to the male
prostate in both histology and secretion (they produce clear fluid similar to
that produced by the male prostate during sexual stimulation).
o The two greater vestibular glands (also known as the Bartholin’s
glands) are located near the opening of the vagina. They secrete mucus
to provide lubrication (equivalent to Cowper’s glands in males).
Fig 11.11: The female reproductive organs
THE MENSTRUAL CYCLE

- Cyclic changes in the female that occur in the:
 Ovaries (= ovarian cycle)
 Uterus (= uterine cycle)
 Other organs (e.g. cervix, vagina and breasts)
- These changes start to occur following puberty and cease at the age of
menopause (between 45 & 55 years old). They can be regarded as
periodic preparations for fertilization and pregnancy.
- The average duration of each cycle is about 28 days, but it varies
between 20 & 35 days.
THE OVARIAN CYCLE
- The ovarian cycle is controlled by the hypothalamo-pituitary axis.
- It is related to the other cycles (in the uterus, cervix and vagina) by the
hormones produced from the ovaries.
- The ovarian cycle is divided into three phases:
 Follicular phase (or preovulatory phase)
 Ovulatory phase
 Luteal phase (or postovulatory phase)
The follicular phase
- Each month following puberty, a few follicles start to grow in response to
FSH. Most of them become atretic & only one reaches maturation.
- In the mature follicle (= Graafian follicle) the ovum (the primary oocyte)
completes its first meiotic division just before ovulation giving secondary
oocyte & first polar body. The secondary oocyte completes the second
meiotic division with fertilization.
- The granulosa cells in the follicles form estrogens and some
progesterone (they are the primary source of estrogen in the follicular
fluid).
- Theca interna cells also form estrogens (they are the primary source of
estrogen in the circulation) and supply the granulosa cells with androgens
to convert it into progesterone.
- Estrogens exert negative feedback effect on both FSH & LH.
- However, towards the midcycle, this –ve feedback effect is converted into
+ve feedback effect (due to unknown cause).
The ovulatory phase

- Usually occurs 14 days prior to the last day of the cycle; for example, at
day 14 (mid-cycle) if the cycle is 28 days or at day 16 if the cycle is 30

days (note that the first day of the cycle is the first day of menstrual
bleeding).
- During the follicular phase, estrogens exert –ve feedback effect on both
FSH & LH.
- Towards the day of ovulation (the mid-cycle), the rising estrogen exerts
+ve feedback on both FSH & LH resulting in mid-cyclic peak of FSH & LH.
- This is followed by rupture of the follicle & shedding of the ova (ovulation)
into the abdominal cavity (usually 9 hours following the LH peak).
- The ova is picked up by the fimbria of the uterine tube and transported
towards the uterus.
- Blood fills the ruptured follicle forming "the corpus hemorrhagicum" and
may escape into the abdominal cavity causing lower abdominal pain due
to irritation of the peritoneum (= an indicator of ovulation).
- Unlike FSH peak, the peak of LH at the mid-cycle is essential for
ovulation.
Fig 11.12: Hormonal changes during the ovarian cycle

The luteal phase
- LH acts on the ruptured follicle following ovulation, resulting in
appearance of yellowish cells rich in lipids known as "the luteal cells"; here
the follicle is called "the corpus luteum".
- The luteal cells secrete both estrogens & progesterone.
- Estrogens and progesterone exert –ve feedback effect on FSH and LH to
reduce their concentrations.
- If there is no pregnancy, the corpus luteum degenerates (usually 4 days
before the end of the cycle) forming "the corpus albicans". Accordingly,
estrogens & progesterone decline whereas FSH & LH rise to start new
cycle (i.e. to stimulate growth of new group of follicles).
- If there is pregnancy, the embryo secretes human chorionic gonadotropin
"hCG", see below.
- This maintains the corpus luteum and therefore maintains estrogen &
progesterone secretion (i.e. no new ovarian cycle, usually until after
delivery).
Fig 11.13: The ovarian cycle

THE UTERINE CYCLE
- Involves changes in the endometrium that are divided into 3 phases:
 Proliferative phase
 Secretory phase
 Menstrual phase
The proliferative phase
- Starts after menstruation and continues to the time of ovulation (e.g. from
day 5 to day 14). It depends on the action of estrogens, which causes
proliferation of the endometrium.
- In the endometrium, the stromal cells and the blood supply are increased
due to estrogen (the thickness is increased 10 times, from 0.5mm to
5mm).
The secretory phase
- Starts from ovulation to menstruation (e.g. from day 14 to the end of the
cycle "day 28").
- Depends on the action of progesterone.
- Under the effect of progesterone, the glands in the endometrium become
tortuous and start to secrete mucus, sugar, amino acids and glycogen.
- Arteries in the superficial two thirds of the endometrium (stratum
functionale), is supplied by long, coiled spiral arteries whereas arteries in
the deep third of the endometrium (stratum basale) are short and straight.
- The length of this phase is constant (about 14 days). It ends if there is no
pregnancy, but continues if there is pregnancy (because the level of
progesterone is not decreased).
The menstrual phase
- Shedding out of the superficial two thirds of the endometrium (stratum
functionale) with bleeding (during the first 3 to 5 days of the cycle) occurs
due to endometrial necrosis as follows:

 Degeneration of the corpus luteum
 Reduction estrogen and progesterone level in plasma
 Thinning of the endometrium (due to loss of the hormonal support)
 The endometrial arteries become more tortuous
 Appearance of foci of necrosis in the endometrium
 Release of lysosomal enzymes from the necrotic cells
 The enzymes stimulate formation of prostaglandins form cellular
phospholipids
 Narrowing of endometrial arteries due to the locally released
prostaglandins
 Extensive endometrial necrosis and shedding of endometrium with
bleeding.
- The lost menstrual blood is generally arterial blood; its volume is about
30 mL but loss of higher volumes (up to 80 mL) is normal.
- It does not clot because it contains fibrinolytic substances (fibrinolysin).
- It also contains cellular debris and prostaglandins.
Fig 11.14: The uterine cycle

CYCLIC CHANGES IN OTHER ORGANS
- Occur due to the effect of ovarian hormones (see below).
- Examples include changes in the cervix, vagina & the breasts.
Changes in the Cervix
- The cyclic changes appear in mucus, not the epithelium, as follows:
 During the proliferative phase (due to the effect of estrogens):
 Mucus in the cervix is thin, alkaline and has high elasticity (can be
stretched into a long thread); these changes facilitates transport of
sperms.
 During the secretory phase (due to the effect of progesterone):
o Mucus in the cervix becomes thick & difficult to penetrate.
Changes in the vagina
- The cyclic changes are less obvious; they appear in the epithelium &
mucus as follows:
o The epithelium becomes cornified.
o The epithelium becomes infiltrated with WBCs and covered by
thick mucus.
Changes in the Breasts
- The cyclic changes appear in the ducts and alveoli of breast tissue as
follows:
o There is proliferation of the ductular system of the breast.
o There is growth of the lobules & alveolar system of the breast,
resulting in breast swelling; that is why some females feel
tenderness in the breast during the last week of the cycle.

Indicators of ovulation
- As mentioned above, ovulation usually occurs 14 days prior the end of
each cycle. Sometimes the cycle is completed without ovulation (=
anovular cycle); here the bleeding at the end of the cycle occurs because
estrogens continue to cause endometrial proliferation until some areas
break down to initiate bleeding; usually before completing 28 days.
- Anovular cycles normally occur for about one year after menarche and
before menopause. However, it may occur in abnormal conditions
resulting in infertility.
- There are certain features that indicate occurrence of ovulation, these
indicators include:
 Rise of body temperature (due to the thermogenic effect of
progesterone)
 LH peak (or surge)
 Secretory phase in the endometrium
 Lower abdominal pain at the time of ovulation
OVARIAN HORMONES
- Hormones secreted by the ovary include:
 Estrogens
 Progesterone
 Relaxin
 Inhibin
Estrogens
Characteristics
- Steroid hormones (C18) with feminizing effects. Their types include:
 17  estradiol: most active
 Estriol: the least active
 Estrone
- Produced from androgens in females by:
 Granulosa cells
 Theca interna cells
 Corpus luteum
 Placenta
 Fat tissue (from androstenedione and testosterone by the action of
aromatase).
- Produced from androgens in males by:
 Fat tissue (the main site of synthesis; from androgens by the action
of aromatase).
 Sertoli cells & Leydig cells in the testes (form small amount of
estrogens)
Transport in plasma
- Most of estrogens (98%) is bound to plasma proteins.
- About 60% is bound to albumin and 38% is bound to the β globulin that
transports testosterone (GBG).
Metabolism
- Site of metabolism: the liver.
- The metabolites are conjugated and excreted in urine.
Control
- Through the hypothalamo-pituitary axis.
- The hypothalamus releases GnRH (at and following puberty).
- The pituitary releases LH & FSH.
- LH acts on theca interna cells to stimulate synthesis of androgens
(androstenedione) from cholesterol; some of this is converted to estradiol
and another part diffuses to granulosa cells.
- The granulosa cells, stimulated by both FSH & LH, convert the androgen
coming from theca interna into estradiol.

- Estradiol formed by theca interna cells enters the circulation whereas
that formed by granulosa cells enters the follicular fluid.
- During each menstrual cycle, estradiol level in plasma peaks just before
ovulation and during the mid-luteal phase. It declines to its lowest values
after menopause.
Estrogen effects
 Growth:
o Increases growth (has anabolic effect)
 Bone:
o Inhibits osteoclasts (that is why old women develop
osteoporosis after menopause)
o Closes epiphysis (that is why females, who have earlier onset of
puberty, develop epiphyseal closure at early ages and become
shorter than men).
 Secondary sex characters at puberty:
o See above (puberty)
 Ovary:
o Responsible for the follicular phase of the ovarian cycle
 Uterus:
o Responsible for the proliferative phase of the uterine cycle
o Increases the bulk of uterine muscle & its blood flow
o Increases motility of uterine tubes
o Facilitates the effect of oxytocin on the uterus (makes it more
excitable)
 Cervix & vagina:
o Makes the cervical mucus more thin
o Makes the vaginal epithelium cornified

 Breast:
o Increases growth of ductular tissue in the breast (responsible for
breast enlargement at puberty).
 The gonadotropins "FSH & LH":
o Has negative feedback effect on both FSH & LH.
o That is why contraceptive pills containing estrogen &
progesterone are used to inhibit FSH & LH and therefore
prevent pregnancy.
o Just before ovulation, it has positive feedback effect on both LH
& FSH.
 Sexual arousal:
o Increases "libido" in humans and "estrous behavior" in animals
(the estrous cycle occurs in the animals that do not menstruate.
o Here the sexual interest of a female animal is aroused at the
time of ovulation).
 Formation of some plasma proteins by the liver:
o Estrogens increase hepatic production of:
 TBG (thyroid binding globulins)
 Angiotensinogens
 Clotting factors (when administered orally to reach the
liver through the portal circulation; that is why estrogen
therapy causes thrombosis).
 Other effects:
o Salt and water retention
o Vasodilatation (by increasing NO production)
o Decreases cholesterol level in plasma
(= cardio-protective effect)

Progesterone
Characteristics
- Steroid hormone (C21).
- Produced by:
 Corpus luteum
 Placenta
 Granulosa cells (from pregnenolone from theca interna cells)
- Since it is formed during steroid biosynthesis in the adrenal cortex and
the testes, small amount is released by these glands into the circulation.
Transport in plasma
- Most of progesterone (98%) is bound to plasma proteins.
- About 80% is bound to albumin and 18% is bound to corticosteroid
binding globulin.
Metabolism
- Site of metabolism: the liver.
- The metabolites are conjugated and excreted in urine.
Control
- The hypothalamo-pituitary axis (through the effect of LH on the corpus
luteum).
Progesterone effects:
 Uterus:
o Responsible for the secretory phase in the uterus.
o Inhibits action of oxytocin on the uterus (decreases
excitability, anti-estrogen effect).
 Cervix and vagina:
o Makes mucus in the cervix and vagina more thick.
 Breasts:
o Increases growth of lobules and alveolar tissue in the breast.

 Thermogenic effect:
o Increases the metabolic rate and therefore the temperature
of the body at ovulation, following ovulation and contributes
to the rise during pregnancy.
 Respiration:
o Stimulates the respiratory center (causes hyperventilation
during pregnancy).
o This explains the low plasma PCO2 during pregnancy & the
luteal phase.
 LH:
o Has negative feedback effect on LH.
o Potentiates the inhibitory effect of estrogens on FSH.
 Natriuresis:
o In large doses, it inhibits the action of aldosterone.
Relaxin
- Polypeptide hormone.
- Produced by:
 Corpus luteum
 Placenta
 Uterus
 Mammary glands
 Prostate in men
Relaxin effects
 Facilitates delivery (relaxes the pelvic joints and dilates the cervix).
 Inhibits uterine contractions.
 Contributes to development of the mammary glands.
 In men: maintains sperm motility and facilitates fertilization.

Inhibin
- Inhibin is a peptide hormone secreted by the gonads in both males and
females (Sertoli cells in the testes of males and granulosa cells in the
ovaries of females). It is also secrted by the placenta and other organs.
- It consists of an α and β subunits linked by disulfide bonds.
- Two forms of inhibin exist in humans (A & B), differ in their β subunits,
but their alpha subunits are identical.
- In both females and males, inhibin inhibits FSH production.
- Measurement of inhibin A in the blood of pregnant women is used as
screeining test for Down syndrome (high result indicates Down syndrome).
Activin
- Activin is a peptide hormone that is partialy similar to inhibin but exerts
an opposite effects (stimulates FSH secretion).
- It contains two β subunit that are identical to either or both β subunits (A
or B) of inhibin, allowing for the formation of three forms of activin: A, AB,
and B.
- It is also produced by the gonads, placenta and other organs in the body.
Terms used to describe menstrual abnormalities:

Primary amenorrhea:
= Absence of menstrual bleeding (bleeding never occurred).
- Example: chromosomal abnormalities "Turner syndrome."
Secondary amenorrhea:
= Absence of menstrual bleeding after being started normally for some
time.
- Example: Pregnancy, emotional stress, systemic diseases &
abnormalities of the hypothalamus, pituitary or the ovaries.

Dysmenorrhea:
= Painful menstruation; caused by accumulation of prostaglandins in the
uterus.
Hypomenorrhea:
= Scanty menstrual bleeding.
Menorrhagia:
= Excessive menstrual bleeding.
Metrorrhagia:
= Bleeding from the uterus between periods
FERTILIZATION, IMPLANTATION & PREGNANCY

FERTILIZATION
- The sperms take 0.5-1 hour to reach the ovum (in stage of 2ary oocyte)
at the uterine tube.
- The ovum remains viable for about 3 days; however, it is fertilizable for
shorter period. On the other hand, sperms are viable for about 3 days
(sometimes up to 5 days).
- That is why the possibility of fertilization is highest with coitus at or one to
two days before ovulation.
- Fertilization occurs at the outer portion of the uterine tubes "the ampulla".
- Before fertilization, sperms complete their maturation at the isthmus of
the uterine tubes "capacitation".
- About 50-100 sperms reach the ovum; however, one of these fertilizes
the ovum as follows:
 Chemoattraction of the sperm to the ovum (by chemicals released
by the ovum)
 Adherence to the zona pellucida (by the sperm protein fertilin)

 Penetration of the zona pellucida & acrosomal reaction (release of
enzymes in the acrosome to facilitate penetration through the zona
pellucida).
 Adherence of the sperm head to the cell membrane of the ovum
and release of its nucleus into the cytoplasm of the ovum.
- After fertilization, the fertilized ovum (blastocyst) takes about 3 days to
reach the uterus.
IMPLANTATION
- When the blastocyst reaches the uterus, it becomes surrounded by two
types of trophoblasts:
 Syncytiotrophoblast
o Multinucleated mass with no cell boundaries
o Erodes the endometrium to allow embedding of the blastocyst
"implantation"
o Release the hormones hCG & hCS (see below)
 Cytorophoblasts
o The inner layer of the trophoblasts (towards the embryo).
o Serve to anchor the embryonic placenta (chorion) to maternal
endometrium.
- The usual site of implantation is the dorsal wall of the uterus; however,
there are abnormal sites of implantation. These include: The uterine tube,
other sites within the uterus and rarely the abdomen (extra-uterine
pregnancy).
Human chrionic gonadotropin "hCG"

- The hormone hCG is a glycoprotein, similar in structure to TSH, LH &
FSH (all these hormones are glycoproteins consisting of two subunits:

alpha and β; they have the same α subunit but the β is different; it is the β
subunit that determines the activity of each of these hormone).
- hCG is released by the syncytiotrophoblast to maintain the corpus luteum
(luteinizing & luteotropic); therefore the corpus leuteum continues its
release of estrogens, progesterone and relaxin to maintain pregnancy.
- After 6 weeks, the placenta takes over the release of estrogen,
progesterone and relaxin; however, the corpus luteum remains functioning
to the end of pregnancy.
- hCG appears in blood after 6 days of implantation; and in urine after 14
days of implantation.
- Its detection indicates pregnancy (= the basis of pregnancy test).
However, it is also detected in patients suffering form some GIT cancers
(= regarded as a tumor marker).
Human chorionic somatomammotropin "hCS"

- The hormone hCS is a protein, similar in structure to GH and prolactin.
- It is produced by the syncytiotrophblasts.
- It is found mainly in maternal blood (not fetal blood).
- Its effects include:
 Promotion of growth (instead of GH which is not increased during
pregnancy).
 Stimulation of milk production (lactogenic); for this reason, it is used
to be called human placental lactogen "hPL".
 Reduction of glucose utilization by the mother (to spare it for the
use of the fetus).
 Lipolysis (to provide the mother with FFAs as another source of
energy).
 Retention of electrolytes (nitrogen, potassium, calcium …).

Functions of the placenta
- Transfer function
 The placenta transfers oxygen, carbon dioxide, glucose, minerals &
IgG antibodies.
- Filtration of toxic substances
 The placenta filters out toxic substances and prevent their passage
into fetal blood; however, certain chemicals and viruses cross the
placenta and cause fetal damage.
- Endocrine function
 The placenta synthesizes the following hormones: hCG, hCS,
progesterone, estrogen (oestriol) relaxin, inhibin and others (GnRH,
CRH, endorphins, MSH, leptin, prolactin …).
Remember that: Estrogen (oestriol), is formed from androgens produced
by fetal liver and adrenal gland; on the other hand, cholesterol metabolites
formed in the placenta are converted to cortisol in the adrenal gland of the
fetus; this is known as "the feto-placental unit").
MATERNAL RESPONSES TO PREGNANCY

- Physiological and anatomical changes develop in many organs during
the course of pregnancy. These changes are due to:
o The metabolic demands of the fetus
o Hormones of pregnancy (particularly progesterone and estrogen)
o The mechanical pressure from the expanding uterus
Changes in body fluids and electrolytes
- There is marked retention of fluids and electrolytes due to:
o Growth of tissues
o Hormones of pregnancy (estrogen)
o Activation of the renin-angiotensin- aldosterone system

Changes in the blood
- The blood volume increases progressively from the 6-8 weeks of
gestation to reach a maximum at approximately 32-34 weeks. The
increase is due to:
o Increased plasma volume (by 40-50%)
o Increased red blood cell mass (by 20-30%)
- The increase in plasma volume is elatively greater than the increase in
red blood cell mass; this causes hemodilution (reduction in the
concentration of hemoglobin, PCV and red blood cell count).
- For this reason, anemia of pregnancy is diagnosed when hemoglobin
concentration becomes lower than 12 g/dL.
- This is usually prevented by adequate nutrition and by taking iron and
folic acid supplementation.
- Other changes in the blood:
o Leukocytes are variable during gestation, but usually normal
o Platelets are increased
o Clotting factors are increased
Note: The blood loss during delivery is compensated by the blood
released by the contracting uterus.
Changes in the cardiovascular system
- Stroke volume: increased (up to 35%)
- Heart rate: increased (up to 15%)
- Cardiac output: increased (more than 8 L/min at term and even higher in
the immediate postpartum period)
- Peripheral resistance: decreased due to skin vasodilatation for heat loss
- Systolic blood opressure: increased due to increased cardiac output
- Diastolic blood pressure: decreased due to decreased peripheral
resistance

- Pulse pressure: increased due to increased systolic and decreased
diastolic blood pressure
Note: From mid-pregnancy, when a pregnant lady lies supine, the
enlarged uterus compresses the abdominal veins. This compression
causes:
o Reduction in venous return followed by reduction in the cardiac output
o Distension of veins & lower limb edema (in some women)
Changes in the respiratory system
- Respiratory mucosa: swelling of mucosa and engorgement of capillaries
due to hormonal changes and increasd blood flow
- Lung volumes and capacities: reduced by the upward displacement of
the diaphragm which is caused by the enlarged uterus.
- Minute ventilation: increased progressively to reach about 50% above
normal levels around the second trimester. This increase is due to:
o Increaed tidal volume (up to 40%)
o Increased respiratory rate (up to 15%, i.e. 2-3 breaths/minute)
- Remember that hyperventilation decreases alveolar and arterial PCO2
and progesterone is partly responsible for this hyperventilation.
Changes in the gastro-intestinal system
- The stomach & intestine: are displaced by the growing uterus.
- Reflux esophagitis: due to increased intragastric pressure caused by
mechanical effect of the uterus and relaxation of the lower esophageal
sphincter.
Changes in the renal system
- Renal blood flow: increased progressively (by up to 50-60% at term) due
to increased blood volume and cardiac output.
- GFR: increased progressively (by up to 50-60% at term) due to increased
renal blood flow.

- Blood urea and serum creatinine: decreased by up to 40%.
- Glucosuria: loss of glucose in urine may occur because:
o During pregnancy the renal threshold for glucose is lower (<180 mg/dL)
o The high GFR causes filtration of high amount of glucose that may
overwhelm the ability of the renal tubules to reabsorb glucose.
- Loss of amino acids and water-soluble vitamins in urine because of the
high GFR.
- Plasma osmolarity: decreased due to the hemodilution.
Changes in metabolism
o Carbohydrate metabolism:
- Characterized by increased glucose utilization during early weeks of
pregnancy followed by decreased utilization in the second half of
pregnancy.
- The early higher utilization is associated with higher response of insulin
to glucose whereas the later lower utilization is associated with higher
insulin level with resistance to insulin effects. This develops due to the
hormones hCS, cortisol and glucagon.
o Protein metabolism: Anabolism due to the placental hormones. The net
gain of protein throughout pregnancy is about 1 kg.
o Fat metabolism: Anabolism in the early stages of pregnancy (to store
energy). The mother stores about 4 kg of fat in the subcutaneous
tissue by the end of pregnancy.
- Note: Total weight gain during pregnancy should be about 11 to 15 kg in
normal women, with normal body mass index (in form of protein, fat, body
fluids, electrolytes and additional tissues “breast, placenta and fetal
tissues”).
- Inadequate weight gain during pregnancy is associated with fetal
abnormalities (e.g. intrauterine growth retardation and low birth weight).

1- LH is:
a. A protein
b. Not present in males
c. Inhibits ovulation
d. Increased in females after menopause
e. Not needed for spermatogenesis
2- Turner syndrome is characterized by:
a. Gynecomastia
b. Male genitalia
c. Absent ovaries
d. Tall stature
e. Mental retardation
3- Most of the seminal fluid is provided by:
a. Prostate
b. Seminal vesicles
c. Cowper’s glands
d. Epididymis
e. Ejaculatory ducts
4- Which of the following hormones is expected to rise following
ovulation:
a. LH
b. FSH
c. Estrogen
d. Progesterone
e. hCG
5- During pregnancy, the corpus luteum:
a. Is known as the corpus albicans
b. Is controlled by the placenta
c. Is essential for maintenance of pregnancy
d. Degenerates during the second trimester
e. Responds to both FSH and LH
6- Normal spermatogenesis requires the following cells:
a. Sertoli cells, Germ cells and acidophils of the pituitary
b. Leydig cells, Germ cells and Chromophobes of the pituitary
c. Sertoli cells, Leydig cells and Basophils of the pituitary
d. Germ cells, Leydig cells and stem cells of the bone marrow
e. Cutaneous cells, Sertoli cells and neural cells in the hypothalamus
7- The corpus luteum of pregnancy:
a. Is under control of LH
b. Is formed only from theca interna cells
c. Produces progesterone but not estrogen
d. Degenerate as soon as the fertilized ovum is implanted
e. Requires human chorionic gonadotrophin

8- Normal spermatogenesis requires:
a. A peak of LH
b. FSH and testosterone
c. A temperature equal to body temperature
d. Low potassium in seminal fluid
e. 120 days for development of sperms
9- During the menstrual cycle, progesterone is responsible for:
a. Proliferative phase in the uterus
b. Thick mucus in the cervix
c. Ovulation
d. LH peak during mid-cycle
e. Ductular growth in the breast
10- Ovulation:
a. Normally occurs 14 days following uterine bleeding
b. Immediately occurs following LH surge
c. Is usually associated with a central abdominal pain
d. Is due to rupture of the corpus luteum
e. Leads to a rise in the body temperature
11- Home-use Kits for determining a woman's pregnancy depends on
detection of this hormone in her blood or urine:
a. FSH
b. Progesterone
c. Estradiol
d. hCG
e. LH
12- Concerning spermatogenesis, which of the following is correct:
a. Sperm production is cyclic
b. Continuous release of GnRH is essential for spermatogenesis
c. Sertoli cells are needed for mitotic and meiotic activity of germ cells
d. FSH acts on Leydig cells to stimulate release of testosterone
e. LH acts on Sertoli cells to stimulate release androgen biding protein
13- During 2nd and 3rd trimester of pregnancy, the primary source of
estrogen and progesterone is the:
a. Corpus luteum
b. Granulosa and theca cells in ovaries
c. Placenta
d. Adrenal cortex
e. Pituitary gland
14- Which of the following statements about estrogen is not true:
a. Interacts with intracellular protein receptors
b. Increases synthesis of thyroid binding protein
c. Decreases uterine contractions
d. Decreases FSH secretion
e. Is released from the testes
15- Testosterone is not:
a. Produced during intra-uterine life

b. An anabolic hormone
c. Mostly protein bound
d. Inhibited directly by inhibin
e. Inhibitory to LH
16- In a normal menstrual cycle:
a. High estrogen maintains the corpus luteum
b. Progesterone is highest during early days of menstrual cycle
c. LH peak is preceded by estrogen peak
d. Ovulation depends on FSH surge
e. The life span of corpus luteum determines duration of the cycle
17- Which of the followings is NOT secreted by Sertoli cells:
a. Androgen binding protein
b. Testosterone
c. Mullerian inhibitory substance
d. Inhibin
e. Estrogens
18- Concerning spermatogenesis:
a- Testosterone is not essential
b- The secondary spermatocyte contains 23 chromosomes
c- FSH has no role
d- The process takes 74 hours
e- Involves division of Sertoli cells to form sperms
19- Progesterone:
a- Acts on cell membrane receptors
b- Stimulates the respiratory centre to increase respiration
c- Acts directly on the hypothalamus to activate the temperature centre
d- Promotes proliferative changes in the endometrium
e- Stimulates development of ducts in the breast
20- Human chorionic somatomammotropin (hCS):
a- Is a steroid hormone
b- Prevents glucose utilization by the fetus
c- Causes lipolysis
d- Is secreted by the granulosa cells
e- Is detected by pregnancy test to diagnose pregnancy
21- Maternal responses to pregnancy do not include:
a- Increased GFR
b- Increased volume of plasma
c- Increased cardiac output
d- Increased lung volumes and capacities
e- Decreased erythropoeisis
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
d c b d b c e b b e d
12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
c c c d c b b b c d

CHAPTER (12)
THE SENSORY SYSTEM
STRUCTURE & FUNCTION
- The sensory system is the part of the nervous system responsible for
detection, transmission, and processing of sensory information about
events occurring at the internal and the external environments.
- It consists of: Receptors, Afferents, Tracts & Sensory cortex.
Fig 12.1: The sensory system
- The sensory information obtained after arrival of action potentials to

the brain include:
o Type of sensation (= modality)
o Site of stimulation (= locality)
o Strength of stimulation (= intensity)
o Duration of stimulation
- Generally, a sensation carried by a somatic afferent neuron is known as
a somatic sensation whereas a sensation carried by an autonomic afferent
neuron is known as a visceral sensation.

- The autonomic afferent neurons carry information that does not reach
consciousness. Examples include information about lung inflation, blood
pressure, blood pH, and ECF volume.
- Some somatic afferent neurons also carry information that does not
reach consciousness. These include information about muscle length from
the muscle spindle and muscle tension from the Golgi tendon organ (see
the motor system).
A- SENSORY RECEPTORS
- Sensory receptors are specialized structures found at the peripheral
ends of afferent neurons.
- They respond to sufficient stimulation by generating action potentials that
are transmitted through afferent neurons towards the brain.
- The stimuli that activate the sensory receptors include various forms of
energy (mechanical, chemical …); therefore, receptors act as transducers
that convert energy into action potentials.
Classifications of receptors
Traditional classification:
1. Special senses (Receptors for hearing, vision, smell, taste, rotational
and linear acceleration)
2. Cutaneous senses (Receptors in the skin for touch-pressure, cold,
warmth and pain).
3. Visceral senses (Receptors in the internal structures)
According to the site of event:
1. Teleceptors (Detect distant events, e.g. visual receptors)
2. Exteroceptors (Detect events at the immediate external environment,
e.g. touch receptors)
3. Interoceptors (Detect events at the internal environment, e.g.
chemoreceptors)
4. Proprioceptors (Detect changes in position of the body. Found at joints,
tendons and ligaments)
According to the type of stimulus (energy):
 Mechanoreceptors (Stimulated by mechanical energy, e.g. touch and
pressure receptors)
 Thermoreceptors (Stimulated by thermal energy, e.g. warm and cold
receptors)
 Nociceptors (These are pain receptors, stimulated by any form of
energy that causes tissue damage)
 Chemoreceptors (Stimulated by chemical changes in body fluids e.g
hypoxia, hypercapnia and acidosis)
 Baroreceptors (Stimulated by elevation of blood pressure)
According to the structure of the receptor:
1. Free nerve endings
- E.g. pain and temperature receptors
- Some of the receptors for other modalities of sensation may be free
nerve endings
2. Encapsulated
- E.g. Pacinian corpuscles for touch and Meissner’s corpuscles for
vibration
Remember that: Pacinian corpuscles are specialized for touch but not
for pressure, which is sustained touch; this is because they adapt
rapidly and dissipate pressure
3. Expanded tip
- Slowly adapting receptors. E.g. Merkel’s discs and Ruffini endings
4. Sense organs
- When the receptors combine with non-neural cells, they form sense
organs. E.g. organ of Corti for hearing & otolithic organ for posture

According to the degree of adaptation:
- Receptors can be rapidly adapting, slowly adapting, or non-adapting (see
properties of receptors).
Fig 12.2: Types of sensory receptors
Properties of receptors
- Receptors are characterized by three characteristics: Adequate stimulus,
excitability and adaptation.
1- Adequate Stimulus
- Each type of receptor is most sensitive to a specific form of energy called
its adequate stimulus. For example:
o Adequate stimulus for touch receptors = Mechanical energy
o Adequate stimulus for temperature receptors = Thermal energy
o Adequate stimulus for visual receptors = Electromagnetic energy
- Note:
o Adequate stimulus for pain is not specific because any form of
energy can cause pain if it causes tissue damage.
o Other types of receptors may respond to stimuli other than their
adequate stimuli, but in a much higher threshold.

2- Excitability of receptors
- Stimulation of the receptor results in Receptor potential (or Generator
potential).
- This may occur due to either:
o Sodium influx
o Calcium influx
o Inhibition of the Na+/K+ pump
- Unlike action potentials, receptor potentials are:
o Localized (not propagated along axons of neurons as action
potentials).
o Graded (increase or decrease in amplitude depending on strength
of stimuli; i.e. their excitability is not all or none as in action
potentials).
o Can be summated (can be added together to reach sufficient
magnitude and cause action potential).
3- Adaptation of receptors
- Results from sustained stimulation of receptors with constant strength.
- This causes decrease in the frequency of action potential generated at
some receptors, especially the encapsulated receptors (e.g. Pacinian
corpuscles).
- Adaptation can be explained as follows:
The capsule that surrounds the terminal part of the axon undergoes
some alterations in its shape due to the sustained stimulation; this
decreases pressure exerted by that capsule on the axon and
therefore decreases frequency of firing.
- Accordingly, receptors can be classified as:
o Rapidly adapting or phasic receptors: e.g. touch receptors
(Pacinian corpuscles)

o Slowly adapting receptors or tonic receptors: e.g proprioceptors
(Ruffini endings)
o Intermediately adapting receptors: e.g. temperature receptors (free
nerve endings)
o Non-adapting receptors: e.g. pain receptors (free nerve endings)
B- AFFERENTS
- The afferent neurons (sensory neurons) carry nerve impulses from the
receptors or sense organs towards the central nervous system.
- There are two types of afferent neurons:
o Somatic afferent neurons
- Conduct impulses from receptors in the skin, skeletal muscles,
tendons, joints, and parietal layers of the pleura and the peritoneum.
- They enter the spinal cord through the dorsal roots & their cell bodies
are located in the dorsal root ganglia.
o Visceral “or autonomic” afferent neurons
- Conduct impulses from smooth and cardiac muscles and from
baroreceptors, chemoreceptors, volume receptors, and taste buds.
- They enter the spinal cord through the dorsal roots & their cell bodies
are located in the dorsal root ganglia or the equivalent ganglia for the
cranial nerves VII, IX & X.
- When they reach the brain stem, they make connections with the
nucleus of tractus solitarius (NTS) which integrate all visceral
information. However, visceral pain ascends in the spinothalamic tract
like somatic pain to reach the sensory cortex.
- Afferent neurons, according to their degree of myelination, can be:
o Thick myelinated (Type A)
 Rapidly conducting neurons

 Further divided into:
 A alpha (its conduction velocity= 70-120 m/s)
 A beta (its conduction velocity= 30-70 m/s)
 A gamma (its conduction velocity= 15-30 m/s)
 A delta (its conduction velocity= 12-30 m/s)
o Thin myelinated (Type B)
 Less rapidly conducting neurons
 Its conduction velocity= 3-15 m/s
o Non myelinated (Type C)
 Slowly conducting neurons
 Its conduction velocity= 0.5 -2 m/s
- Generally, specialized receptors (for proprioception & touch) send their
impulses via type Aβ fibers whereas free nerve endings (for pain and
visceral sensation) send their impulses via type A delta or C fibers.
C- SENSORY TRACTS
- These are two types of ascending pathways in the white matter of the
spinal cord:
 Dorsal column tract (DCT) or (Lemniscal tract)
 Spinothalamic tract (STT) or (Anterolateral tract)
1- Dorsal column tract (DCT) or (Lemniscal tract)
- Carries: Fine touch & pressure, vibration, position sense & two point
discrimination.
- Afferents are type A beta fibers.
2- Spinothalamic tract (STT) or (Anterolateral tract)
- Carries: Crude touch, temperature (hot and cold), pain, sexual sensation
and itching sensation.
- Afferents are type A delta or C fibers.

Pathways:
- Each tract consists of 3 orders of neurons as follows:
 The dorsal column tract:
 1st order neurons:
- Cell bodies in dorsal root ganglia.
- Axons pass from the receptors to the spinal cord. Then they ascend
in the dorsal white matter of the spinal cord (dorsal column) until they
reach the medulla where they synapse with second order neurons.
 Second order neurons:
- Cell bodies in the Gracile and Cuneate nuclei in the medulla.
- Axons cross to the opposite side and ascend in the medial lemniscus
until they reach the specific nuclei of the thalamus (the ventro-posterior
nuclei of the thalamus “VPNT”) where they synapse with third order
neurons.
 Third order neurons:
- Cell bodies in the thalamus (VPNT). Axons ascend in the sensory
radiation to reach the sensory cortex (in the post-central gyrus).
 The spinothalamic tract:
 1st order neurons:
- Cell bodies in dorsal root ganglia.
- Axons pass from the receptors to the spinal cord. Then they enter the
gray matter in the posterior horn of the spinal cord where they synapse
with second order neurons.
 Second order neurons:
- Cell bodies in the posterior horn.
- Axons cross to the opposite side in front to the central canal of the
spinal cord and ascend in the white matter until they reach the specific
nuclei of the thalamus (the VPNT).

 Third order neurons:
- Cell bodies in the thalamus (VPNT). Axons ascend in the sensory
radiation to reach the sensory cortex (in the post-central gyrus).
Note: In the STT, axons of second order neurons cross to the opposite
side in front of the central canal of the spinal cord. That is why these
neurons are damaged in Syringomyelia whereas neurons of the DCT
remain intact.
- Sensory signs of Syringomyelia include loss of pain and temperature
sensations, but intact touch, vibration and position sensations. This
characteristic sign is known as “dissociated sensory loss”). Whereas
damage to motor neurons in syringomyelia results in paralysis or paresis.
Fig 12.3: The sensory tracts

Note
- The gray matter of the spinal cord that forms the posterior horn is sub-
divided into 6 laminae (from I to VI). Other laminae include lamina VII that
lies in the intermediate zone, lamina VIII that lies in the anterior horn (for
interneurons), lamina IX lies in the anterior horn (for alpha and gamma
motor neurons) and lamina X for neurons surrounding the central canal.
- Synapses of the first order neurons (of the spinothalamic tract with the
second order neurons at these laminae are distributed as follows:
 Type C afferents (carrying pain & temperature), synapse at laminae
I & II
 Type Aδ afferents (carrying pain & cold), synapse at laminae I & IV
 Type Aδ afferents (carrying mechanoreceptor sensation) synapse
at III & IV
 Type Aβ afferents (carrying mechanoreceptor sensation) at laminae
III, IV, V & VI
Remember that mechanoreceptor sensation is mainly carried through Aβ
afferents; however, type Aδ & C afferents (mainly for pain and
temperature) carry some mechanoreceptor sensation.
Fig 12.4: Laminae of the gray matter in the spinal cord

- Within the spinothalamic tract (antero-lateral tract), touch fibers mainly
ascend in the anterior part whereas pain fibers mainly ascend in the lateral
part.
- Within the spinothalamic tract, fibers carrying sensation from the lower
parts of the body (lower limbs and buttocks) are pushed laterally by the
fibers which enter the spinal cord at higher segments, as they cross the
midline and ascend. In other wards, fibers of the spinothalamic can be
classified (from lateral to medial) as sacral, lumbar, thoracic, and cervical
fibers. For this reason, extramedullary tumors (tumors arising outside the
spinal cord) compress the spinal cord from outside and present with loss
of pain and temperature sensation in the buttocks and lower limbs
whereas intrameduulary tumors (tumors arising from inside the spinal
cord) present with sensory loss at a higher level.
- Fibers of the dorsal column tract are similarly distributed, but with the
sacral fibers medially and the upper fibers laterally.
Fig 12.5: Distribution of fibers within the sensory tracts

D- SENSORY CORTEX
- The site that receives sensory tracts. There are two sensory areas:
o Area I or primary sensory area (in the postcentral gyrus).
o Area II or secondary sensory area (in the wall of Sylvian fissure).
Fig 12.6: The sensory cortex
- Function of the sensory cortex: Perception and discrimination between

modalities, localities, intensities, and durations of different sensations.
- All parts of the body are well represented in the postcentral gyrus, with
legs at the top and head at the bottom of the gyrus.
- The size of representation of each part is proportional to the number of
its receptors (therefore the cortical areas for the lips, tongue and hands
are very large, compared with the cortical areas for the trunk and the
back).
- The right postcentral gyrus contains a map for the left half of the body
and vice versa.
- Representation at area II is not as detailed as in area I.

Coding of sensory information
- All types of sensation reach the brain in form of action potentials. In spite
of that, the brain can discriminate four features for each sensation:
o Type of sensation (modality)
o Site of sensation (locality)
o Strength of sensation (intensity)
o Duration of sensation
- The information processing in the brain that results in discrimination of
the above four features is known as “coding of sensory information.”
- How can the brain discriminate each feature is explained as follows:
1- Modality (= doctrine of specific nerve energies)
- Each modality of sensation generally has specific adequate stimulus,
specific receptor, specific afferent, specific sensory tract, and specific
sensory area in the cerebral cortex to be activated. In other words, the
sensory pathway for each modality (from the receptor to the cortex) is
different from the pathways of other modalities.
- When action potentials of one sensory pathway reach the cerebral
cortex, the sensation perceived is that to which the receptor is specialized
for; even if the stimulation is applied along the pathway, not directly on the
receptor. This principle is known as doctrine of specific nerve energies.
2- Locality (= law of projection)
- To discriminate between different localities of various stimuli, the brain
projects the coming impulses of each stimulus to the site of the receptor;
even if the stimulation is applied along the pathway, not directly on the
receptor. This is known as the law of projection.
- The law of projection explains the phenomenon of “phantom limb” in
which a subject with an amputated limb feels pain at the absent limb; for
example at the big toe of an amputated foot. This occurs due to

stimulation or spontaneous firing of nerve fibers (previously coming from
the big toe) at the site of amputation. To localize the coming impulses, the
brain projects them to the site of the receptors (i.e. the absent big toe).
3- Intensity
- The brain discriminates between different intensities of stimulation
(whether weak, moderate or strong) by variation in the number of
receptors stimulated and frequencies of action potentials generated.
- When these are increased or decreased, the brain interprets that as an
increase or decrease in the intensity of stimulation.
4- Duration
- The brain discriminates the duration of stimulation by determining the
period from the onset of receptor activation to the end of activation (i.e.
from the time of energy gain in the receptor to the time of energy loss).

SENSORY MODALITIES
PAIN
Definition
- Defined as unpleasant sensation produced by stimuli that cause tissue
damage.
- It is associated with both emotional and physical reactions.
- The physical reaction that accompanies pain is regarded as a protective
reflex (e.g. the withdrawal reflex; to get a way from the painful stimulus).
Quality of pain
 Pricking pain:
- Also known as fast or first pain. It occurs immediately following
stimulation, well localized and transmitted through type A (delta) fibers.
 Burning pain:
- Also known as slow or second pain. It develops slowly, not well
localized and transmitted through type C fibers.
Pain receptors
- These are free nerve endings (found in almost all tissues in the body).
- Their adequate stimulus is not specific (any form of energy can cause
pain if it causes tissue damage).
- Tissue damage releases pain-producing substance (PPS or P factor).
This substance stimulates pain receptors to cause pain.
- The nature of PPS is unknown. However, it could be a substance
released from the damaged tissues like K+ ions.
Afferents
 Type A (delta):
o For fast pain (conduction velocity = 12-30 m/s)
o Terminate on laminae I & V
o Release the neurotransmitter glutamate

 Type C:
o For slow pain (conduction velocity = 0.5-2 m/s)
o Usually found on the lateral part of the dorsal roots
o Terminate on laminae I & II
o Release the neurotransmitter substance P
Note: The dorsal horn, especially substantia gelatinosa, which is formed
by lamina II & part of lamina III, is regarded as a gate for pain.
Tract
- Spinothalamic tract (mainly the lateral part)
Sensory cortex
- Pain activates the contra-lateral primary (S1) & the secondary (S2)
sensory areas in the cerebral cortex. It also activates other areas in the
brain like the cingulate gyrus, frontal lobe, insula, and cerebellum (Note
that frontal lobotomy abolishes the emotional reaction to pain).
- The sensory cortex can discriminate intensity and locality of pain; it also
mediates the emotional reaction to pain. However, the modality of pain is
discriminated at a lower level (at or even below the thalamus; that is why
thalamotomy is used sometimes to treat severe pain).
Types of pain
- According to the site of receptors, pain can be classified into 3 types:
cutaneous, deep somatic and visceral pain.
 Cutaneous pain
- Receptors are found in the skin
- Has two types:
 Fast (accurately localized, transmitted through Aδ fibers)
 Slow (not well localized, transmitted through C fibers))
- Not referred and not associated with autonomic stimulation (sweating,
vomiting, tachycardia) or contraction of nearby muscles

 Deep somatic pain
- Receptors are found deep in muscles, joints, bones
- Generally has one type (slow), this is because it is usually transmitted
by type C fibers (little Aδ fibers).
- Not well localized and can be referred
- Associated with autonomic stimulation (sweating, vomiting,
tachycardia)
- Associated with contraction of nearby muscles
 Visceral pain
- Receptors are found in the viscera (small in number)
- Generally has one type (slow), this is because it is usually transmitted
by type C fibers (little Aδ fibers).
- Poorly localized
- Can be referred
- Associated with autonomic disturbances (sweating, vomiting,
tachycardia)
- Associated with spasm of overlying skeletal muscles, making the
abdominal wall rigid. This protects the viscera from external trauma; for
this reason, it is known as “guarding.” It is an important clinical sign in
cases of “acute abdomen”.
Note
- Ischemic pain in muscles is a classical deep somatic pain.
- Here the pain occurs due to tissue damage caused by inadequate blood
supply during exercise and disappears upon rest.
- The low blood supply is caused by partial arterial obstruction (as in
atherosclerosis).
- Examples include angina pectoris (due to myocardial ischemia) &
intermittent claudication (pain in leg muscles due to ischemia).

- Exercise induces pain because the pain producing substance
accumulates (due to tissue damage). However, during rest, the PPS is
washed out and pain disappears.
- When the obstruction is complete (as in myocardial infarction) pain
appears during rest and persists until the tissues become non-viable
(infarcted).
Referred pain
- Pain is felt in another area, not the diseased structure (usually the skin of
the same dermatome “or embryonic segment” from which the diseased
structure was developed).
- It is a feature of deep somatic and visceral pain.
- Occurs according to the dermatomal rule (pain is referred to the skin
supplied by the same dorsal root that supplies the organ).
Common examples:
o Pain originating from the heart= is felt on the skin of inner aspect of
left arm
o Pain originating from the appendix= is felt around the umbilicus
o Pain originating from the diaphragm= is felt on the tip of the
shoulder
o Pain originating from the teeth= is felt on the head
o Pain originating in the kidneys and ureters= is felt in the testicles
Mechanism of referred pain:
- Referred pain can be explained by Convergence & Facilitation theories
Convergence theory:
- Afferents from a diseased viscus and from skin of the same dermatome
converge on the same spinothalmic second order neuron. The brain,
which is used to receive impulses from the skin and not from the viscus,
localizes pain sensation from the viscus to the skin.

Facilitation theory:
- Pain fibers from the skin are always carrying impulses that are normally
not enough to stimulate the second order neuron & cause pain.
- Impulses arising from a diseased viscus are carried through afferents
that give collaterals to the same second order neuron that comes from the
skin; provided that the skin and the viscus were originated from the same
dermatome.
- Through the collaterals, impulses from the viscus facilitate stimulation of
the second order neuron; this gives sensation of pain in the skin and not
the viscus.
Fig 12.7: Mechanisms of referred pain
Central inhibition of pain

- The following mechanisms explain how the perception of pain may be
inhibited within the central nervous system:
 The gate control theory
 The opiate system of the brain
The gate control theory
- The substantia gelatinosa is a gate for pain.
- It opens with pain impulses coming through type C fibers (the 1st order
neuron of spinothalamic tract) and closes with touch impulses coming

through collaterals from type Aβ fibers (the first order neuron of dorsal
column tract).
- Rubbing at or around the painful area in the skin stimulates touch
receptors in that area; this causes closure of the gate (through the Aβ
fibers) and therefore inhibits pain sensation.
The opiate system of the brain
- Morphine, a medication derived from opium, is a highly potent analgesic
drug. It acts on certain receptors within the central nervous system.
- These receptors also respond to morphine-like peptides synthesized
within the body to relieve pain.
- The synthesis of these morphine-like peptides is highly increased during
stress. They are known as opioids and they include:
 Encephalins (found in the hypothalamus, periaqueductal gray
matter, thalamus, limbic system and spinal cord)
 Endorphins (produced by the hypothalamus & the pituitary gland
from the large precursor molecule “pro-opio-melanocortin” which
also gives ACTH)
- The opioid receptors are synthesized within the dorsal root ganglia. Then
they migrate peripherally and centrally to be located at the following sites:
 Peripheral tissues (when inflammation occurs at these tissues, the
opioid receptors respond to opioid peptides released by immune
cells to relieve pain)
 The dorsal horn (this is the site of the gate, here the opioid
receptors respond to opioids to cause presynaptic inhibition of type
C fibers, this inhibits release of substance P and therefore closes
the gate)
 Limbic System (receptors at these sites respond to opioids to give a
sense of well-being)

 Periaqueductal area within the midbrain (the receptors at this site
respond to encephalins to activate descending tracts that release
serotonin to mediate closure of the gate).
- The above mechanisms can explain the following observations:
 Rubbing around injury decreases pain:
o Because rubbing closes the gate by generating touch
impulses that are transmitted through Aβ fibers
 Ignorance of pain during emotional stress as in games and battles:
o Because stress increases production of opioids, which act
centrally to inhibit pain sensation
 Analgesia induced by acupuncture:
o Because acupuncture induces release of opioids (when the
site of analgesia is far from the site of acupuncture)
o Because acupuncture generates touch impulses to close the
gate (when the site of analgesia is near to the site of
acupuncture)
Fig 12.8: Central inhibition of pain (the gate theory)

TOUCH
Receptors
- Receptors for touch and pressure (which is maintained touch) are
specialized, rapidly adapting receptors (e.g. Pacinian corpuscles).
However, some free nerve endings also act as receptors for touch.
- Known as mechanoeceptors because they are stimulated by mechanical
energy.
Afferents
- Type Aβ fibers; however, some Aδ & C fibers transmit touch sensation
from the free nerve endings.
Tracts
- The two sensory tracts are involved in transmission of the two types
touch sensation:
 Fine touch (well localized, low threshold touch) through the dorsal
column tract
 Crude touch (poorly localized, high threshold touch) through the
spino-thalamic tract
Cortex
- The contra lateral sensory cortex (the primary & secondary sensory
areas).
TEMPERATURE
Receptors
- Free nerve endings.
- Cold receptors are more numerous than heat receptors (by 4 to 10
times).
- Known as thermoreceptors because they respond to thermal energy.
- Their stimulation is determined by the temperature of the subcutaneous
tissue.

- Cold receptors respond to 10-38 ºc whereas heat receptors respond to
30-45 ºc.
Afferents
- Type Aδ & C fibers for cold sensation, and type C for heat sensation.
Tracts
- Spino-thalamic tract (mainly the lateral division).
Cortex
areas) and the ipsilateral insular cortex.
PROPRIOCEPTION
Receptors
- Slowly adapting receptors, found in and around the joints (tendons and
ligaments).
Afferents
- Type Aβ fibers.
Tracts
- The dorsal column tract.
Cortex
areas).
- Many fibers go to the cerebellum to give information about position of the
body. Together with the touch sensation and impulses from muscle
spindles and Golgi tendon organs, proprioception gives conscious image
about position of the body in space.
- Damage to the dorsal column tract results in sensory ataxia. However,
ataxia appears when the patient closes his eyes because this eliminates
the compensation of position image created by the visual sensation (= the
basis of Romberg’s sign).

TWO POINT DISCRIMINATION
- The ability to discriminate between two stimuli applied simultaneously
into two different points, close to each other, is known as two-point
discrimination.
- It depends on intact touch sensation (transmitted through the dorsal
column tract) and intact sensory cortex.
- The minimal distance required to discriminate between two points is
larger at the back than at the tip of the fingers. This is related to the higher
density of receptors at the tip of the fingers.
STEREOGNOSIS
- The ability to identify objects by handling, with the eyes closed (e.g. keys,
coins, papers …).
- It depends on intact touch sensation (transmitted through the dorsal
column tract). However, the sensory cortex plays a major role in the
identification.
- Failure to identify objects by handling "astreognosis" is an early sign of
parietal lobe lesions.

1. The receptor potential is:
a. Propagated
b. All or none
c. Perceived as a light sensation
d. Related to intensity of stimulation
e. Only generated in encapsulated receptors
2. Concerning pain sensation:
a. It is transmitted through the dorsal column tract
b. Receptors are encapsulated nerve endings
c. Slow pain is transmitted in C fibres
d. Modality discrimination occurs at the sensory cortex
e. Localization occurs at the level of the thalamus
3. The dorsal column tract carries:
a. Crude touch
b. Pain
c. Vibration sense
d. Temperature sensation
e. Itching sensation
4. Localization of a touch sensation is a function of:
a. Adequate stimulus
b. Encapsulated receptors
c. Sensory cortex
d. Thalamus
e. Spinal cord laminae IV & V
5. Visceral pain is characterized by all the following except:
a. Its receptors are free nerve endings
b. Its localization is a function of the cerebral cortex
c. It is associated with autonomic activation
d. It is associated with contraction of nearby muscles “guarding sign”
e. It is referred to another visceral structure, not the diseased one
6. The intensity of a stimulus is determined by:
a. Type of receptor
b. Type of nerve fibre
c. Type of sensory tract
d. Frequency of action potential
e. Personality of subjects
7. Regarding adaptation of receptors:
a. Depends on type of adequate stimulus applied
b. Occurs at the same rate in different receptors
c. Is due to release of inhibitory neurotransmitters
d. Is due to inactivation of ion channels
e. Never occurs in free nerve endings

8. Sensory ataxia:
a. Results from damage to spinothalamic tract
b. Is associated with negative Romberg’s sign
c. Is characterized by loss of proprioceptive sensation
d. Is a cause of drunken man gait
e. Causes coma when a patient closes his eyes
9. Which of the following receptors are “phasic”:
a. Touch receptors
b. Pain receptors
c. Temperature receptors
d. Chemoreceptors
e. Proprioceptors
10. Hemisection of the right side of the spinal cord results in:
a. Loss of pain on the right side
b. Loss of temperature sense on the same side
c. Loss of vibration sense on the opposite side
d. Intact touch on the same side
e. Loss of position sense on the right side
11. Which of the following neurons has the highest conduction velocity:
a. Type A delta
b. Type B
c. Type Ib
d. Type A alpha
e. Type III
12. The first pain:
a. Receptors are Pacinian corpuscles
b. Is carried by type C fibres
c. Is transmitted in the lateral part of the spinothalamic tract
d. Is usually visceral
e. Is a burning sensation
13. Concerning the deep somatic pain, which of the following is not true:
a. Is associated with sweating and vomiting
b. Is associated with contraction of nearby skeletal muscles
c. Is well localized
d. Is carried through type C afferents neurons
e. Can be referred
14. Which of the following receptors is non-adaptive:
a. Touch receptor
b. Vibration receptors
c. Pain receptor
d. The muscle spindle
e. Pressure receptors
15. Which of the following statements about sensory modalities is not true:
a. Pain receptors are naked nerve endings
b. Slowly adaptive receptors are protective
c. Teleceptors convey information about distant events

d. Pain is inhibited by stimulation of paraventricular area in the brain
stem
e. First order neurons carrying vibration sense cross to opposite side in
the spinal cord
16. Pacinian corpuscles:
a. Are only present in the skin
b. Are slowly adaptive
c. Their afferents synapse with second order neurons in the medulla
oblongata
d. Are stimulated by all types of energy
e. Their afferents synapse with second order neurons in substantia
gelatinosa
17. Concerning temperature sensation, which of the following is not true:
a. Receptors are free nerve endings
b. Cold spots in the skin are 4-10 times higher than warm spots
c. Afferents for cold receptors are type A delta and C fibres
d. Pathway is the ventral spinothalamic tract
e. Afferents for warm receptors are type C fibres only
18. Concerning position sense, which of the following is not true:
a. Depends on impulses coming from receptors in and around joints
b. Receptors are probably Pacinian corpuscles
c. Receptors are known as muscle spindles
d. A large proportion goes to the cerebellum
e. Lesions results in sensory ataxia
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
d c c c e d d c a e d
12. 13. 14. 15. 16. 17. 18.
c c c e c d c

CHAPTER (13)
THE SPECIAL SENSES
VISION
THE EYES
- The eyes are complex sense organs specialized for vision.
- Each eye consists of the following structures:
1- The sclera
- The outer opaque protective layer of the eye.
- Contains collagen and elastic fibers (usually whitish in color).
- It maintains the shape of the globe and provides insertions for the
extraocular muscles.
Fig 13.1: Structure of the eye

2- The cornea
- The transparent anterior part of the sclera.
- Allows light rays to enter the eye.
- Together with the lens, it refracts light to be focused on the retina (its
contribution to light refraction in the eye is higher than that of the lens).
- It has no blood supply. It gets oxygen directly from the air; that is why
contact lenses reduce oxygen supply to the cornea.
3- The choroid
- It is part of the uveal tract which forms the middle layer of the eye.
- The uveal tract lies between the retina and the sclera. It is formed by
the choroid, ciliary body, iris and the area located near the attachment
of the iris and sclera (called pars plana).
- Contains blood vessels that supply the eyeball structures.
- Contains darkly colored melanin pigments to prevent reflections of
light within the eye.
4- The retina
- The inner layer which lines the posterior two thirds of the choroid.
- Contains the visual receptors (rods and cons) that respond to light.
- The output from the retina (in form of action potentials) passes
through the optic nerve and other structures of the visual pathway to
give perception of light.
- Characterized by presence of an area that lacks visual receptors
called the optic disc (or the blind spot). It lies 3 mm medial to and
slightly above the posterior pole of the eye. It is the area where the
optic nerve leaves the eye and the blood vessels enter it.
- Temporal to the optic disc there is another area known as the macula.
- At the center of the macula is the fovea centralis; the area with the
highest visual acuity (contains cons only).

Fig 13.2: The retina
5- The ciliary body

- The anterior part of the choroid.
- Consists of the ciliary muscle which adjusts the convexity of the lens
and the ciliary processes which are the inward folding of the choroid
layers.
- It participates in accommodation (see below), produces the aqueous
humor and maintains the lens zonules.
6- The lens
- The transparent biconvex structure that refracts light rays to the
retina.
- The ciliary muscle increases or decreases its convexity to focus the
eye on objects at different distances from it (= accommodation).
7- The suspensory ligament (zonule)
- The ligament that holds the lens in its position.
- It is attached to the ciliary body.
8- The iris
- The pigmented part of the eye.
- It contains two types of muscle that adjust the diameter of the pupil to
control the amount of light reaching the retina.

- The muscles are:
 Dilator pupillae: contains radial muscle fibers that cause
pupillary dilatation in response to sympathetic stimulation.
 Sphinctor pupillae: contains concentric muscle fibers that cause
pupillary constriction in response to parasympathetic stimulation.
9- Vitreous humor
- The clear gelatinous material that fills the space between the lens and
the retina. Consists of water, salts, sugars and collagen fibers.
- It provides structural support to the eyeball and allows passage of
light rays to the rtina.
10- Aqueous humor
- The clear liquid that fills the space between the lens and the cornea.
- Provides nutrients to the avascular parts of the eye (the lens and
cornea) and eliminates their waste products.
- Its pressure maintains the normal convexity of the cornea.
- Produced by diffusion and active transport from plasma in the ciliary
body and reabsorbed into a venous system “the canal of Schlemm”
(which is found in the anterior chamber at the junction between the iris
and the cornea). Increased production of the aqueous humor or
decreased drainage through the canal leads to increased intraocular
pressure (normal range 10-20 mmHg). This is especially serious in
patients with glaucoma. Here, the high intraocular pressure aggravates
the damage to the optic nerve causing severe visual loss and
eventually complete blindness.
- For this reason, the intraocular pressure should be lowered in these
patients by β blockers or carbonic anhydrase inhibitors (both decrease
aqueous humor production) or by cholinergic agonists (increase
aqueous humor drainage).

The retinal cells
- In addition to the rods and cons, the retina consists of many types of
neuronal cells arranged in 10 layers. These neuronal cells include: Bipolar
cells, ganglion cells, horizontal cells and amacrine cells.
- Light rays pass through these cells before reaching the rods and cones
which are found at the back of the eye, next to the choroid. The rods and
cones converge on bipolar cells and these converge on ganglion cells.
- The axons of the ganglion cells form optic nerve. The horizontal cells
make connections between the rods and cones to form the outer plexiform
layer. The amacrine cells make connections between the ganglion cells to
form the inner plexiform layer.
- The rods are about 120 millions in each eye; they are specialized for
dark vision whereas the cones are about 6 millions in each eye; they are
specialized for day vision & color vision.
Fig 13.3: The retinal cells
The visual pathway

- Light rays are refracted by the cornea and lens to be focused on the
retina. This results in generation of action potentials in the rods and cones.
- Action potentials are transmitted through the visual pathway to the
cerebral cortex to give the sensation of vision.
- The visual pathway consists of the following structures:
 Optic nerve (Each nerve carries both nasal fibers (from the medial side
of each eye) and temporal fibers (from the lateral side of each eye).
 Optic chiasma (here the two optic nerves meet and pass to the optic
tract. The nasal fibers in each optic nerve cross to the other side
whereas the temporal fibers pass uncrossed on the same side).
 Optic tract (each optic tract carries temporal fibers from the same side
and nasal fibers from the other side).
 Lateral geniculate body (a relay station in the thalamus).
 Optic radiation (where the visual fibers travel through the deep white
matter of the cortex “as the geniculocalcrine tract” towards the occipital
lobe).
 The primary visual cortex in the occipital lobe (= area 17, at the sides
of the calcarine fissure).
Fig 13.4: The visual pathway

Interruption of the visual pathway (= Visual field defects)
- The visual field is the total area in which objects can be seen while the
eye is focused on a central point. It is divided into nasal and temporal
fields.
- Because of the spherical shape of the eye globe:
 Optic nerve fibers originating from the nasal half of the retina
look to the temporal field of vision.
 Optic nerve fibers originating from the temporal half of the retina
look to the nasal field of vision.
 Optic nerve fibers originating from the upper half of the retina
look to the lower field of vision.
 Optic nerve fibers originating from the lower half of the retina
look to the upper field of vision.
Fig 13.5: The retina & the visual field
- Lesions occurring at different locations of the visual pathway cause

different forms of visual field defects.
- The defects are either uniocular or binocular.
- Uniocular field defects are caused by lesions at the optic nerve. Here the
defects occur at the same eye.
- Binocular field defects are caused by lesions at or behind the optic
chiasma. Here the defects occur in both eyes.

- Examples of visual field defects (A-E) can be studied from this figure:
Fig 13.6: The visual field defects
 Optic nerve lesions (A):

- Cause complete unilateral blindness on the same side.
- Partial optic nerve damage may cause scotomas (areas of reduced

vision):

 Optic chiasma lesions (B):
- Cause bitemporal hemianopia (i.e. heteronymous hemianopia).
 Optic tract lesions (C):

- Cause homonymous hemianopia.
 Optic radiation lesions (D):

- Cause homonymous quadrantopia.
 Occipital lobe lesions (E):

- Causes cortical blindness. (Note the macular sparing!).

The light reflex
This reflex occurs directly and indirectly.
 Direct light reflex:
- When light is shone on an eye, its pupil constricts
 Indirect (Consensual) light reflex
- When light is shone on an eye, the pupil of the other eye constricts
Fig 13.7: The light reflex
The pathway of the light reflex:

–The first order neuron passes through:
 Optic nerve
 Optic chiasma
 Optic tract
 Superior colliculus and then pretectal nucleus in the midbrain
–The second order neuron:
 From the pretectal nucleus to oculomotor nerve nucleus “Edinger
Westphal nucleus” (on both sides)
–The third order neuron:
 Oculomotor nerves (on both sides) to the ciliary ganglion (on both
sides)
–The fourth order neuron:
 From the ciliary ganglion to the ciliary body.
Note: The pathway on the same side mediates the direct light reflex
whereas that on the other side mediates the consentual light reflex.

The near response
- Light rays are refracted by the cornea and lens to be focused on the
retina.
- On looking to a distant object (more than 6 meters):
–light rays are coming in parallel.
–ciliary muscle is relaxed & the lens is flat.
–the rays are brought to a focus on the retina.
- On looking to a near object (closer than 6 meters):
–light rays are diverging.
–they will be focused behind the retina. However, this is prevented
by the near response.
–the near response consists of:
1. Increased convexity of the lens (accommodation)
2. Convergence of the visual axis
3. Pupillary constriction
The near point

- The nearest point to the eye where an object can be clearly seen.
- Here, the lens is convex to the maximum.
- By increasing age, the lens looses elasticity and its convexity is
decreased.
- Therefore the near point (where one can see clearly) is increased with
age as follows:
 From 9 cm at 10 years
 to 18 cm at 40 years
 to 100 cm at 70 years
- That is why old people use convex lens for reading.

Abnormalities involving the light reflex & the near response
Argyll Robertson pupil
- Loss of the light reflex with intact near response (i.e. intact
accommodation).
- Caused by syphilis.
- Both pupils are affected but to a symmetrical degree.
Holmes-Adie (myotonic) pupil
- Loss of the light reflex with sluggish accommodation.
- Usually unilateral and more common in women.
- Occurs due to defect in the postganglionic neurons from the ciliary
ganglion to the sphincter pupillae and the ciliary muscle.
- Benign condition (does not need treatment).
Horner’s syndrome
- Occurs due to loss of sympathetic supply to the face because of cervical
sympathectomy.
- Characterized by many signs in the face including constriction of the eye
pupil (meiosis) on the affected side.
Errors of refraction
1- Hypermetropia (farsightedness):
- Occurs when the eye ball is shorter than normal. Therefore the light rays
are focused behind the retina.
- For this reason patients can see distant objects better than near ones.
- To see near objects, excessive accommodation is needed. This causes
hypertrophy of ciliary muscles, headache and may predispose to squint.
- The condition is corrected by convex lenses.
2- Myopia (near sightedness):
- Occurs when the eye ball is longer than normal.

- Therefore the light rays are focused infront of the retina.
- For this reason patients can see near objects better than distant ones.
- The condition is corrected by biconcave lenses.
Fig 13.8: Errors of refraction
3- Astigmatism
- Occurs when the curvature of the cornea is irregular.
- Therefore light rays are focused at different locations; producing blurred
image.
- Patients are characteristically unable to localize the point where a
horizontal and a vertical line cross.
- The condition is corrected by cylindrical lenses.
4- Presbyopia
- Occurs when the lens elasticity is decreased (e.g. by advancing age)
resulting in loss of accommodation.
- Subjects become unable to read without wearing glasses with convex
lenses.

The visual receptors & the photosensitive pigments
- The following figure summarizes the structure of the visual receptors (the
rods and cones).
Fig 13.9: The visual receptors
- The photosensitive pigments are found in the outer segments of the rods
and cones. They consist of 2 proteins:
–Retinene1 (the aldehyde of vitamin A, so it is called retinal)
–Opsin
In rods:
- The pigment is called rhodopsin
- Rhodopsin consists of retinene1 and opsin (opsin is also called
scotopsin).
- In the dark, light changes the shape of retinene1 in rhodopsin
- This changes the configuration of the opsin
- This initiates reactions resulting in action potential transmitted by the
optic nerve. The reactions can be summarized as follows:
 Light
 Structural change in retinene1
 Conformational change in opsin

 Activation of transducin (a G protein coupled with rhodopsin)
 Activation of the enzyme phosphodiesterase
 Decreased intracellular cGMP (converted to 5’-GMP)
 Closure of sodium channels (because they are maintained open by
cGMP)
 Hyperpolarization
 Decreased release of the transmitter (which is released
continuously from the synaptic terminals of the rods)
 Electrical responses in the bipolar cells due to reduction in
transmitter release
 Action potentials in the ganglion cells
 Conduction through the visual pathway
In cones:
- There are 3 different types of retinene1 & opsin (in 3 different types of
cones).
- Their responses to light are similar to that of rhodopsin.
- Each cone pigment is most sensitive to one of the 3 primary colors: (red,
green & blue).
- The input from one type of cone gives a sensation of one of the primary
colors.
- When the input is added to that from the other cones in the pathway to
the cortex, it gives the sensation of the other colors.
- The sensation of any color is determined by the frequency of impulses in
each of the 3 types of cones (Young-Helmholtz theory).
Recovery following transduction:
- After the change in shape of retinene1 in rhodopsin, it separates from the
opsin and undergoes reduction by the enzyme alcohol dehydrogenase in
the presence of NADH to form vitamin A1. This vitamin reacts with opsin to

form rhodopsin again. However, direct regeneration of rhodopsin also
occurs.
- Generation of cGMP following transduction occurs due to reduction of
calcium concentration in the photoreceptors because of the light. The low
calcium inhibits the phosphodiesterase (which decreases cGMP) and
activates guanylyl cyclase (which increases cGMP). Then the high cGMP
opens the sodium channels.
Tests for vision

 Fundoscopy (ophthalmoscopy)
- For examination of the retina (macula, optic disc and blood vessels).
- The ophthalmoscope is used for this examination.
- Fundoscopy is important in conditions like glaucoma, diabetes and
hypertension.
- It is especially important to do fundoscopy before doing lumbar puncture
in a patient suspected to have high intracranial pressure.
- Here detection of papilledema with the ophthalmoscope (swelling of the
optic disc) indicates intracranial hypertension & therefore lumbar puncture
is contraindicated.
 Visual Acuity
- This is the degree to which the details and contours of objects are
perceived. The “Snellen’s charts” are used for this examination.
- The charts include letters that are located at a distance of 6 m (20 ft)
from patients who are are asked to read the smallest line that can be
clearly seen; then the results are expressed as a fraction (e.g. 6/6 if the
acuity is normal or 6/36 if it is low).
- A value of 6/36 indicates that acuity of the patient from 6 meters is similar
to that of a normal subject from 36 meters.

 Color vision
- The “Ishihara charts” are used for this examination.
- These charts are polychromatic plates containing figures printed with
special colors so as not to be seen by patients with color blindness.
- Color blindness is inherited as X-linked recessive (this is because two of
the cone pigments are encoded by genes on chromosome X).
- For this reason it is more common in males than females (Note: females
are carriers whereas males are victims).
Fig 13.10: Instruments used in eye examination
 Visual field
- As mentioned above, the visual field is the total area in which objects can
be seen while the eye is focused on a central point (see the visual field
defects). It can be tested with the following methods:
o Confrontation method
- The doctor sits infront of the patient.
- He compares his own peripheral visual filed with that of the patient.

Fig 13.11: Confrontation method
o Perimetry
- The systematic evaluation of the visual field using dedicated
machinery.
- Examples include:
o Goldmann kinetic perimetry (here a trained examiner maps
the visual field).
o Automated perimetry (here a computer program maps the
visual field according to patient’s responses to flashing light).
Fig 13.12: Automated perimetry
 Other tests:
- Slit lamp examination (= examination of the anterior eye structures with
the slit lamp machine).
- Tonometry (= Measurement of intra-ocular pressure with a tonometer).

HEARING
- Hearing is the ability to detect sound. It is a function of the ear.
- The ear converts sound waves into nerve impulses that are perceived by
the brain. It is divided into 3 parts: external ear, middle ear, & internal ear.
The External ear
- Consists of:
 Auricle (ear pinna)
 External auditory meatus (ear canal)
 Tympanic membrane (ear drum)
-Directs sound waves to pass through the external auditory meatus and
strike on the tympanic membrane.
Fig 13.13: The ear
The Middle ear

- Air filled cavity within the temporal bone.
- Opens into the pharynx through the Eustachian tube (auditory tube).
- This tube equalizes the air pressure between the two sides of the
tympanic membrane.
- The middle ear contains 3 ossicles and 2 muscles.
- The three ossicles are: Malleus, incus, and stapes.
- Vibrations of the tympanic membrane move the malleus, which is fused
with the tympanic membrane, the malleus moves the incus and this moves
the stapes (all these ossicles are attached to each other). The stapes
knocks on the oval window, which is part of the inner ear (part of the
cochlea). This generates pressure waves in the cochlear fluid (see below).
- The 2 muscles are:
 Tensor tympani muscle (increases tension of the tympanic
membrane)
 Stapedius muscle (separates the stapes from the oval window)
- These muscles prevent transmission of very loud sound to the inner ear
& therefore protect the inner ear from damage by the very loud sound.
The inner ear

- The inner ear (or the labyrinth) is series of channels in the petrous part of
the temporal bone (= bony labyrinth) duplicated by membranous structures
(= membranous labyrinth).
- Between the bony and membranous labyrinth there is fluid called
perilymph whereas inside the membranous labyrinth there is fluid called
endolymph.
- The perilymph is similar to the extracellular fluid (rich in sodium) whereas
the endolymph is similar to intracellular fluid (rich in potassium).
- Structures that form the labyrinth are six structures:
 One organ for hearing: cochlea
 Five organs for equilibrium: three semicircular canals plus utricle
and saccule (the utricle and the saccule are known collectively as
the vestibule).
- Receptors in all these structures are hair cells stimulated by movement of
the endolymph.

The cochlea
- Coiled tube, 35 mm long (makes less than 3 turns). Divided into 3
chambers by the Basilar membrane & the Reissner’s membrane.
- The three chambers are Scala vestibule, scala media, & scala tympani.
- Both scala vestibuli and scala tympani contain perilymph and
communicate with each other through the helicotrema (small opening at
the apex of the cochlea); whereas scala media contains endolymph and
does not communicate with the other chambers.
- Scala vestibuli ends on the oval window, which is attached to the stapes;
whereas the scala tympani ends on the round window (both windows
bulge into the middle ear).
Fig 13.14: The middle and inner ears
- When the stapes knocks on the oval window, it generates pressure

waves in the perilymph of both scala vestibuli and and scala tympani. The
waves are transmitted to the endolymph through the thin, Reissner’s
membrane.
- Hair cells are found in the basilar membrane, they are the auditory
receptors. Together with phalangeal cells, they form the organ of Corti (the
sense organ of hearing).

- The organ of Corti extends throughout the length of the basilar
membrane. It is formed by 4 rows of hair cells, three rows lateral to the
rods of Corti (outer hair cells) and one row medial to the rods of Corti
(inner hair cells).
- The rods of Corti are pillar like cells that support a tough membrane
pierced by the processes of hair cells (the reticular lamina). In addition, the
outer hair cells are covered by a thin, elastic membrane known as the
tectorial membrane.
Fig 13.15: The organ of Corti
Mechanism of hearing
 Sound waves are directed by the ear pinna to strike on the
tympanic membrane.
 Vibrations of the tympanic membrane result in movement of the
ossicles in the middle ear (malleus, incus, and stapes).
 The stapes knocks on the oval window.
 This generates pressure waves in the perilymph of the scala
vestibuli and scala tympani. Waves in the perilymph generate
waves in the endolymph of scala media.
 The endolymph moves the tectorial membrane; this stimulates the
hair cells in the organ of Corti (by causing potassium influx).

 The resulting action potentials are transmitted through the cochlear
division of the vestibulo-cochlear nerve (the 8th cranial nerve) to the
dorsal and ventral cochlear nuclei in the medulla, then to the medial
geniculate body in the thalamus.
 They eventually reach the auditory cortex at the temporal lobe (in
the Sylvian fissure) to give the sensation of hearing.
Mechanism of hair cell stimulation

- Hair cells are found in all structures of the inner ear (cochlea, utricle,
saccule, and semicircular canals).
- In each of these structures, they combine with sustentacular cells to form
the following sense organs:
 Organ of Corti in cochlea for hearing
 Otolithic organ in utricle for equilibrium (detects linear movement in
the horizontal plane)
 Otolithic organ in saccule for equilibrium (detects linear movement
in the vertical plane)
 Crista ampullaris in each of the three semicircular canals for
equilibrium (detects rotational movement)
- Hair cells have two types of hair processes projecting from their apical
membranes:
 Stereocelia:
o Motile cilia, found in all types of hair cells
o Increase progressively in height towards the other type (the
kinocilium)
 Kinocilium:
o One immotile, large cilium
o Found in all structures of the inner ear except the cochlea

- The processes of hair cells are bathed into the endolymph (which is rich
in potassium ions) whereas their bases are bathed into perilymph.
- Pressure waves in the endolymph pushes the shorter stereocilia towards
the kinocilium (or towards the highest stereocilium as in the cochlea); this
causes opening of mechanically gated cation channels, allowing
potassium, and calcium influx.
- The generated action potential stimulates release of a neurotransmitter
(most probably glutamine) from the bases of hair cells. This generates
afferent impulses in either the cochlear or the vestibular division of the
vestibule-cochlear nerve.
Fig 13.16: Mechanism of hair cell stimulation
Intensities & frequencies of sound waves

- Sound waves travel through air at a speed of about 344 m/s, at 20 cº at
sea level; the speed becomes higher with temperature, altitude, and water.
- They differ in their amplitudes and frequencies.
- Generally, the frequency of a sound determines its pitch and its
amplitude determines its loudness (note that frequency also affects
loudness and other factors may contribute to both pitch and loudness).
- The frequency (or pitch) of sound is expressed in Hz (cycles per second).

- The frequencies audible to humans range from 20 to 20,000 Hz.
However, the best audible frequencies (or pitches) lie in the range 1000 to
4000 Hz (note that the voice pitch of humans during conversation is about
120 Hz for males and 250 Hz for females).
- Amplitude of sound (or its intensity) is expressed in decibels (dB).
- Number of dB = 10 log x intensity of sound/intensity of standard sound.
- Because this is a log scale, when the number of dB = zero, the intensity
of sound is equal to the intensity of standard sound (which is the sound
that is just audible to average humans).
- Sound intensity of 140 dB is damaging to the hair cells in the cochlea.
“Why do we have two ears?”... “For sound localization!”

- When sound waves reach the two ears on both sides of the head, there
are differences in:
 Time of arrival (less time on the side closer to the source of the
sound)
 Intensity of sound (louder sound on the side closer to the source of
the sound)
- These two factors enable the brain to determine the source of sound
(sound localization).
- Because the ear pinna is turned slightly forward, sounds coming from in
front or behind the ears differ in their quality. This difference in quality is
used for localization.
DEAFNESS
- Deafness is loss of hearing. It is two types:
 Conductive deafness
 Nerve deafness

Causes of conductive deafness
 Occlusion of the external ear by foreign body or wax
 Otitis media (causes thickening or perforation of the tympanic
membrane)
 Otosclerosis
Causes of nerve deafness
 Acoustic neuroma
 Drugs (aminoglycosides like streptomycin and gentamycin)
 Advanced age (due to gradual loss of hair cells and neurons)
 Genetic causes (e.g. Pendred’s syndrome which is characterized by
deafness and goiter)
Tests for hearing

- The following tests are used to diagnose deafness and to differentiate
between its two types (conductive and nerve deafness).
Weber’s test
 Done by placing base of vibrating tuning fork on vertex of the skull
to allow bone conduction
 Normal subjects hear equally on both sides (= negative test)
 Patients with conductive deafness hear better on the affected side
(due to loss of the masking effect of the environment)
 Patients with nerve deafness hear better on the normal side
Rinne’s test
 Done by placing base of vibrating tuning fork on mastoid process
behind the ear (for bone conduction) until the sound disappears,
then its apex is placed in air next to the ear (for air conduction)
 Normal subjects hear vibrations in air after the bone conduction is
over (i.e. air conduction is better than bone conduction)- (= negative
test)
 Patients with conductive deafness hear bone conduction but not air
conduction
 Patients with complete nerve deafness do not hear any sound
wether conducted by air or bone; however, those with partial nerve
damage hear vibrations in air after the bone conduction is over
Audiometry
 An audiometer is used to measure the degree of hearing loss
 The device presents tones with different intensities and frequencies
to a subject through earphones; the subject responds when he
hears a sound
 Audible frequency is plotted against intensity on a graph paper as a
percentage of normal hearing
THE SEMICIRCULAR CANALS

- Found on each side of the head.
- Lie perpendicular to each other.
- Oriented in 3 planes
- Each has dilated end (ampulla) containing hair cells that form a receptor
organ known as crista ampullaris.
- The endolymph inside the semicircular canals moves in rotational
movements. This stimulates the hair cells in crista ampullaris.
- Action potentials are transmitted through the vestibular division of the 8 th
cranial nerve to the vestibular nuclei in the medulla and the
vestibulonodular lobe in the cerebellum.
- From the vestibular nuclei (superior & medial nuclei), fibers project to the
nuclei of the cranial nerves III, IV & VI (which control eye movements) and
then to the somatosensory cortex, through the thalamus.

UTRICLE AND SACCULE
- Concerned with linear movement in the:
–Horizontal plane (utricle)
–Vertical plane (saccule)
- Hair cells inside them form receptor organs known as the otolithic organs
or maculas (formed by hair cells + sustentacular cells + otolithic
membrane in which CaCO3 crystals are embedded).
- Action potentials are transmitted through the vestibular division of the 8 th
cranial nerve to the vestibular nucleus in the medulla and the
vestibulonodular lobe in the cerebellum.
- From the vestibular nucleus (lateral or Deiters’ nucleus), some fibers
project to the spinal cord through the vestibulospinal tract. Other fibers
project to the reticular formation and the somatosensory cortex, through
the thalamus.
SMELL & TASTE

THE SENSE OF SMELL (OLFACTION)
- Depends on chemoreceptors found in the mucosa of the superior portion
of the nasal cavity.
- Some air reaches this poorly ventilated area with each respiratory cycle.
- The amount of air reaching the olfactory mucosa is greatly increased with
sniffing, which is usually performed when an odor attracts attention.
- Molecules can be detected once dissolved in the mucus layer.
Pathway
 Chemoreceptors
o Found in the olfactory mucus membrane
o Rapidly adapting receprors

 Olfactory nerve
o Its neurons pierce the cribriform plate of the ethmoid bone
 Olfactory bulb
o The neurons pass from the olfactory bulb to the cerebral cortex
o Smell is the only modality of sensation that does not pass
through the thalamus
 Olfactory cortex
o Smell area is located in the orbitofrontal gyri of the frontal lobe
o It is part of the limbic system; however, some fibers pass to
other parts of the limbic system (e.g. the amygdala) to mediate
the emotional reaction to smell. Other fibers pass to areas
concerned with olfactory memories.
Note
- Humans can recognize more than 10,000 different odors (because there
are large number of different odor receptors, large number of olfactory
neurons, special organization of different cells within the olfactory bulb,
and different receiving areas in the olfactory cortex).
- The ability to discriminate different intensities of an odor is poor; a
concentration change of about 30% is needed before a difference in
intensity can be perceived.
- Females (in all ages) are slightly superior to males in odor identification.
Fig 13.17: Olfactory pathway

Smell disorders
Anosmia & hyposmia
 Anosmia is loss of smell whereas hyposmia is reduced ability to smell
 Causes:
o Upper respiratory tract infections (common cold)
o Head injury (with fracture base of the skull)
o Kallmann’s syndrome (hypothalamic hypogonadism with
anosmia)
o Advancing age
Hyperosmia
 Hyperosmia is hightened sense of smell
 Causes pregnancy and psychological disorders (e.g. hysteria)
Dysosmia
 Distortion of smell (i.e. odors smell diifferent)
 Causes include sinusitis, mouth infections, depression and viral
hepatitis
TASTE SENSATION
- Depends on chemoreceptors in taste buds.
- The taste buds are scattered in the tongue, epiglottis, palate, and
pharynx.
- The taste buds are the sense organ for taste (each taste bud consists of
four types of cells; one of these types acts as cheoreceptor for taste).
- The chemoreceptive cells in each taste bud have microvilli on their apical
surfaces; the microvilli project into the taste pore, an opening in the upper
surface of the taste bud.
- The cells are exposed to chemicals through this taste pore.

Fig 13.18: The taste bud
Tate pathway
 Afferent neurons from taste buds (1st order neurons):
o Chorda tympani branch of the facial nerve (from the anterior two
thirds of the tongue)
o Glossopharyngeal nerve (from the posterior third of the tongue)
o Vagus nerve (from the pharynx)
 Nucleus of tractus solitarius in the medulla (cell bodies of 2 nd order
neurons): Axons ascend in the medial lemniscus to the thalamus
 The ventral posteromedial nucleus of the thalamus (cell bodies of 3 rd
order neurons): Axons pass in the sensory radiation to the postcentral
gyrus and insular cortex
Taste modalities
- Taste is usually described as:
 Sweet (stimulated by sugars)
 Salt (stimulated by sodium chloride)
 Sour or acid (stimulated by protons “hydrogen ions”)
 Bitter (stimulated by poisons and some drugs like quinine)
 Umami (A pleasant taste stimulated by mono-sodium glutamate, added
recently to taste modalities. Sauces with umami and salty tastes are
very popular for cooking, such as tomato sauces and ketchup).

Areas of taste on the tongue
- Taste buds in the tongue are found in the fungiform papillae (mainly near
the tip of the tongue) and the vallate papillae (mainly at the back of the
tongue); but not the filiform papillae (on the dorsum of the tongue).
- The five modalities of taste are sensed from all areas of taste sensation
in the tongue. The common misperception that each taste modality is
confined to special area in the tongue “taste map” is obsolete.
Important notes
- The receptors for sour and salty taste are ion channels whereas the
receptors for sweet, bitter, and umami are coupled to G-protein.
- The ability to discriminate different intensities of a taste sensation is poor;
a concentration change of about 30% is needed before a difference in
intensity can be perceived.
- Flavor of food is produced by the combination of taste, smell, touch and
temperature.
Taste disorders
Ageusia & hypoguesia
 Aguesia is total loss of taste whereas hypoguesia is reduced taste
sensitivity
 Causes:
o Drugs like penicillamine & captopril (cause transient aguesia)
o Local inflammation
o Deficiency of vitamin B3 (Niacin) or zinc
o Advancing age
o Damage to the afferent nurons (e.g. Bell’s palsy)

1. Conductive deafness is caused by:
a. Cochlear damage
b. Foreign body in the auditory tube
c. Otosclerosis
d. Streptomycin
e. Acoustic neuroma
2. The sense organ for hearing is known as:
a. Macula
b. Cochlea
c. Crista ampularis
d. Organ of corti
e. Otolithic organ
3. Weber test in a patient with conductive deafness:
a. Gives results similar to nerve deafness
b. Shows better hearing on the affected side
c. Shows better hearing on the normal side
d. Shows equal hearing on both sides
e. None of the above is correct
4. Concerning vision, which of the following is not true:
a. Refraction of light is larger at the cornea than at the lens
b. Myopia is corrected with biconcave lenses
c. Rods are responsible for color vision
d. Color blindness is found in males more than females
e. The fovea centralis does not contain rods
5. Heteronymous hemianopia is caused by damage to:
a. Optic nerve
b. Optic tract
c. Optic chiasma
d. Optic radiation
e. Cerebral cortex
6. Concerning tests for hearing, which of the following is correct:
a. In normal subjects, bone conduction is better than air conduction
b. Using W eber test, conductive deafness is diagnosed when
hearing is better on the normal side
c. Audiometry is useful in deaf children
d. In audiometry frequency of sounds are expressed in decibels
e. In partial nerve deafness air conduction is better than bone
conduction
7. Homonymous hemianopia is caused by damage to the:
a. Optic nerve
b. Optic tract

c. Optic chiasma
d. Optic radiation
e. Angular gyrus
8. The sense organ for linear acceleration is known as:
a. Organ of Corti
b. Crista ampularis
c. Otolithic organ
d. Calcium carbonate crystals
e. Hair cells
9. Which of the following statements is correct:
a. Semicircular canals are concerned with hearing
b. Negative Runne’s test indicates nerve deafness
c. Wax in the external auditory canal is a recognized cause of
nerve deafness
d. Acoustic neuroma presents with nerve deafness, ataxia and
vertigo
e. Taste sensation from anterior two thirds of the tongue are
carried in trigeminal nerve
10. Which of the following is a recognized cause of both hyperosmia
and hypergeusia:
a. Kallmann syndrome
b. Vitamin A deficiency
c. Pregnancy
d. Addison’s disease
e. Frontal lobe tumor
11. Vertigo occurs due to damage to:
a. Cerebellum
b. Mid brain
c. Vestibular system
d. Cerebral cortex
e. Thalamus
12. The sense organ for rotational acceleration is known as:
a. Organ of Corti
b. Crista ampularis
c. Otolithic organ
d. Calcium carbonate crystals
e. Hair cells
13. When the light rays are focused behind the retina, the subject is:
a. Hypermetropic
b. Myopic
c. Presbyopic
d. Immetropic
e. Normal
14. Which of the following structures gives the eye its characteristic color:
a. Cornea
b. Lens
c. Iris
d. Retina
e. Sclera
15. In a patient with hypermetropia:
a. The eye ball is larger than usual
b. Light rays are focused in front of the retina
c. Near objects can be seen better than distant objects
d. Visual acuity is usually 6/6
e. Vision is improved with convex lenses
16. Concerning the intraocular pressure, which of the following is not true:
a. It is normally between 10 and 20 mmHg
b. It increases with age
c. High pressure is a risk factor for glaucoma
d. High pressure can be lowered by taking acetazolamide
e. High pressure causes catarct
17. The tympanic membrane:
a. Reduces frequency of sound waves reaching the year
b. Bulges inwards when the auditory tube is blocked
c. Separates the middle year from the inner year
d. Is directly attached to the stapes
e. Cannot transmit sound waves if it is perforated
18. All the following statements about visual adaptation of a subject
entering a dark room are correct except:
a. Adaptation to poor light takes about 20 minutes
b. The major cause of adaptation is regeneration of bleached receptor
pigments
c. Adaptation involves the cones before involving the rods
d. Adaptation is better for peripheral (rods) than central vision (cones)
e. The threshold light intensity starts to rise
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
c d b c c e b c d d c
12. 13. 14. 15. 16. 17. 18.
b a c e e b e

CHAPTER (14)
THE MOTOR SYSTEM
- The motor system comprises all the following systems: pyramidal
system, the extrapyramidal system, the vestibular system and the
cerebellum.
- These systems control posture, reflexes, muscle tone and voluntary
movement of muscles.
- Their pathways originate in the brain or brainstem and descend down the
spinal cord to control spinal motor neurons.
- The spinal motor neurons originate in the anterior horns of the spinal
cord; they send their axons via the ventral spinal roots and spinal nerves
to control motor activities of skeletal muscles. They also form the final
common pathway for the spinal reflexes, which are integrated at the spinal
cord.
THE SPINAL CORD & REFLEXES

Anatomy of the spinal cord
- The spinal cord is the part of the nervous system that is protected and
enclosed by the bony vertebral column.
- The adult human spinal cord is about 45 cm in males and 42 cm in
females; extending from the medulla oblongata to the conus medullaris at
the vertebral level of “L1-2” where it ends in a fibrous extension known as
the filum terminale.
- The outer region of the spinal cord is a white matter consisting of the
ascending and descending neural tracts. This surrounds a “butterfly” or “H”
shaped central region of gray matter consisting of the cell bodies of
sensory and motor neurons.

- The cell bodies of the sensory neurons are found in the posterior horns
of the gray matter whereas the cell bodies of motor neurons are found in
the anterior horns.
- At the center of the gray matter is the central canal which is an extension
of the brain ventricles. It contains cerebrospinal fluid (CSF).
Fig 14.1: The spinal cord
Fig 14.2: The gray and the white matters of the spinal cord

- Like the brain, the spinal cord is covered by the three meninges:
 Dura mater “outer layer”, Arachnoid mater “middle layer” & Pia
mater “inner layer”
- The arachnoid mater is separated from the pia mater by the
“subarachnoid space” which also contains cerebrospinal fluid.
- The cerebrospinal fluid is a clear, isotonic fluid produced from blood by
the choroid plexus in the lateral and fourth ventricles in the brain, it flows
from the lateral ventricles to the third ventricle through the interventricular
foramina “foramen of Monro”, then to the fourth ventricle through the
cerebral aqueduct and then to the subarachnoid space through the
foramena of Luschka and framen of Magendie; from there it is reabsorbed
back to the venous blood (in the cerebral venous sinuses) by the
arachnoid villi.
- Functions of the CSF:
 Mechanical protection of the brain “Cushion effect”
 Distribution of some neuroendocrine factors
 Homeostasis & metabolism of the brain
 Prevention of brain ischemia (absorption of the fluid decreases
intracranial pressure & allows blood to flow through the vessels).
Table 14.1: Characteristics of the CSF
Character CSF
Volume 150 ml
Daily production 550 ml/day
Protein 15 to 40 mg/dL; or 0.3% of plasma protein
concentration
Cells 0-5 mono-nucleaar cells
Glucose 50-80 (two-thirds of blood glucose)
Pressure 70 - 180 mmH2O

- The spinal cord consists of segments. Each segment has a pair of spinal
nerves.
- Each spinal nerve is formed of:
 A dorsal root (contains sensory axons of neurons located in the
dorsal root ganglion)
 A ventral root (contains motor axons of neurons located at the
anterior horn)
- The spinal nerves that originate from these segments are divided into
four groups:
 Cervical (8 spinal nerves, from C1 to C7)
 Thoracic (12 spinal nerves, from T1 to T12)
 Lumbar (5 spinal nerves, from L1 to L5)
 Sacral (5 spinal nerves, from S1 to S5)
Functions of the spinal cord

 Contains ascending (sensory) and descending (motor) tracts
 Acts as an integrating center for spinal reflexes
The sensory tracts (Ascending tracts)
o The antero-lateral tract
o The dorsal column tract
The motor tracts (Descending tracts)
o The pyramidal tracts: (the corticospinal & the corticobulbar tracts)
o The extrapyramidal tracts: (the rubrospinal tract, the reticulospinal
tract, the vestibulospinal tract & the tectospinal tract).
The spinal reflexes
- These are the reflexes which are integrated at the spinal cord.
- The basic structure features and the most important examples of these
reflexes are described in the following section.

THE REFLEX ARC
- The reflex arc is the basic unit of integrated neural activity; it controls
many autonomic and somatic functions.
- It consists of receptor, afferent, synapse (or center), efferent and effector.
Fig 14.3: The reflex arc
The Receptors
- Special structures found at the peripheral ends of afferent neurons.
- According to the site of receptors, reflexes are classified into:
(1) Superficial reflexes
 Receptors in the skin
 Example: Withdrawal reflex, abdominal reflexes, plantar reflex &
cremastric reflex.
(2) Deep reflexes
 Receptors are found deep within a muscle (intrafusal fibers or
tendons)
 Examples: Stretch reflex, Golgi tendon reflex & stepping reflex
(3) Visceral reflexes
 Receptors in viscera
 Example: Micturition reflex, defecation reflex, vomiting reflex &
erection reflex.

The Afferent
- Enters the spinal cord through the dorsal root. Its cell body is at the
dorsal root ganglion.
The synapse (or center)
- The site of integration of the reflex. It represents a direct synapse
between the afferent and the efferent neurons or n indirect synapse
(through one or more interneurons).
- According to the number of synapses, the reflex can be:
(1) Monosynaptic
 One synapse between the afferent and the efferent neurons
 Example: Stretch reflex
(2) Bisynaptic
 Two synapses between the afferent and the efferent neurons
Example: Golgi tendon reflex
(3) Polysynaptic
 Many synapses between the afferent and the efferent neurons
 Example: Withdrawal reflex
Fig 14.4: Types of reflexes

The efferent
- The motor neuron that leaves the spinal cord through the ventral root.
The effector
- The muscle or the myo-epithelial cell in a gland that perform the effect.
THE STRETCH REFLEX

- Deep / Monosynaptic / Spinal reflex (see above).
The receptor
- The muscle spindle (or the intrafusal fibers).
- The muscle spindle is few muscle fibers (up to 10 fibers), of less
striations; enclosed within a connective tissue capsule; found deep within
the substance of skeletal muscle.
- Its intrafusal fibers lie parallel to the other muscle fibers (or the extrafusal
fibers).
- The fibers of the muscle spindle are two types:
 Nuclear bag (with nuclei in a central dilatation).
 Nuclear chain (with nuclei spreading in a chain).
- Nuclear bag fibers are two fibers: fiber-1 (with low myosin ATPase
activity) & fiber-2 (with high myosin ATPase activity).
- Nuclear chain fibers are thinner & shorter but have higher number of
fibers when compared to nuclear bag fibers.
- The central parts of the muscle spindle fibers (where afferents are
attached) are sensitive to stretch whereas the ends (where gamma
efferents are attached) are contractile.
- The muscle spindle can be stimulated by:
 External stretch to the whole muscle.
 Contraction of the ends of its fibers (by gamma efferent discharge,
see below).

- The muscle spindle is not stimulated by contraction of the whole skeletal
muscle (extrafusal fibers) because this causes shortening rather than
stretch.
The afferents
- Two types:
 Type (Ia); the primary sensory endings:
o Rapidly conducting fibers.
o Ends on both nuclear bag (1 & 2) and nuclear chain fibers.
o The fibers wrap around the muscle spindle fibers to form
terminations known as the "annulospiral endings".
 Type (II) fibers; the secondary sensory endings:
o Have lower conduction velocity than type Ia.
o End only on the nuclear chain fibers.
o Their terminations are known as the "flower spray endings".
- There are two types of afferent input carried by the primary sensory
endings:
 Dynamic: The rapid discharge while the muscle is being stretched
(i.e. during stretching); comes from the nuclear bag fibers
 Static response: The discharge from stretched muscle (i.e. during
the period of static stretching); comes from the nuclear chain fibers
The center (synapse)

- The synapse in the spinal cord is a direct (single) synapse between the
primary afferent neuron (Ia) and the cell body of the efferent neuron (A
alpha); the neurotransmitter is glutamate.
- The afferent neuron (Ia) reaches the efferent at the anterior horn.
- The secondary afferent neuron (II) has little contribution to the reflex
through both monosynaptic and polysynaptic connections.

Fig 14.5: The muscle spindle
The efferents
- Two types:
 (A -alpha) efferents: supply the extrafusal fibers to do the effect;
however, they also supply the intrafusal fibers.
 (A-gamma) efferents: supply the intrafusal fibers to increase their
sensitivity to stretch and generate muscle tone. They have two
types of endings: plate ending on the nuclear bag fibers & trail
endings: on the nuclear chain fibers.
- The dynamic and static afferent inputs mentioned above initiates
dynamic (phasic) and static reponses through the A α and A γ efferent
neurons.
- The dynamic response increases sensitivity of the muscle spindle to rate
of change in stretch whereas the static response increases its sensitivity to
maintained stretch.

Role of A gamma discharge= generation of muscle tone
- The A gamma fibers are small motor neuron that supply the muscle
spindles.
- They constitute 30% of all motor neurons in the ventral roots of the spinal
cord.
- Their tonic discharge causes contraction of the ends of the intrafusal
fibers; this stretches the sensitive areas in the fibers of muscle spindle “=
the central portions” resulting in reflex contraction of the extrafusal fibers
(i.e. A gamma discharge causes an indirect contraction of the extrafusal
fibers).
- Some descending tracts from the brain inhibit the A gamma motor
neurons to reduce their tonic discharge and minimize their indirect effect
on the extrafusal fibers. But in spite of that, the A gamma discharge is still
present.
- When trying to move a relaxed limb of a subject during clinical
examination, one can feel slight degree of resistance to the passive
movement of that limb. This resistance to the passive movement is known
as the muscle tone.
- It is a normal finding as long as it is caused by the normal tonic discharge
of the A gamma efferents. However, certain factors may affect the A
gamma discharge resulting in either hypertonia or hypotonia.
Hypertonia:
 Occurs when the A gamma discharge is increased (a sign of UMNL,
see below).
 The affected muscles are spastic or rigid, offering high resistance to
passive stretch.
 Spasticity is present when hypertonia occus in one group of muscles;
e.g. flexors but not extensors.

 Rigidity is present when hypertonia occus in both groups of muscles
“agonists & antagonists”.
 Hypertonia is also desribed as:
 Clasp knife (when the examiner of muscle tone feels resistance to
passive stretch initially, then the resistance disappears). This typically
occurs when someone closes a clasp knife. It occurs with spasiticity
rather than rigidity and it is explained by the lengthening reaction (see
below).
 Lead pipe (when the examiner of muscle tone feels resistance
throughout the whole range of movement). It occurs with rigidity.
 Cog Wheel (when the examiner of muscle tone feels interrupted
resistance that appears and disappears many times). It occurs with
rigidity.
Hypotonia:
 Occurs when the A gamma discharge is decreased (a sign of LMNL).
 The affected muscles are flaccid, offering very low resistance to
passive stretch.
The lengthening reaction:

- Occurs in spasticity when the resistance to passive stretch appears
initially then disappears because the antagonist muscle is hyperstretched.
- For example, during examination of the upper limbs in a patient with
spasticity, flexing the forearm at the elbow joint initially causes stretch of
triceps (the antagonist muscle that causes extension) followed by
hyperstretch. The stretch stimulates the stretch reflex causing contraction
of triceps (and therefore resistance to flexion), and then the hyperstretch
stimulates the Golgi tendon reflex (see below) causing relaxation (and
therefore disappearance of the resistance).

Fig 14.6: The stretch reflex
Factors affecting the discharge of A gamma

 Descending tracts from the brain:
o The pyramidal tract: facilitatory (i.e. increases A gamma discharge)
o The extrapyramidal tract: inhibitory (i.e. decreases A gamma
discharge)
o The cerebellum: facilitatory (i.e. increases A gamma discharge)
Note: Loss of inhibition to A gamma neurons as in transection of the
spinal cord or basal ganglia lesions results in increased A gamma
discharge and therefore increased muscle tone (hypertonia) whereas loss
of facilitation as in cerebellar lesions results in decreased A gamma
discharge and therefore decreased muscle tone (hypotonia).

 Anxiety: Increases A gamma discharge; that is why it is associated with
hyperreflexia (see below).
 Unexpected movement: Increases A gamma discharge.
 Painful stimulus to the skin: Increases A gamma discharge to the
flexors and decreases discharge to the extensors on the same side.
The opposite occurs on the other side
 Alpha-gamma linkage: Increased Aα discharge to a muscle to initiate
its movement is associated with increased A gamma discharge to the
muscle spindle to keep it sensitive to stretch during shortening of the
skeletal muscle.
 Pullings the hands apart while hooking the fingers (Jendrassik’s
maneuver): Increases A gamma discharge. This maneuver is usually
performed during clinical examination of tendon reflexes. The
increased A gamma discharge increases sensitivity of the muscle
spindle and therefore makes the reflex more evident; that is why it is
also known as “reinforcement”. Hard clenching of the teeth exerts the
same effect.
Clinical application of the stretch reflex
- Clinical examination of deep reflexes (tendon jerks) is based on the
stretch reflex. Here a hammer is used to stretch a muscle by a gentle blow
on its tendon. The resulting stretch initiates a reflex that causes
contraction of that muscle. The reflex contraction (or response) can be
normal, increased or decreased/ absent.
- An abnormal reflex (increased or absent reflex) indicates either:
 Upper motor neuron lesion (UMNL): when there is increased reflex
contraction (hyperreflexia).
 Lower motor neuron lesion (LMNL): when there is decreased or
absent reflex contraction (“hyporeflexia” or “a reflexia”).

- In upper motor neuron lesions (UMNL) the motor neurons descending
from the brain are damaged at the brain or the spinal cord (i.e. at the
CNS).
- In lower motor neuron lesions (LMNL) the motor neurons leaving the
spinal cord are damaged; either peripherally at the axons or centrally at
the cell bodies in the spinal cord.
Signs of UMNL:
 Paralysis or weakness (paresis) of skeletal muscles
o Due to interruption of the descending orders from the brain.
 No or minimal wasting of muscles
o Generally, wasting does not occur in UMNLs; however, minimal
wasting may occur due to disused atrophy.
 Hypertonia
o Due to increased A gamma discharge, see above.
 Hyperreflexia of the deep tendon reflexes
o Due to increased A gamma discharge, see above.
 Clonus
o Occurrence of regular, rhythmic contractions of a muscle when
subjected to sudden, maintained stretch.
o The maintained stretch causes repetitive stimulation of the
stretch reflex.
o Examples: ankle clonus & patellar clonus.
 Absence of abdominal & cremasteric reflexes
o These superficial reflexes are elecited by scratching the skin of
the abdomen (from the outer side towards the midline) & the
inner aspect of the upper thigh.
o The normal responses are contraction of abdominal muscles (in
abdominal reflex) & contraction of the cremaster muscle with

elevation of the scrotum (in cremasteric reflex). These
responses are absent in both UMNLs and LMNLs.
 Extensor plantar response
o The plantar reflex is a cmplicated polysynaptic superficial reflex
that normally causes flexion of the toes.
o It is stimulated by scraping a blunt object across the lateral side
of the sole of foot (starting from the heel towards the small toe)
and then arching medially towards the big toe.
o A positive reflex (known as Babinski’s sign) is obtained when
there is an extensor response (upgoing of the big toe with
fanning of the other toes).
o This abnormal response is normally inhibited by the lateral
corticospinal tract. Therefore it appears in UMNLs.
 Hoffmann’s sign
o A sign of UMNL elicited in the hands by tapping the terminal
phalanx of the 3rd or 4th finger resulting in flexion of the terminal
phalanx of the thumb (this response is inhibited in the normal
states by descending tracts from the brain).
o It is equivalent to the Babinski’s sign in the foot; but unlike the
Babinski’s sign, it involves a monosynaptic reflex rather than a
polysynaptic reflex.
Signs of LMNL:
 Paralysis or weakness (paresis) of skeletal muscles
o Due to interruption of theit motor supply (the Aα motor neurons).
 Hypotonia
o Due to decreased A gamma discharge.
 Hyporeflexia or a reflexia of the deep tendon reflexes
o Due to decreased A gamma discharge.

 Fasciculation
o This is a small, local, involuntary twitching of muscle visible
under the skin.
o Occurs early following the LMNL; due to hypersensitivity of
skeletal muscles to preformed acetylcholine that is released
spontaneously from the damaged motor neurons.
o It disappears later when the release of the preformed
acetylcholine stops completely.
 Wasting of muscles
o Due to loss of the trophic effect of the motor neurons.
 Absence of superficial reflexes
o The abdominal cremasteric and plantar reflexes are absent in
LMNLs; due to interruption of a reflex component (afferent,
center or efferent).
Significance of reflexes in localization of UMNLs
- Reflexes are not only useful in differentiating between UMNL & LMNL,
but also in localizing sites of lesions within the CNS. However, localization
needs knowledge about the root values of reflexes (i.e. the roots of
segments that integrate the reflexes). For example, a patient with
hyperreflixia of the knee jerk with normal biceps reflex most probably
suffers from an UMNL below C5 and above L2; accordingly investigations
may be requested to visualize that site (e.g. CT myelography, MRI …).
- The root values of the deep tendon reflexes (tendon jerks):
 Biceps reflex for biceps muscle; (C5 & C6)
 Triceps reflex for triceps muscle; (C6 & C7)
 Supinator reflex for brachioradialis muscle; (C5 & C6)
 Knee jerk for quadriceps muscle; (L2, L3 & L4)
 Ankle jerk for gastrocnemius muscle; (S1)

- The root values of the superficial reflexes:
 Plantar reflex (L4, L5, S1 & S2)
 Abdominal reflexes (T8, T9 & T10 below & T10, T11 & T12 above
the umbilicus).
 Cremasteric reflex (L2 & L3)
OTHER REFLEXES
The Golgi tendon reflex
- This is a deep/ spinal/ bisynaptic reflex.
- Stimulus: strong stretch (hyperstretch) of skeletal muscle.
- Receptor: Golgi tendon organ (network of nerve endings within the
tendon of a muscle).
- Afferent: Ib (myelinated, rapidly conducting neuron).
- Synapse: Bisynaptic (there is a single inhibitory interneuron between the
afferent and the efferent neurons).
- Efferent: The Aα fibers (it is inhibited by the inhibitory interneuron).
- Effector: Skeletal muscle.
- Response: relaxation of the skeletal muscle.
Note: - This reflex is also known as the "inverse stretch reflex" because
when its receptors are stimulated by strong stretch, its response is
relaxation of skeletal muscle (rather than contraction).
Fig 14.7: The Golgi tendon reflex

Withdrawal reflex
- Deep/ polysynaptic/ spinal reflex.
- Stimulus: painful stimulus (or noxious stimulus).
- Response: Contraction of flexors and inhibition of extensors on the same
limb to get a way from the stimulus. The opposite may occur on the other
limb (contraction of extensors and relaxation of flexors to support the body
(crossed extensor response).
- When contraction of flexors is accompanied by inhibition of extensors (or
vice versa); this is known as reciprocal innervation (or inhibition). It is an
important property of withdrawal reflexes. Other properties include local
sign, irradiation, summation, recruitment, after discharge, fractionation &
occlusion (see below).
Fig 14.8: The withdrawal reflex

GENERAL PROPERTIES OF REFLEXES
 Adequate stimulus
- Each reflex is stimulated by a precise specific stimulus known as the
adequate stimulus. For example the adequate stimulus for stretch
reflex is stretch, for withdrawal reflex is a painful stimulus and for
scratch reflex in a dog is crawling of an insect across the skin, but not
jumping!
 Stereotyped response
- Reflexes provide stereotyped reactions to their adequate stimuli.
- In spite of being stereotyped, some reflex responses may be modified
by experience (e.g. habituation and sensitization; which are examples
of non-associative learning in implicit memory "or memory of skills").
- Habituation: when the stimulus is repeated many times, the subject
becomes habituated to it and ignores it. It is associated with decreased
Ca++ in the sensory endings resulting in decreased release of
neurotransmitters (NTs) following the stimulation.
- Sensitization: in spite of repetition of the stimulus, it produces greater
response (opposite to habituation). It is associated with increased
Ca++ in the sensory endings resulting in increased release of
neurotransmitters following stimulation.
 Local sign
- The pattern of the reflex response depends on the site of stimulation
(i.e. it depends on the afferent neuron which carries sensation from
that site).
- Example: when the withdrawal reflex is stimulated from the medial
side of the foot, the reponse includes flexion and some abduction of
the lower limb; whereas when it is stimulated from the lateral side, the
response includes flexion and some adduction.

 Irradiation
- When the intensity of stimulation is very high, the impulses irradiate
within the spinal cord to involve more and more segments (i.e. they
activate more motor neurons). For example: in the withdrawal reflex of
a lower limb, the upper limbs also respond to the stimulus.
Note: Paraplegic patients with automatic bladder can scratch the skin
of the inner aspect of the thigh; this causes stimulation and irradiation
of impulses within the sacral segments of the spinal cord and other
segments causing “a mass reflex” that includes micturition, defecation,
sweating and fluctuation in blood pressure.
 Summation
- Summation occurs within the spinal cord when the strength of a
noxious stimulus is increased. This generates more EPSPs that may
undergo either spatial or temporal summation resulting in activtion of
more motor neurons.
- Spatial summation occurs when multiple EPSPs are generated
simultaneously "at the same time" whereas temporal summation
occurs when successive EPSPs are generated due to repeated
stimulation.
 Fractionation & occlusion
- Fractionation and occlusion occur in the withdrawal reflex. Here the
total reflex response is less than what is expected on direct stimulation
of the muscles. Fractionation is explained as follows: the afferent iputs
reaching the spinal cord result in fractionation of the motor neurons
(i.e. divide them into several independent groups). As a result,
contraction occurs in a part of a muscle; not the whole muscle.
- Occlusion occurs because several afferent inputs share the same
motor neuron.

 Final common pathway
- Many afferents converge on the same motor neuron (the efferent).
For this reason, the motor neuron is regarded as the final common
pathway for many afferent inputs (up to 10,000 synaptic knobs).
 Response time (or reaction time)
- Depends on the conduction velocity of the afferent and efferent
neurons & the central delay. Since a single synapse delays conduction
for at least 0.5 ms, the central delay in a polysynaptic reflex is
dependent on the number of synapses between the afferent and the
efferent neurons (i.e. more synapses = more prolonged reaction time).
 Reciprocal innervation (inhibition)
- Reflex contraction of agonist muscle is accompanied by inhibition of
the antagonist muscle (reciprocal innervation) as occurs in the
withdrawal reflex.
 Recruitment & after discharge
- Recruitment occurs when repeated stimulation activates additional
number of motor neurons.
- After discharge is continuation of a response after cessation of the
stimulus; due to repeated firing of the motor neuron (repeated firing
requires “reverberating circuits”).
Fig 14.9: The reverberating circuits

SPINAL CORD TRANSECTION
Etiology
- Traumatic damage to the spinal cord may result from motor vehicle
accidents, community violence, sport injuries and falls).
- Spinal cord damage can also occur due to tumors (primary or secondary
intramedullary tumors), infections (e.g. tuberculosis of the spine), cervical
spondylosis and cord infarction due to anterior spinal artery occlusion.
Severity
- Severity of spinal cord transection is related to the degree of transection
(complete or partial) and the level of transection (higher lesions are more
serious than lower ones); for example:
 Upper cervical lesions cause quadriplegia (paralysis of both upper
and lower limbs). If the lesion is above C4, it causes immediate
death unless the patient is mechanically ventilated. This is because
the diaphragm & other respiratory muscles are paralyzed.
 Thoracic lesions: cause paraplegia (paralysis of both lower limbs).
Types
 Complete transection
 Hemisection (Brown-Sequard syndrome)
Complete transection of the spinal cord
- The patient passes through the following phases:
 Spinal shock
 Retention of reflexes
 Extensor contraction
Spinal Shock
- The cause of spinal shock is unknown; it takes about 1-2 weeks in
humans (but less than that in animals).

- It is characterized by the following below the level of the lesion:
 Complete paralysis of muscles (i.e. power grade “0”).
 Loss of all types of sensation
 Hypotonia
 Loss of all types of reflexes: (superficial, deep, visceral & autonomic
reflexes)
Note: Deep reflexes reappear in the second phase and muscle tone
returns back in the third phase (see below). However, power, sensation
and superficial reflexes never return back.
Retention of Reflexes
- Reflexes start to reappear, usually higher than normal (hyperreflexia),
after the spinal shock.
- Generally visceral reflexes return earlier than tendon reflexes & flexors
before extensors; however, superficial reflexes like abdominal reflexes
remain absent as a sign of UMNL.
- The retained visceral (or autonomic) reflexes include the automatic
evacuation of the bladder and rectum and the spinal sexual reflexes
(erection and ejaculation).
- The retained deep tendon reflexes show hyperreflexia.
- The threshold of the retained withdrawal reflex is very low, that is why it
occurs in response to minor noxious stimuli. It also shows many features
like irradiation and after discharge (the limb remains in flexion for long
periods of time“= flexor spasm”).
- The mass reflex (see above) is sometimes used by paraplegic patients to
control micturition & defecation. It involves stroking the skin of the upper
thigh resulting in irradiation of impulses within the spinal cord; this
stimulates many reflexes including micturition, defecation, sweating and
limb withdrawal.

- In spinal animals, the positive supporting reaction can be demonstrated.
When a finger is placed on a sole of a foot, the limb extends following the
finger as it is withdrawan (magnet reaction). This reflex can support these
spinal animals to stand for 2-3 minutes.
Extensor contraction
- Occurs 3-4 weeks following the transection.
- Here tone returns back, usually higher than normal (hypertonia).
Hemisection of the spinal cord (or Brown Sequard Syndrome)

- Here there is transverse section of one half of the spinal cord.
- The same phases above will also occur.
- There are signs of LMNL at the level of the lesion (the damaged
segments) and signs of UMNL below the level of the lesion (the segments
that lost their connections with the brain).
Fig 14.10: Hemisection of the spinal cord
- There is characteristic sensory loss in Brown-Sequard syndrome:

 Loss of dorsal column tract sensations on the same side of the lesion
(fine touch and pressure, position sense, vibration and two point
discrimination).
 Loss of spinothalamic tract sensations on the other side (pain,
temperature, crude touch and itching sensation).

 Hyperaesthesia: (Increased sensitivity to cutaneous stimulation due to
a diminished threshold or an increased response to stimuli) occurs in
the skin supplied by the segments immediately above the level of the
lesion.
Complications of spinal cord transection:

- Immobilized patients suffering from quadriplegia or paraplegia develop
serious complications that eventually lead to death. These include:
 Skin Breakdown: (also termed “bed or pressure sores”). Occurs due
to pressure of bones (especially bones of the buttock) on the skin
blood vessels causing big ulcers; known as decubitus ulcers. These
ulcers may become infected causing septicemia.
- They can be prevented by proper nursing (changing postion of the
immobilized patient regularly, from one side to another).
 Protein breakdown: Occurs in almost all immobilized patients (-ve
nitrogen balance).
 Osteoporosis: In immobilized patients (with decreased muscle activity
and no bearing of weight) bones begin to lose protein matrix.
 Hypercalcemia & hypercalciuria: Immobilization increases bone
resorption. This results in hypercalcemia & hypercalciuria.
 Renal stones: Loss of high amount of calcium in urine predisposes to
stone formation.
 Hypoventilation & aspiration pneumonia: Patients with spinal cord
injuries above the T4 level are at increased risk to develop respiratory
complications like hypoventilation & aspiration pneumonia.
 Autonomic Dysreflexia: It is related to disconnection between the
higher control mechanisms and their targets resulting in swinging of
blood pressure and some bouts of sweating.

 Deep vein thrombosis (DVT) & pulmonary embolism:
Immobilization causes stasis of blood and therefore predisposes to
DVT & pulmonary embolism.
 Urinary tract infection (UTI): A very common complication of spinal
cord transection. It is predisposed by urinary stasis (caused by bladder
paralysis and stone formation).
THE PYRAMIDAL SYSTEM

- The pyramidal system is a major motor system comprised of:
 The corticospinal tracts (ventral & lateral)
 The corticobulbar tract
- It is called “pyramidal system” because the descending axons of the
lateral corticospinal tract form the pyramids in the medulla; however, other
axons of the pyramidal system do not pass through the pyramids in the
medulla and they are not described as “extrapyramidal”!
- The lateral corticospinal neurons are concerned with fine, skilled
movements (movements of the distal limb muscles: fingers, hands & feet)
whereas the ventral corticospinal neurons are concerned with postural
adjustments and gross movements (movements of the trunk and proximal
limb muscles).
- The corticobulbar neurons are involved with movements of the neck,
face, oral cavity, and larynx.
- Damage to either the corticospinal or corticobulbar tracts above the level
of the decussation in the medulla or the efferent cranial nerve nuclei (see
below) in “humans”, results in inability to perform voluntary movements on
the opposite side of the body.

Origin of the pyramidal system “The cortical motor areas”
- The corticospinal & corticobulbar tracts originate from the following motor
areas in the cerebral cortex:
 The motor cortex
o The area of the precentral gyrus in the frontal lobe (also known
as the primary motor cortex, M1 or Brodmann's area 4).
o Represents the origin of about 30% of the neurons in the
pyramidal system
o Receives projection from the supplementary motor area. This
supplementary area is concerned with planning and
programming motor sequence.
o Also receives projection from the premotor cortex.
 The premotor cortex
o Found on the lateral surface of the brain.
pyramidal system.
o Connected to the motor cortex the postural control areas in the
brain stem and the somatic sensory areas.
o Its function is unknown; it may be concerned with setting
suitable posture to perform planned movements.
 The posterior parietal lobe & the somatic sensory areas (I & II)
o Somatic sensory area I (in post central gyrus) & area II (on the
wall of Sylvian fissure).
pyramidal system.
o Lesions affect motor performance of some learned, skilled
movements.

Note:
- The body is represented in the precentral gyrus “upside-down”, with feet
at the top and face at the bottom of the gyrus.
- The size of representation at the motor cortex is proportional to the
degree of skill with which that part of the body moves. For example, the
size of the areas that control hand and finger movements (especially the
thumb) and speech movements (especially the lips and tongue) are very
large, compared with the areas for trunk and proximal limb movements.
- These motor maps of the motor cortex are not rigid; a specific area may
enlarge with experience or shift to another area when affected by a lesion
(= plasticity of motor cortex).
- Each side of the motor cortex controls the opposite side of the body.
However, the dominant hemisphere (usually the left one, see chapter 15)
which mainly controls the right hand also participates in control of the left
hand.
Fig 14.11: The cortical motor areas

The pathways of the corticospinal tracts
 The corticospinal tract is the largest descending pathway in humans.
 It originates from the pyramidal cells (Betz cells) in the motor cortex
(and other brain cells in the premotor and somatosensory areas) in
each side of the brain and descends through the posterior limb of the
internal capsule, then through the cerebral peduncles of the midbrain
and then the pyramids of the medulla.
 About 80% of the fibres from each hemisphere, decussate in the
pyramidal decussation at the lower part of the medulla, and continue to
descend in the white matter of the spinal cord as the lateral
corticospinal tract of the opposite side.
 The remaining 20% continue to descend down ipsilaterally as the
ventral corticospinal tract of the same side; however, the fibers of this
tract end on interneurons at the spinal segments that supply the target
muscles. The interneurons supply motor neurons on both sides.
 The crossed fibres comprise both sensory axons and motor axons. The
sensory axons project into the dorsal horn of the grey matter, to exert
feedback regulation of the input pathways. The motor axons, as
mentioned above, terminate on motor neurons of the distal muscles
either directly, or indirectly via interneurons.
The pathway of the corticobulbar tract

 This pathway connects the motor cortex to the motor nuclei of the
cranial nerves in the brain stem that supply muscles of the face, head
and neck. Its axons, as in the corticospinal tract, descend from the
motor cortex through the internal capsule to the medial part of the
cerebral peduncle.
 The axons then synapse with the motor neurons of the cranial nerve
nuclei that are located in the brain stem (midbrain, pons and medulla).
Fig 14.12: The corticospinal tract
Lesions affecting the pyramidal system

- Selective damage to the pyramidal lobe, without damaging
extrapyramidal tracts, is expected to cause hypotonia and weakness
(flaccid paresis) rather than hypertonia & complete paralysis (spastic
paralysis). However, this selective damage rarely occurs clinically.
 Lesions at the cortex result in:
o Weakness in a limited area of the opposite side of the body (e.g. one
limb “monoparesis”, face or hand); because the pyramidal fibers are
widely distributed to be damaged by a localized lesion in the cerebral
cortex.
Note: this is the possible site of pure pyramidal lesions that cause
hypotonia.
 Lesions at the internal capsule result in:
o Paralysis or weakness in the opposite side of the body (hemiplegia or
hemiparesis); because fibers in the internal ccapsule are bundled

together so closely that a small stroke can damage all fibers coming
from one side of the motor cortex.
 Lesions at the brain stem result in:
o Paralysis or weakness in the opposite side of the body (hemiplegia or
hemiparesis) plus cranial nerve palsy contralaterl to the hemiplegia.
 Lesions at the spinal cord result in:
o Quadriplegia or paraplegia (in complete transection)
o Hemiplegia or monoplegia (in hemisection)
o The degree of motor deficit depends on the level of lesion (see above).
THE EXTRAPYRAMIDAL SYSTEM

- The extrapyramidal system is the major motor system in non-mammalian
species.
- In humans, it is the part of the motor system (excluding the pyramidal
system) that is involved in regulation of posture, muscle tone, and
involuntary movements.
- Unlike the pyramidal system, the neurons of the extrapyramidal system:
 Do not pass through the medullary pyramids
 Do not directly innervate motor neurons of the spinal cord or
brainstem (i.e. do not synapse directly with the lower motor
neurons).
- There is no definitive list of the extrapyramidal system structures, but all
lists would include:
 The basal ganglia
 The subthalamic nucleus
 The substantia nigra
 The cerebellum (the lateral portions)
 The red nucleus

- The extrapyramidal tracts (which arise from the brain stem and subcorticl
structures) target the motor neurons in the spinal cord; they are modulated
by various parts of the central nervous system (the basal ganglia,
cerebellum, vestibular apparatus and cerebral cortex).
- They include:
 Rubrospinal tract
 Tectospinal tract
 Vestibulospinal tract
 Reticulospinal tract
THE BASAL GANGLIA

- These are a group of interconnected subcortical nuclear masses found
bilaterally within the white matter of the brain. They include the following
structures:
 Caudate nucleus
 Putamen
 Globus pallidus
 Two other “functionally related” structures:
o The subthalamus
o The substantia nigra
 Historically, the amygdaloid nucleus (which is part of the limbic system)
was included with the basal ganglia; however, its function is different.
 The caudate + putamen form the corpus striatum.
 The globus pallidus + putamen form the lenticular nucleus.
 The globus pallidus has two segments: Internal segment & external
segment.

 The substantia nigra (meaning the black substance because its
neurons are pigmented with melanin) has two parts: Pars compacta &
pars reticularis.
Fig 14.13: The basal ganglia
Connections
The main afferent inputs to the corpus striatum:
 From the cerebral cortex (excitatory input by releasing glutamate; in
addition, some interneurons release acetylcholine).
 From substantia nigra (from pars compacta; inhibitory input by
releasing dopamine. Damage to this pathway, dopaminergic
nigrostriatal pathway, causes Parkinson’s disease)
- Remember that the substantia nigra also inhibits the thalamus & brain
stem by releasing GABA.
 Other afferent inputs to the corpus striatum come directly from the
limbic system and indirectly from the brain stem (through the
thalamus).

Fig 14.14: Connections of the basal ganglia
The main efferent outputs from the corpus striatum:

 To both internal and external segments of globus pallidus (direct and
indirect pathways; inhibitory outputs by releasing GABA).
 To substantia nigra (pars reticularis) which receives inhibitory output
from the corpus striatum by GABA.

Remember that: The efferent pathways towards the globus pallidus are
two pathways: direct and indirect. The direct pathway directly inhibits the
internal segment whereas the indirect pathway inhibits the external
segment that inhibits the internal segment (= indirect). The external
segment also inhibits subthalamus (see below).
- The inhibitory output from the corpus striatum to the globus pallidus
cancels the inhibitory effect of globus pallidus on the thalamus (see
below).
The main efferent outputs from the globus pallidus:

 Outputs from the external segment of the globus pallidus to the
subthalamus (inhibitory outputs through GABA).
 The subthalamus feeds back to the globus pallidus (internal and
external segments) through excitatory neurons that release glutamate.
 Outputs from the internal segment of the globus pallidus pass to the
thalamus.
o This is the principal output from the basal ganglia.
o It is an inhibitory output; the neurotransmitter is GABA
o The thalamus sends excitatory impulses to the cortex (the
prefrontal and the premotor cortex) to complete a loop.
 Other inhibitory outputs from the internal segment pass to the brain
stem.
Functions of the basal ganglia

- Still unknown; however, lesions in experimental animals and diseases
affecting the basal ganglia in humans suggest that they are concerned
with:
Planning and programming of voluntary movement.

Initiation of voluntary movement (discharge from the basal ganglia and
lateral portions of the cerebellum is noticed before a movement starts).
Associated movements (e.g. swinging the upper limbs while walking).
Inhibition of muscle tone.
Posture taken to perform some voluntary movements.
Cognitive function (the caudate nucleus).
DISEASES OF THE BASAL GANGLIA

- Damage to the basal ganglia has little effect on animals, but severe
effects on humans. In general, diseases of the basal ganglia are
characterized by: Hyperkinesia (excessive movement), hypokinesia
(poverty of movement) or both.
Parkinson’s disease (Paralysis agitans or Shaking palsy)

- “Parkinsonism” is a neurological syndrome characterized by the triad of
rigidity, akinesia and tremor, plus many other signs including stooped
posture and shuffling gait (see below).
- It is caused by a wide range of etiologies but the most common cause of
Parkinsonism is “Parkinson’s disease” which was originally described by
James Parkinson in 1817.
Pathogenesis of Parkinson’s disease
- Parkinson’s disease occurs due to degeneration of the dopaminergic
nigrostriatal neurons. This usually occurs in old subjects (above 65 y) due
to the aging process; however, the degree of degeneration in Parkinson’s
disease is accelerated due to unknown cause (= idiopathic).
- Loss of the dopaminergic nigrostriatal neurons releases the corpus
striatum (especially the putamen) from the inhibitory effect of dopamine
whereas the excitatory effect of acetylcholine becomes unopposed.

- This results in imbalance at the globus pallidus because of the higher
inhibition from the corpus striatum, especially on the external segment
(through the indirect pathway).
- Accordingly, the internal segment of the globus pallidus receives less
inhibition (through the indirect pathway) and more excitation (from the
subthalamus).
- Therefore, the inhibitory discharge from the internal segment of the
globus pallidus to the thalamus is increased, and the excitatory discharge
from the thalamus to the cerebral cortex is decreased resulting in the
clinical features of the disease.
Fig: 14.15: Pathogenesis of Parkinson’s disease
Other causes of Parkinsonism

- Damage to the substantia nigra or loss of the dopaminergic nigrostriatal
neurons may also occur due to:
 Dopamine antagonists which block D2 receptors. These include:
o Antipsychotic drugs like haloperidol & chlorpromazine
o Antiemetic drugs like metoclopramide
o Antidepressant drugs like the tricyclic antidepressants

 Repeated head trauma (such as injuries sustained in boxings)
 Toxins like MPTP (1-methyl-4-phenyl-tetrahydropyridine) which is a
byproduct of an improper technique for synthesizing a form of synthetic
heroin
 Cerebral atherosclerosis
 Encephalitis
 Parkinson’s Plus syndromes (Group of neurological disorders
characterized by neuronal degeneration at various parts of the CNS.
They have comlex clinical presentations; however, since they have
Parkinsonian features in common, they are known collectively as
Parkinson’s Plus syndromes). They include:
o Multiple system atrophy
o Shy Drager syndrome
o Olivopontocerebellar atrophy
o Striatal Nigral Degeneration
o Progressive supranuclear palsy
o Corticobasilar ganglionic degeneration
Note: The Parkinson’s Plus syndromes differ from Parkinson’s disease in
that: they show no response to dopamine, they may present with ocular
signs (e.g. failure of upward & downward gaze) and they may present with
early onset of dementia, postural instability and autonomic dysfunction
(e.g. postural hypotension or urinary incontinence).
Clinical features of Parkinson’s disease

- Symptoms appear when the majority of the nigrostriatal neurons are lost
(loss of 60-80%).
- The major feature is the triad of rigidity (hypertonia), akinesia and tremor:
 Rigidity
o Defined as hypertonia in both agonists and antagonists
o Types of rigidity (hypertonia) in Parkinson’s disease:
 Lead pipe & cog-wheel
o Hypertonia affects flexors more than extensors (resulting in
stooped posture) & proximal muscles more than distal muscles.
 Akinesia
o Defined as poverty of movements
o Failure to initiate movement is an example of akinesia
 Tremor
o Regular rhythmic tremor (with a rate of about 4-8 Hz).
o Because of the thumb movements, it is described as pill-rolling
tremor.
o Occurs mainly at rest, increases with emotions & disappears
with activity.
o Occurs due to regular, alternating contractions of agonist and
antagonist muscles.
Note: Akinesia is a hypokinetic feature whereas tremor and rigidity are
hyperkinetic features (= Both hyper and hypokinetic features are present).
-Other signs:
 Expressionless face (mask face)
 Decreased blinking (detected by the glabbellar reflex)
 Loss of associated movements
 Failure to elevate the lower limbs while walking (Shuffling gait); with
progressive increase in speed of walking (festination)
 Soft & slow monotonous speech (due to reduced movements of the
muscles involved in speech and failure to initiate sentences)
 Difficulty in writing (micrographia)
 Drooling of saliva (due to decreased frequency of swallowing)
 Anxiety & depression

 Impaired recent memory
 Dementia (late sign)
Diagnosis
- The diagnosis of Parkinson’s disease is based on medical history and
neurological examination. There is no specific test for confirmation.
Treatment
Dopamine (in form of L-dopa “levodopa”):
 This is to replace the lost dopamine in the basal ganglia
 Levodopa “a precursor of dopamine” is given because dopamine can
not cross the blood brain barrier (BBB) whereas levodopa can.
However, L dopa should be combined with a decarboxylase inhibitor
(e.g. Carbidopa) that prevents decarboxylation of L dopa to dopamine
in the peripheral tissues (to prevent the side effects of dopamine).
 Example of this combination: SINEMET ® (Carbidopa-Levodopa).
 Dopamine agonists (like Bromocriptine) are also helpful.
 The therapeutic effects of dopamine disappear in 5-7 years
Anticholinergics
 To decrease the excitation of the corpus striatum by the cholinergic
neurons
 Example: Artane ® (Trihexyphenidyl)
Surgery
- Still under development but may help to control symptoms refractory to
medical treatment). Surgical procedures include:
 Pallidotomy (lesions in the globus pallidus “internal segment”)
 Implanting electrodes “deep brain stimulation”
 Implantation of dopamine secreting tissues in the region of basal
ganglia (e.g. Patient’s own adrenal medulla, carotid body or fetal
striatal tissue).

Hyperkinetic abnormalities
Chorea
- Due to damage to the caudate nucleus (with or without the putamen)
resulting in less release of GABA & therefore less inhibition of the globus
pallidus.
- Characterized by spontaneous, uncontrolled, non-repetitive dancing
movements of the distal extremities and muscles of the face, tongue, and
pharynx.
- It increases with emotions (e.g. when a patient is aware of being
watched).
- Associated with hypotonia.
- Causes:
 Rheumatic fever (chorea is one of the cardinal features of
rheumatic fever).
 Huntington’s disease (genetic problem inhertited as AD; appears
between 30-50 years of age. Its abnormal gene in chromosome 4 is
characterized by multiple trinucleotide repeats of cytosine-adenine-
guanine “CAG”).
- Treatment: Dopamine antagonists (e.g. haloperidol).
Athetosis
- Occurs due to damage to the globus pallidus.
- Characterized by involuntary, continuous, slow writhing (twisting)
movements of the hands, and feets (distal parts of the body); but other
parts like the neck & face may be affected.
- Associated with spasm of the affected muscles (varying degrees of
hypertonia).
- Treatment: Anticholinergic drugs.

Ballism
- Occurs due to lesions to the subthalamic nucleus.
- Characterized by violent, flailing contractions of the proximal limb
muscles (arms and legs).
- Usually affects one side of the body (= Hemiballismus) as in unilateral
stroke.
- May be associated with hypotonia.
- Treatment: Dopamine antagonists (e.g. haloperidol or phenothiazines).
THE CEREBELLUM
Structure
- The cerebellum (= the little brain) is the part of the nervous system that is
concerned with coordination of motor functions of the brain.
- It lies in the posterior fossa, dorsal to the brain stem and inferior to the
occipital lobe.
- It is connected to the brain stem by three bundles of white matter:
 Superior peduncle
 Middle peduncle
 Inferior peduncle
- It consists of:
 Vermis (lies in the central part of the cerebellum; divided into 10
smaller lobules).
 Two hemispheres (lie lateral to the vermis).
- Compared to the cerebral surface, the surface of the cerebellum has:
 Less weight (about 10% of that of the cerebral cortex)
 Less surface area (about 75% of that of the cerebral cortex)
 More extensive folds and fissures (these increased the surface area
to a relatively high degree if compared with the low weight).

Divisions of the cerebellum
Anatomical divisions:
- Divided by two fissures (the primary fissure and the posterolateral
fissure) into 3 lobes:
1. Anterior lobe
2. Posterior lobe
3. Folliculo-nodular lobe
Functional divisions:
1. Vestibulocerebellum
o = The flocculonodular lobe
o Has vestibular connections (receives input from the semicircular
canals and the vestibular nuclei and sends output back to the vestibular
nuclei).
o Also receives input from the visual cortex through the pons (the
cortico-ponto-cerebellar pathway).
o Concerned with equilibrium (balance) and eye movement.
2. Spinocerebellum
o = The vermis + adjacent medial parts of the hemispheres.
o Receives proprioceptive sensation through the spinal cord
(spinocerebellar tracts) and a copy of motor plan from the cerebral
cortex; by comparing them, it coordinates movements of the body.
o The vermis controls movement of axial and proximal limb muscles.
o The hemispheres control movement of distal limb muscles.
o It also receives input from the trigeminal nerve, the visual and the
auditory systems.
o It sends fibers to the deep cerebellar nuclei which in turn project to
the brain stem and the cerebral cortex (to modulate the descending
motor plan).

3. The neocerebellum
o = Cerebro-cerebellum
o Well developed in humans than animals.
o Participates in planning and programming of movements.
o It receives input exclusively from the cerebral cortex (especially the
parietal lobe) via the pontine nuclei (forming cortico-ponto-cerebellar
pathways).
o It sends fibres mainly to the ventrolateral nuclei of the thalamus.
Fig 14.16: Devisions of the cerebellum
The deep cerebellar nuclei & the cerebellar cortex

- The gray matter of the cerebellum is formed by the cerebellar nuclei
(deep) and the cerebellar cortex (superficial). They are separated from
each other by white matter.
The deep cerebellar nuclei include:
 Dentate nucleus

 Globose nucleus
 Emboliform nucleus
 Fastigial nucleus
- Note: Globose + emboliform = Interpositus nucleus.
The cerebellar cortex contains 5 types of cells:
 Purkinje cells (inhibitory; release the neurotransmitter GABA)
 Granular cells (excitatory; release the neurotransmitter Glutamate)
 Basket cells (inhibitory; release the neurotransmitter GABA)
 Golgi cells (inhibitory; release the neurotransmitter GABA)
 Stellate cells (inhibitory; release the neurotransmitter GABA)
The cerebellar cortex consists of 3 layers:
 Superficial molecular layer:
- Contains two types of inhibitory cells: stellate and basket cells.
- It also contains the dendritic arbors of purkinje cells and parallel fibers
from the granular cells. These form many synapses with each other.
 Middle (Purkinje) layer:
- Contains the Purkinje cells (very big cells with extensive dendrites).
- The Purkinje cells receive excitatory input from:
o The climbing fibers (coming from the inferior olivary nucleus in
the medulla)
o The parallel fibers (from the granular cells)
- The Purkinje cells receive inhibitory input from:
o The Basket cells
- The Purkinje cells send inhibitory output to:
o The deep cerebellar nuclei.
 Deep granular layer:
- Contains two types of cells: granular cells and golgi cells.
- The granular cells are the most numerous neurons in the brain.

- They receive excitatory input from Mossy fibers (coming from the
pontine nuclei) and inhibitory feedback from the golgi cells (note that
the golgi cells are excited by the granular cells and Mossy fibers).
- They send T-shaped axons (known as parallel fibers to the superficial
molecular layer to synapse with the dendrites of the Purkinje cells).
Fig 14.17: Connections within the cerebellum
The cerebellar inputs and ouputs:

- The main afferent input to the cerebellar nuclei and cortex comes
through:
 Climbing fibers
o Excitatory to the Purkinje cells and the deep cerebellar
nuclei.
o Comes from the medulla (inferior olivary nucleus).

 Mossy fibers
o Excitatory to the granular cells, Golgi cells and and the deep
cerebellar nuclei.
o Comes from the pons (pontine nuclei).
o Efferents from the cerebellar cortex to the deep cerebellar
nuclei pass through the axons of Purkinje cells, the only cells
that leave the cerebellar cortex.
o Efferents from the cerebellar cortex to outside of the
cerebellum are always excitatory.
- They pass from and to the following sites:
 From the vestibulocerebellum to the brain stem (pass directly, not
through the deep nuclei).
 From the spinocerebellum to the deep nuclei (all the nuclei except
the dentate) and then to the brain stem.
 From the neocerebellum to the dentate nucleus and then to the
ventrolateral thalamus.
Functions of the cerebellum

 Coordination of voluntary movements (controls the rate, range and
direction of movement).
 Increases muscle tone (send facilitatory impulses to the Aγ motor
neurons).
 Controls posture and balance (has connections with the vestibular
apparatus).
 Makes adjustments and predictions (based on prior learning and
experience) to make the repeated motor tasks easier (i.e. can be
done with greater speed, greater accuracy and less effort). After
some time these tasks can be done automatically.

Note: About learning in the cerebellum:
- Learning in cerebellum depends on the input from the olivary nuclei to
the Purkinje cells; through the climbing fibers. Each Purkinje cell receives
input from one climbing fiber. However, its dendrites make a lot of
synapses with it.
- The input from the climbing fibers produces a large and complex spike in
the Purkinje cell. This spike modifies the pattern of input from the mossy
fibers to the same Purkinje cell.
Cerebellar ataxia
- Ataxia (meaning lack of coordination) is defined as incoordination of
voluntary motor activity due to errors in rate, range, force and direction of
movement.
- There are many types of ataxia (e.g. cerebellar ataxia, sensory ataxia,
vestibular ataxia …).
- Cerebellar ataxia also comprises many types of ataxia resulting from
damage to various parts of the cerebellum (e.g. deep cerebellar nuclei,
spinocerebellum, vestibulocerebellum or neocerebellum).
- Generally, damage to the deep cerebellar nuclei produces more
generalized defects than damage to the other parts of the cerebellum.
- In general, cerebellar ataxia is caused by:
 Toxic substances like alcohol and some drugs (e.g.
anticonvulsants, barbiturates …)
 Tumors of the cerebellum
 Autoantibodies (e.g. paraneoplastic cerebellar degeneration)
 Viral encephalitis and cerebellar abscess
 Hereditary problems (Spinocerebellar ataxia, Friedreich’s ataxia …)
 Congenital problems (e.g. Arnold Chiari malformation)

- Signs of cerebellar ataxia:
 Wide based, unsteady gait (described as drunken man gait)
 Nodding of the head (yes-yes or no-no movements)
 Nystagmus (jerky movements of the eyeball; usually horizontal in
this type of ataxia)
 Dysarthria (slurred speech; described as scanning speech)
 Tremor (irregular, large amplitude, coarse tremor, absent at rest,
occurs when a patient stretches his hand out to reach something;
therefore it is described as kinetic or intention tremor).
 Past pointing or dysmetria (due to loss of the braking effect of the
cerebellum)
 Dysdiadochokinesia or adiadochokinesia (failure to do rapid
alternating opposing movements; e.g. repeated supination &
pronation of the hands).
 Hypotonia (due to loss of the facilitatory effect on the Aγ discharge)
 Rebound phenomenon (due to loss of the braking effect of the
cerebellum; for example, when a patient is asked to flex his forearm
against reistance and then the resistance is suddenly released, he
can not stop the forearm before striking his face or shoulder).
 Decomposition of movement (the patient performs actions that
require simultaneous movements of more than one joint in stepwise
manner; i.e. each joint at a time).
 Difficulty in swallowing (due to incoordination; appears as coughing
or choking).

CONTROL OF POSTURE
- Control of posture is due to integration of reflexes at various levels of the
CNS. Centers of integration include:
 Spinal cord
 Medulla
 Midbrain
 Cerebral cortex
- These centers of integration send multiple inputs that converge on the
cell bodies of spinal motor neurons and the equivalent neurons in the
cranial nerves.
- It is the integrated activity of these multiple inputs that regulate posture of
the body.
- The spinal reflexes are simple whereas the reflexes which are integrated
at higher levels are more complex.
- Postural reflexes not only maintain the body in an upright, balanced
position; but also produce the necessary adjustments in posture before
and during the voluntary activity.
- Therefore they can be grouped into:
 Static reflexes (produce sustained contraction of muscles to
maintain posture).
 Dynamic or phasic reflexes (produce transient movements for
postural adjustments).
- As mentioned above, these postural reflexes are affected by neural
pathways from various levels in the CNS. Therefore, a transection in the
CNS releases reflexes below the level of transection from control of higher
centers; therefore they appear to be accentuated.
- For this reason, postural reflexes were studied in experimental animals in
which the neural axis was transected at various levels.

- Sites of transection in experimental animals include:
 At the superior border of the pons:
o Results in decerebrate rigidity
o This rigidity is in fact “spasticity”; it develops immediately (no
neuronal shock) in the extensors of the four limbs in animals
(i.e. antigravity muscles).
o It can be explained by increased Aγ discharge & by direct
increased excitability of Aα neurons.
Note:
- Decerebrate rigidity allows study of medullary reflexes in animals. It is
rare in humans because it is incompatible with life. However, animals like
cats and dogs can stand, walk and run after complete destruction of the
pyramidal tracts.
- In patients with decerebrate posturing, the head is arched back, the arms
are extended by the sides, and the legs are extended (= known as
extension posturing).
Fig 14.18: Posture of decerebrate rigidity
 At the superior border of the midbrain:

o Results in extensor rigidity similar to decerebrate rigidity.

o The rigidity develops due to increased A gamma discharge.
However, it appears only at rest and not during movement;
because during movement it is obscured by the phasic postural
reflexes.
Note: This level of transection in animals allows study of the midbrain
reflexes “midbrain animals”. These animals can stand walk and right
themselves (i.e.correct their posture). Therfore, unlike the medullary
reflexes, midbrain reflexes include righting reflexes.
 At the cerebral cortex:
o Results in decorticate rigidity
o The rigidity develops due to loss of the cortical area that inhibits
the A gamma discharge. However, as in midbrain animals, it
appears only at rest and not during movement; because during
movement it is obscured by the phasic postural reflexes.
o All the reflexes in midbrain animals are also present in
decorticate ones. In addition, decorticate animals can survive for
longer periods of time. In humans, decorticate rigidity can be
seen in hemiplegic patients.
o Patients with decorticate posturing present with the arms flexed,
or bent inward on the chest, the hands are clenched into fists,
and the legs extended (= known as flexion posturing).
Fig 14.19: Posture of decorticate rigidity

- It is important to note that most of the postural reflexes are present in
humans during the early neonatal period (therefore they are known as
primitive reflexes); however, they disappear after afew months (after full
development of the nervous system). Persistance of these reflexes after
infancy indicates congenital brain damage (= cerebral palsy).
Spinal cord reflexes

o As mentioned above, transection of the spinal cord allows
study of spinal cord reflexes.
o These reflexes include:
 Stretch reflex
o Receptors: Muscle spindle (stimulated by stretch)
o Response: Muscle contraction
 Withdrawal reflex
o Receptors: Skin receptors (stimulated by noxious stimui)
o Response: flexion of the same limb (to get away from the
stimulus) & extension of the other (to support the body)
 Positive supporting reaction
o Receptors: Proprioceptors in distal flexors
o Response: Extension of the lower limbs to support the body
- When a finger is placed on a sole of a foot, the limb extends following the
finger as it is withdrawan (magnet reaction). This reflex can support the
spinal animals to stand for 2-3 minutes.
 Negative supporting reaction
o Receptors: Proprioceptors in extensors
o Response: Release of the positive supporting reaction
- When the sole of the foot is raised up from the supporting surface, the
limb is flexed (the opposite response to the above reflex).

Fig 14.20: Positive & negative supporting reactions
Medullary reflexes
- As mentioned above, decerebrate rigidity allows study of medullary
reflexes in animals.
- Appearance of spasticity after decerebration in the extensors of the four
limbs explains how these static (or tonic) reflexes support the body against
gravity.
- Investigations in animals showed that the pattern of decerebrate rigidity
is affected by:
 Position of the body (whether the animal stays prone, on its side or
on its back; the change in postion is detected by the otolithic organ
in the innere ear “the labyrinthe” and the resulting reflexes are
known as labyrinthine reflexes. These medullary reflexes are static
“tonic” since no correction of posture occurs (i.e. no righting reflex)).
 Movement of the head relative to the body (this produces static
(tonic) medullary reflexes that support the body in its new position;
the receptors that detect the movement of the head are
proprioceptors in the neck and the responses are flexion in some
limbs and extension in others).
- The medullary reflexes include:
 Tonic labyrinthine reflexes
o Receptors: Otolithic organ in the inner year (detects change
in position of the body in relation to gravity)
o Response: increase or decrease in the tone of antigravity
muscles.
o Example: Placing a decerbrate animal on its back (supine
position) produces extension in all limbs, on its side
decreases the rigidity and on the prone postion decreases it
further to a very minimal degree in extensors (but increases
rigidity in flexors).
Fig 14.21: Tonic labyrinthine reflexes in a child with cerebral palsy
 Tonic neck reflexes

o Receptors: Neck proprioceptors (detect movement of the
head relative to the body)
o Response: extension in some limbs and flexion in others
o Examples: Turning the head to:
 Left side: causes extension of limbs in the left &
decreases rigidity in the right side; the opposite occurs
on turning the head to the other side.
 Up: causes flexion of lower limbs and extension of
upper limbs

 Down: causes flexion of upper limbs and extension of
lower limbs
Fig 14.22: Tonic neck reflexes in a neonate
Midbrain reflexes
- As mentioned above, mid brain reflexes were studied in midbrain
animals.
- The rigidity appears due to midbrain static responses (in the absence of
phasic responses).
- The phasic responses (known as righting reflexes) appear due to
stimulation of various receptors including the otolithic organ, muscle
spindle, visual cues and exteroceptors. They act to maintain the normal
upright position of the head and the body. They include:
 Labyrinthine righting reflexes
o Receptors: Otolithic organs (stimulated by tilting the head)
o Response: contraction of the neck muscles to upright the
head
 Body on head righting reflex
o Receptors: Exteroceptors on one side of the body
(stimulated by pressure on that side; when the animal is laid
on its side)
o Response: contraction of the neck muscles to upright the
head (even if the labyrinthine is destroyed).

 Neck righting reflexes
o Receptors: Muscle spindle in the neck muscles (stimulated
when the head is upright but the body is tilted)
o Response: Contraction of the neck muscles to correct the
thorax then abdomen and pelvis.
 Body on body righting reflex
o Receptors: Exteroceptors on one side of the body
(stimulated by pressure on that side; when the animal is laid
on its side)
o Response: Muscle contraction to upright the body even if the
head is prevented from righting.
 Vestibular placing reaction
o Receptors: Otolithic organs (stimulated by lowering a
blindfolded animal rapidly)
o Response: Preparation of the animal to land (by extending
its legs and spreading its toes).
Note: if the eyes of the animal are not blindfolded, they act as receptors to
another type of placing reaction integrated in the cerebral cortex, see
below.
Cerebral cortex reflexes

- Cortical reflexes are lost in decorticate animals. They include:
 Optical righting reflexes
o Receptors: The eyes (stimulated by visual cues)
o Response: Upright posture (righting) in the absence of
labyrinthine or body stimulation.
 Placing reactions
o Receptors: Various visual, exteroceptors and proprioceptors

o Response: Feet (or hands) placed firmly on a supporting
surface
 Hopping reactions
o Receptors: Muscle spindles (stimulated by lateral
displacement of an animal while standing)
o Response: Hopping to maintain the limbs in position to
support the body.
Fig 14.23: Optical placing reaction in a neonate
CONTROL OF VOLUNTARY MOVEMENT “SUMMARY”

- First, it is worth noting that much is still unknown about control of
voluntary movement.
- Before ordering and executing a voluntary movement it should be
planned.
- Planning occurs at the cortical association area, basal ganglia and lateral
parts of the cerebellum (the neocerebellum). Impulses from these sites are
transmitted to the ordering sites (the premotor and motor cortex) either
directly or through the thalamus.

- The premotor and motor cortex send their orders through the
corticospinal and corticobulbar tracts to the motor neurons to execute the
movement. They also send feedback information to the basal ganglia and
the neocerebellum; and a copy of the motor plan to the spinocerebellum.
- The spinocerebellum, to co-ordinate the movement, projects to the brain
stem which sends its main descending tracts (rubrospinal, reticulospinal,
vestibulospinal and tectospinal tracts) to the spinal motor neurons.
- The brain stem also receives direct input from the motor cortex and
collaterals from the corticospinal and coticobulbar tracts. Therefore its
tracts, in addition to co-ordination and regulation of posture, are also
concerned with voluntary movements.
The muscles which execute the movement and the, joints, ligaments and
skin send feedback information to the motor area and the
spinocerebellum.

1. Long standing lower motor neuron lesions are characterized by:
a. Clonus
b. Fasciculation
c. Extensor plantar response
d. Wasting of affected muscle
e. Rigidity
2. The gamma motor discharge is inhibited by:
a. Motor area 4 of the cerebral cortex
b. The cerebellum
c. The vestibular nuclei
d. Medullary reticular formation
e. Pontine reticular formation
3. The spinal shock phase of complete spinal cord transaction is
characterized by:
a. Muscle wasting
b. Rigidity
c. A reflexia
d. Loss of touch sensation just above the lesion
e. Fasciculation
4. The muscle spindle:
a. Is the receptor of the inverse stretch reflex
b. Is supplied by A alpha motor neurons
c. Results in relaxation of extrafusal fibers in response to over stretch
d. Is Stimulated when extrafusal fibers contract
e. Is stimulated by the gamma motor discharge
5. All the following statements about Renshaw cells are correct except
that they are:
a. Inhibitory interneurons
b. Found in the grey matter of the spinal cord
c. Excited by collaterals from alpha motor neurons as they leave the
spinal cord via the ventral root
d. Representative of negative feedback mechanism that controls firing
of alpha motor neurons
e. Cholinergic neurons
6. The muscle spindle is not:
a. Stimulated by stretch
b. Innervated by Ia afferents
c. Covered by a connective tissue capsule
d. Acting as a receptor of a deep reflex
e. Found in tendons of muscles
7. The following is a polysynaptic reflex:
a. The knee jerk reflex
b. The withdrawal reflex
c. The ankle jerk reflex

d. The biceps jerk reflex
e. The inverse stretch reflex
8. The inverse stretch reflex is:
a. Caused by stimulation of the Ia sensory afferents
b. Caused by stimulation of alpha motor efferent
c. Induced by over stretch of the muscle tendon
d. Protective against over excitation of the muscle spindle
e. A monosynaptic reflex
9. In a lower motor neuron lesion there is:
a. Exaggerated abdominal reflexes
b. Hypotonia
c. Persistent fasciculation
d. Minimal muscle wasting
e. Hyperreflexia
10. Cog wheel rigidity is a feature of:
a. Pyramidal lesions
b. Cerebellar ataxia
c. Parkinsonism
d. Chorea
e. Spinal cord transaction
11. Parkinson’s disease is characterized by:
a. Muscle weakness
b. Muscle wasting
c. Kinetic tremors
d. Spasticity
e. Brady-kinesia
12. Athetosis is caused by damage to:
a. Corpus striatum
b. Substantia nigra
c. Subthalamus
d. Globus pallidus
e. Thalamus
13. The following does not occur in Parkinson's disease:
a. Clonus
b. Akinesia
c. Mask face
d. Rigidity
e. Tremor
14. Chorea occurs due to damage to the:
a. Caudate nucleus
b. Lenticular nucleus
c. Globus pallidus
d. Substantia nigra
e. Subthalamus
15. The following is not a basal ganglia structure:
a. Putamen

b. Subthalmic nucleus
c. Thalamus
d. Globus pallidus
e. Caudate nucleus
16. Which of the following is characterized by muscle paralysis:
a. Syringomyelia
b. Cerebellar ataxia
c. Parkinson’s disease
d. Hemibalismus
e. Vestibular damage
17. Athetosis is caused by damage to:
a. Corpus striatum
b. Substantia nigra
c. Subthalamus
d. Globus pallidus
e. Thalamus
18. The following represents a spinocerebellar function:
a. Planning of voluntary movement
b. Initiation of involuntary movement
c. Coordination of voluntary movement
d. Inhibition of muscle tone
e. Control of bladder function
19. Cerebellar lesions result in:
a. Resting tremor
b. Muscle wasting
c. Dysmetria
d. Micrographia
e. Exaggerated reflexes
20. The stretch reflex is:
a. Polysynaptic reflex
b. Superficial reflex
c. Integrated in the spinal cord
d. Exaggerated in lower motor neuron lesions
e. Not found in children
21. All the following abnormalities are characterized by tremors except:
a. Cerebellar disease
b. Subthalamic lesion
c. Substantia nigra lesion
d. Hyperthyroidism
e. Stress
22. The optical righting reflex is integrated at:
a. The spinal cord
b. The medulla oblongata
c. The midbrain
d. The cerebral cortex
e. The cerebellum

23. The stretch reflex is:
a. Polysynaptic reflex
b. Visceral reflex
c. Integrated in the brain stem
d. Absent in lower motor neuron lesions
e. Not found in children
24. Which of the following is a medullary postural reflex:
a. The positive supporting reaction
b. The corneal reflex
c. The tonic labyrinthine reflex
d. The hopping reaction
e. The body on body righting reflex
25. The following does not occur in Parkinson's disease:
a. Stooped posture
b. Shuffling gait
c. Kinetic tremor
d. Hypertonia in both agonists and antagonists
e. Bradykinesia
26. A lesion at superior border of the pons in an experimental animal
results in all the following except:
a. Decerebrate rigidity
b. Easy demonstration of tonic neck reflexes
c. Hypertonia that develops immediately
d. Extended posturing
e. Appearance of righting reflexes
27. The deep cerebellar nuclei are directly inhibited by:
a. Granular cells
b. Purkinje cells
c. Climbing fibers
d. Mossy fibres
e. Golgi cells
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
d d c e e e b c b c e
12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.
d a a c a d c c c b d
23. 24. 25. 26. 27.
d c c e b

CHAPTER (15)
AWAKE & SLEEP STATES
INTRODUCTION
- Perception of the various sensory impulses that ascend through the
sensory pathways requires processing in the alert or conscious brain.
- Radiation of impulses within the cerebral cortex, especially between the
thalamus and the cortex, produces characteristic patterns in the EEG (see
below) and correlates well with the behavioral state (i.e. degree of
alertness).
- Afferents from the specific nuclei of the thalamus (the medial & lateral
geniculate bodies and the ventrobasal nuclei) terminate on layer IV of the
neocortex whereas afferents from the non specific nuclei (the midline and
the intralaminar nuclei) terminate on the layers I-IV.
- The behavioral states range from deep sleep through light sleep, REM
sleep, and the two awake states: relaxed awareness and full awareness
with concentrated attention.
THE RETICULAR FORMATION

& THE RETICULAR ACTIVATING SYSTEM
- The reticular formation is a complex area of small interconnected
neurons located within the brain stem and has ascending and descending
extensions.
- The ascending extension (known as the reticular activating system
“RAS”) projects to all areas of the cerebral cortex. It is composed of
several neurons connecting the brain stem with the cerebral cortex. It is
concerned with arousal, attention and sleep (see below).
- The descending extension participates in control of motor activity (see
below).

Fig 15.1: The reticular formation
Functions of the reticular formation:

o Motor functions:
 Receives collaterals from the spinothalamic tract and receives input
from the cerebral cortex and the red nucleus and projects to the
cerebellum.
 Sends 2 descending tracts (= medial and lateral reticulospinal
tracts) that carry motor commands generated in the reticular
formation itself.
 The descending tracts also receive input from the cerebral cortex
and the basal ganglia.
o Sensory functions:
 Sends descending tracts to inhibit some sensory pathways in the
spinal cord (related to pain perception).
 Receives collaterals from ascending sensory tracts.
o Visceral functions:
 Contains many of the areas concerned with regulation of heart rate,
blood pressure and respiration.
o Level of consciousness.
 Sends ascending tracts (= ascending reticular activating system
“RAS”) to make direct connections with the thalamus,
hypothalamus, basal ganglia and cerebral cortex. Those to the
thalamus terminate in the intralaminar nuclei and from there project
to widespread area in the cerebral cortex.
 These ascending tracts “RAS” are concerned with arousal, attention
and sleep.
 Bilateral damage to these tracts results in coma.
THE ELECTROENCEPHALOGRAM “THE EEG”

- A record of the electrical activity of the brain using electrodes.
- The electrodes are placed on the scalp or directly on the surface or
within the cortex of the brain.
- The recording may be unipolar or bipolar.
Types of normal EEG waves:
 Alpha waves
o Frequency 8-12 Hz (or cycle/s) in humans; slightly more rapid
in some animals.
o Amplitude about 50-100 microvolt (when recorded from the
scalp).
o Appear mainly on the parieto-occipital region (but also
observed in other areas).
o Recorded when the adult subject is a wake, relaxed and
closing his eyes.
o Disappears or replaced by rapid low voltage waves upon
opening the eyes or during emotional tension; this is known
as “alpha block”.

Fig 15.2: Alpha waves
 Beta waves
o Have higher frequency: 18-30 Hz & less amplitude.
o Seen on the frontal region.
o Recorded during emotional tension; however, highly
concentrated attention may result in appearance oscillations
with more rapid frequency (> 30 Hz). These are known as
“gamma oscillations”.
Fig 15.3: Beta waves
 Theta waves
o Have less frequency: 4-7 Hz & higher amplitude: about 100
microvolt.
o Recorded in children from the parietal and temporal regions.
o Can be recorded in adults during sleep (stage 2&3).
Fig 15.4: Theta waves

 Delta waves
o Have the least frequency: 1-3.5 Hz & the highest amplitude.
o Recorded in children from the occipital regions.
o Can be recorded in adults during sleep (stage 4).
Fig 15.5: Delta waves
Note:
- The type of the EEG rhythm is affected by the following factors:
 Age (alpha rhythm in the occipital lobe appears during adolescence).
 Behavioral state (ranging from deep sleep to concentrated attention).
 Hypoglycemia (decreases frequency of alpha waves).
 Hypothermia (decreases frequency of alpha waves).
 Hypercapnia (decreases frequency of alpha waves).
 Addison’s disease (decreases frequency of alpha waves).
 Hyperventilation (used to induce EEG abnormalities).
Clinical uses of the EEG
1- Diagnosis of epilepsy:
 Appearance of multiple spikes indicates grand mal epilepsy
Fig 15.6: Grand mal epilepsy

 Appearance of spikes and waves (typically 3 spike & wave
discharges per second) indicates petit mal epilepsy (or absence
seizures).
Fig 15.7: Alpha waves
2- Localization of space occupying lesions (e.g. brain tumor or subdural

hematoma):
 For example by appearance of unilateral delta waves in the EEG.
Fig 15.8: Delta waves
Epilepsy
- Epilepsy is a common neurolological disorder characterized by recurrent
unprovoked seizures.
- The seizures are transient signs and/or symptoms caused by abnormal,
excessive synchronous discharge of the neurons in the brain.

- There are two types of seizures:
 Partial (or focal seizures): when the source of the seizure in the
brain is localized. These are further divided into simple partial
seizure (when there is no loss of consciousness) or complex partial
seizure (when there is loss of consciousness).
 Generalized seizures: when the source of the seizure in the brain is
distributed. These are further divided according to their effects on
the body into: absence (or petit mal), tonic-clonic (or grand mal),
myoclonic, clonic and atonic seizures.
- The type of epilepsy can be diagnosed from history, examination and
investigations like the EEG, CT scan, MRI and other investigations.
- Epilepsy can be controlled by anti-epileptic drugs (e.g phenytoin,
carbamazepine …).
Note: Absence seizure (or petit mal seizure) occurs most often in children.
It involves a brief, sudden lapse of consciousness; during which the child
appears as staring into space for a few seconds. Although mild, the
attacks may be dangerous if they occur during certain activities like
swimming. In addition, they may occur hundreds of time each day thus
interfering with the school performance.
- Tonic-clonic seizure (or grand mal seizure) starts with loss of
consciousness and falling down. This is followed by a period of muscle
rigidity (tonic phase) lasting for about 15 to 20 seconds. Then a period of
violent, rhythmic convulsions (clonic phase) lasting for 1 to 2 minutes.
During the attack, some patients may pass urine or feces (= sphincteric
disturbance). Most seizures last from 30 seconds to five minutes. After the
seizure, patients may feel headache, drowsiness or confusion. Seizures
often occur randomly, but in some cases they are triggered by sleep
deprivation, excessive alcohol consumption and stimuli like light &sound.

SLEEP
- Sleep is a state of transient loss of consciousness from which a subject
can be aroused by appropriate stimuli.
Stages of sleep (from the EEG recording):
Alert wakefulness
–Beta waves (high frequency).
Quiet wakefulness
–Alpha waves (subject is relaxed, quiet and cloding his eyes).
Light sleep (stage 1)
–Rapid low-voltage waves broken by sleep spindles.
Slow- wave sleep (stages 2-4)
–Theta waves (stage 2 & 3)
–Delta waves (stage 4)
Types of sleep
- There are two different types of sleep:
 Slow-wave sleep (Non rapid eye movement; non REM)
 Rapid eye movement (REM)
 Slow-wave sleep (Non REM)
o Constitutes 75% of sleep time
o Exceedingly restful
o Associated with:
- Decrease in peripheral vascular tone
- Decrease in BP
- Decrease in respiratory rate
- Decrease in metabolic rate
- Delta and theta waves on the EEG
o Not associated with dreams:
- Called dreamless sleep
- Dreams may occur but cannot be remembered (because it is
not consolidated in the memory).
 Rapid eye movement sleep (REM)
o Occurs in episodes of 5-30 min, every 90 min.
o Constitutes 80% of total sleep in premature babies, 50% in
neonates and 25% in older children and adults; then falls further in
old subects.
o Tiredness decreases the duration of each episode ,but as the
person becomes restful, the duration is increased
o A person is more difficult to be awakened during the REM sleep.
o REM sleep is associated with:
- Rapid movement of the eyes
- Active dreaming (can be remembered later)
- Muscle tone is depressed (hypotonia)
- Excitation of reticular inhibitory centers
- Heart & respiratory rates may become irregular
- Ponto-geniculo-occipital spikes (PGO) & β waves in the EEG
Fig 15.9: Types of sleep

The ponto-geniculo-spikes (PGO) & beta waves in sleep:
- The PGO spikes are large phasic potentials that originate in the pons
and pass to the lateral geniculate body and then to the occipital cortex
(i.e. ponto-geniculo-occipital). They stimulate the inhibitory reticular
area and are therefore responsible for the hypotonia in REM sleep.
- The Beta waves indicate increased brain activity inspite of sleep
(therefore REM sleep is called paradoxical sleep).
Mechanism of sleep
- Sleep is an active process (not only an absence of wakefulness). This
was confirmed by many observations in experimental animals; for
example: Stimulation of certain sites in the brain causes sleep and EEG
pattern of sleep and inhibition of some parts of the RAS produces
alertness.
- Stimulation of the following sites may cause sleep:
o The diencephalon (including the posterior hypothalamus & the
intralaminar and anterior nuclei of the thalamus. The suprachiasmatic
nuclei of the hypothalamus are responsible for sleep circadian rhythm.
o The reticular formation in the medulla oblongata (areas around the
nucleus of tractus solitarius “NTS”).
o The Basal forebrain (the preoptic area and the diagonal band of
Broca).
o Mechanoreceptors in the skin (produce sleep possibly via the brain
stem).
Neurotransmitters in sleep
- The neurotransmitter responsible for sleep is still unknown.
- The following neurotransmitters may have a role:
o Adenosine is a sleep producing factor; that is why caffeine
“adenosine antagonist” inhibits sleep.

o Prostaglandin D2 causes sleep.
o Prostaglandin I2 causes wakefulness.
o Noradrenaline contributes to wakefulness.
o Serotonin suppresses sleep (serotonin agonists suppress sleep
whereas serotonin antagonists (ritanserin) increase slow-wave
sleep)
Disorders of sleep
Insomnia
- A sleeping disorder characterized by difficulty in falling sleep or
insufficient sleep despite an adequate opportunity.
- Can be transient, acute or chronic.
- Causes include medications (caffeine, amphitamines …), hormonal
disturbance (menstruation, hyperthyroidism …), stress or mental disorder
(depression, anxiety …).
Fatal familial insomnia
- Progressive prion disease (prion diseases are spongiform
encephalopathies transmissible to animals). It is characterized by neuronal
loss and gliosis of some thalamic and meullary nuclei.
- Patients suffer from increased insomnia, dementia and impaired motor
and autonomic functions.
Sleep walking (somnambulism)
- Occurs during the non REM sleep.
- Subjects eat, dress themselves or even walk with open eyes and avoid
obstacles, but they can not remember the episode.
Narcolepsy
- Episodic sudden loss of muscle tone (cataplexy) and un-resistable urge
to sleep even during day time activities. This is explained by early and

sudden occurrence of REM sleep (i.e. not after a period of non-REM sleep
as occurs normally).
- Patients may also suffer from sleep paralysis (inability to talk or move
while waking), frightening hallucinations and automatic behavior (i.e.
continue to talk or put things away while sleeping).
Obstructive sleep apnea

- Occurs during REM sleep (when the hypotonic pharyngeal muscles
obstruct the airways).
- Obstruction of the airways results in loud snoring, carbon dioxide
retention and sudden awakenings when breathing stops; for this reason
patient is usually sleepy during the day time.
REM behavior disorder
- Here there is no hypotonia during REM sleep.
- Patients seem to act out their dreams (move or even jump out of bed).
- Responds to treatment with benzodiazepines.
Night terror
- An abrupt awakening from sleep with behavior consistent with terror.
- Occurs during non-REM sleep.
Nocturnal enuresis (or bed wetting)
- Also occurs during the non-REM sleep (see the renal system).

CHAPTER (16)
HIGHER FUNCTIONS OF THE NERVOUS SYSTEM
- The term higher functions of the nervous system includes memory,
learning, speech, judgment and many other functions of the mind.
- These functions distinguish humans from animals. They enable them to
learn, read, communicate and earn high university degrees; however,
some of these functions can be demonstrated in some animals. For
example the conditioned reflex in dogs and some sort of language
communication in some monkeys (chimpanzees).
- The techniques used for studying these functions in humans are very
advanced and highly sophisticated. They include:
 PET scanning (Positron Emission Tomography; a nuclear medicine
medical imaging technique often used to measure local glucose
metabolism).
 fMRI (Functional Magnetic Resonance Imaging; is the use of MRI to
measure the hemodynamic response, e.g. increase in blood flow to an
area in the brain following neuronal activity. This increase in blood flow
is due to increased oxygen consumption by the neurons during their
activity.
 Other techniques include direct stimulation of the cortex & use of
implanted electrodes.
MEMORY & LEARNING
Definition
- Memory is the ability of the brain to store, retain, and subsequently
retrieve (recall) information.
- Learning is the acquisition of memories (or information) to alter behavior.

Stages of memory
- There are four stages of memory:
 Reception of sensory information
 Formation of memory trace
 Consolidation of memory trace
 Recall of memory trace (or retrieval)
Reception of sensory information
- The information is received and interpreted in the sensory cortex.
Formation of memory trace
- A memory trace is a chemical change in tissue that represents formation
of a memory. Its exact site within the cerebral cortex is unknown. May be
the temporal lobe.
- Before the process of consolidation (i.e. during the first minutes of
formation); the memory trace is vulnerable to loss by trauma or drugs
(because it requires at least 5 to 10 minutes for minimal consolidation).
Consolidation
- The process by which the information is stored and becomes resistant to
erasing.
- Involves protein synthesis in neurons.
- Involves the hippocampus and its connections.
Recall (or retrieval)
- The process by which the stored information is called back.
- The information may be called back (remembered) by one of the
following mechanisms:
o Recollection: Pieces of memories fit together based on an event or
clue (e.g. an essay question in an exam).
o Recall: Regeneration of the memory without being provided any clue
(e.g. filling the blank spaces in a question).

o Recognition: The ability to identify something as a memory when the
stimuli from the memory are experienced again (e.g. multible choice or
a matching question).
o Relearning: When someone takes less time in memorizing information
that is learned in a previous time (e.g. one takes less time in reading a
book for the second time compared to the first time).
Classification of memory
- There are several ways for classification of memories. For example it can
be classified according to the duration of memory retention or according to
the type of information.
 Classification according to the duration of memory retention
1. Immediate (or sensory memory):
o Its duration is less than one second
o Either fades a way or changes into primary or secondary memory
2. Primary (short term or recent memory).
o Lasts for few minutes. It develops from the sensory memory
o Rely mostly on an acoustic code (listening) and to a lesser extent a
visual code
o The capacity of the brain for this type of memory is small, but its recall
is rapid (=the working memory)
3. Secondary (long term or remote memory)
o This is the memory that lasts for long time (up to several years)
o It develops from either sensory or primary memory by either repetition
of information or practice
o The hippocampus is essential to the consolidation of information from
short-term to long-term memory, although it does not seem to store
information itself

 Classification according to the type of information
1. Explicit memory
o Also known as declarative or recognition memory
o Associated with awareness
o Its retention depends on the hippocampus and the temporal
lobes
o Can be divided into:
 Episodic memory (memory for events)
 Semantic memory (memory for words, rules and language)
2. Implicit memory
o Also known as non-declarative or reflexive memory
o Not associated with awareness
o Its retention does not depend on the hippocampus; however, the
cerebellum and the basal ganglia are involved.
o Includes skills, habits and conditioned reflexes
o Can be divided into two types:
 Non-associative learning (i.e. learning about one
stimulus).
 Associative learning (learning about two stimuli related
together).
Examples of non-associative learning

1- Habituation: when the stimulus is repeated many times, the subject
becomes habituated to it and ignores it. It is associated with decreased
Ca++ in the sensory endings resulting in decreased release of
neurotransmitters following the stimulation.
2- Sensitization: in spite of repetition of the stimulus, it produces greater
response (opposite to habituation). It is associated with increased Ca++ in

the sensory endings resulting in increased release of neurotransmitters
following the stimulation.
Examples of associative learning

1- The conditioned reflex: A reflex response to a stimulus that previously
had no effect, after pairing it repeatedly with another stimulus capable of
producing the response. It was first described by Pavlov in the 1890s.
- In his famous experiment, Pavlov used a bell (= conditioned stimulus) to
call a dog to his meal (= unconditioned stimulus that normally causes
salivation). After a few repetitions; the dog learned that the bell is followed
by food; so it started to salivate in response to the bell.
Note:
- Explicit memory (and many forms of implicit memory) can be retained for
short periods of time (sensory or short term memory) or long periods of
time (long term memory); see above.
- Riding a bicycle initially requires the explicit memory (e.g. the rules); then
after learning, it requires the implicit memory (i.e. it becomes a skill).
Mechanism of memory
- Memories are caused by enhancement of synaptic transmission. This is
achieved by:
 Activation of reverberating circuits.
 Short term (post-tetanic) synaptic potentiation (increased
intracellular calcium).
 Structural (anatomical) changes in the presynaptic terminal (e.g.
increase the number of the transmitter vesicles)

Table 16.1: The role of hippocampus and its connections in memory
Structure Role in memory Note
Hippocampus Formation of long Lesions (as in Alzheimer’s
term memory disease) results in failure to form
(consolidation) new long term memories
Prefrontal Temporary storage Recall of words is related to the
cortex of working memory left frontal lobe & pictures to the
right frontal lobe
Mamillary Formation of recent Lesions (as in alcoholics) develop
bodies memory impairment of recent memory
Amygdala Encodes emotions Events associated with strong
related to memory emotions are remembered better
than those without
Temporal lobe Interpretation of the Lesions may result in “déjà vu”
surroundings as (feeling familiar in strange places)
familiar or not or “jamais vu” (feeling strange in
familiar places).
Amnesia
- Amnesia or loss of memory has the following types:
• Retrograde amnesia: inability to recall memories from the past,
specially the recent events (i.e. before consolidation of the memory
trace). It is caused by brain concussion or an electrical shock.
• Anterograde amnesia: inability to form new Long-term memories (but
the already stored are intact); caused by lesions of the hippocampus.
• Hysterical (psychogenic) amnesia: occurs due to severe psychological
stresses, and it often recovers completely.
• Global amnesia: occurs in extensive brain lesions; resulting in both
retrograde & anterograde amnesia.

THE NEOCORTEX
- The neocortex is the part of the cerebral cortex that is involved in higher
functions such as conscious thought and language.
- In humans it constitutes 90% of the cerebral cortex.
- It is made up of six layers, labeled I (superficial) to VI (deep). These
layers contain different types and sizes of neurons. The fibers of these
neurons (association, commissural and projection fibers) form complex
connections and feedback control on the cells of origin.
- The projection fibers to extra-cortical sites originate mainly from layer V
(the layer of the large pyramidal cells “Betz cells”) and also from layer VI
(to a lesser extent); whereas afferents from the specific nuclei of the
thalamus end in layer IV.
- The neocortex includes the following three major association areas:
o Frontal association area
 Infront of the premotor area
o Parietal-temporal-occipital area
 Between the somatesthetic and visual cortices
o Temporal area
 From the lower portion of the temporal lobe to the limbic
system
Functions of the neocortex

- One of the most important functions of the neocortex is related to
language (see below); however, this function is localized to one of the two
hemispheres.
- The hemisphere that is concerned with language is known as the
categorical (or dominant) hemisphere whereas the other is known as the
representational (or non-dominant) hemisphere.

- The categorical hemisphere is the left hemisphere in almost all right
handed and most left handed subjects (e.g. in some populations: the left
hemisphere is dominant in 96% of right handed and 70% of left handed
people).
Functions of the categorical hemisphere
o Language functions
Note: Lesions in this hemisphere produce language disorders (see below)
and apraxia.
- Apraxia is defined as a disorder of skilled movement not caused by
weakness, akinesia or any other organic movement disorder.
- A patient with apraxia has no paralysis but lost the information about how
to do skilled movements. This is usually associated with left sided lesions;
however, right sided lesions also may be implicated. Examples include:
 Constructional apraxia: inability to copy 3-dimensional assemblies
(associated with left or right parietal lobe lesions and may be other
sites in the brain).
 Dressing apraxia: associated with right parietal lobe lesions (part of
the neglect syndrome; see below).
Functions of the representational hemisphere
o Identification of objects by their form
o Recognition of musical themes
o Recognition of faces
Important clinical points:
- Lesions in the representational hemisphere cause agnosias and hemi-
neglect.
- Agnosias are group of disorders caused by right brain lesions (especially
the parietal lobe), characterized by inability to identify objects, persons,
sounds, or smells while the sensory modality is intact. Examples include:

 Astereognosis (inability to identify objects by feeling them)
 Finger agnosia (inability to distinguish fingers of the hand)
 Prosopagnosia (inability to recognize familiar faces; see below)
 Auditory agnosia (inability to hear environmental sounds such as a
dog barking).
- Hemineglect (or sensory inattention) is caused by lesions in the inferior
parietal lobule. Affected patients ignore stimuli coming from one half of
their bodies
Fig 16.1: The neocortex
LANGUAGE “SPEECH”
- Language (spoken or written) is a key part of human culture; it is the
mean of communication between people.
- It requires integrity of the categorical (dominant) hemisphere which is the
left cerebral hemisphere.

- It has two aspects:
1. Sensory aspect (language input)
2. Motor aspect (language output)
- Sensory aspect (language input):
 Requires integrity of the Wernicke’s area at the posterior end of
the superior temporal gyrus.
 This area is concerned with understanding auditory and visual
information (i.e. spoken and written speech).
 It projects via the arcuate fasciculus to the Broca’s area.
- Motor aspect (language output):
 Requires integrity of the Broca’s area at the frontal lobe (infront of
the inferior end of the motor area).
 After processing the information received from the Wernicke’s area;
it projects to the motor cortex to initiate movements of the lips,
tongue and larynx to produce words.
Fig 16.2: The speech areas

Language disorders (Aphasias)
- Aphasia is defined as loss of the ability to produce and/or comprehend
language, due to injury to the brain areas specialized for these functions.
- It is caused by lesions in the categorical hemisphere (i.e. the left
hemisphere in most cases). For example stroke, head injury or brain
tumors.
- It can be classified into fluent, non-fluent and pure types:
 Fluent aphasias:
o Wernicke’s aphasia (sensory aphasia):
- Caused by damage to the Wernicke’s area.
- The patient can see and hear words but he can not understand
the speech of others.
- May speak in long sentences that have no meaning and add
unnecessary new words.
o Anomic aphasias:
- Caused by lesions affecting the angular gyrus in the dominant
hemisphere without affecting the Wernicke’s or Broca’s areas.
- The angular gyrus is concerned with processing of visual
information. The resulting abnormality is failure in understanding
pictures and written language.
o Conduction aphasia:
- Caused by damage to the arcuate fasciculus (it appears that the
affected areas are in and around the auditory cortex).
- Auditory comprehension is near normal, and oral expression is
fluent with occasional paraphasic errors and poor repetition ability.

 Non-fluent aphasias:
o Motor aphasia:
- Caused by lesions involving the Broca’s area.
- Patient understands both, spoken & written words, but he can not
talk easily (= non fluent aphasia). He can produce short, meaningful
phrases with great effort.
- He often omits small words such as "is", "and", and "the". For
example, a person with Broca's aphasia may say, "Walk dog"
meaning, "I will take the dog for a walk".
- Unlike the sensory aphasia, patients with motor often have right
sided hemiplegia.
o Global (general aphasia):
- Caused by severe lesions of the categorical hemisphere (involving
motor and sensory speech).
- Patients have severe communication difficulties and will be
extremely limited in their ability to speak or comprehend language.
 Pure aphasias:
o Agraphia (writing aphasia):
- Selective impairment in writing.
- Caused by damage to the writing center in the area of hand skills.
o Dyslexia (inability to read or word blindness):
- Selective impairment in reading. Its cause is unknown but
probably related to a defect in the visual association area.
o Pure word deafness:
- Caused by damage to Wernicke’s area or disruption of auditory
input to this region.
- It exhibits itself as inability to comprehend the meaning of speech,
but in most cases still being able to hear, speak, read, and write.

 Other speech disorders:
o Stuttering:
- Stuttering (or stammering) is a speech disorder in which the flow
of speech is disrupted by involuntary repetitions and prolongations
of sounds or words and involuntary silent pauses or blocks.
- The exact etiology of stuttering is unknown; however, it is found to
be associated with right cerebral dominance and widespread over
activity in the cerebral cortex and cerebellum.
o Damage to the non-dominant hemisphere:
- Lesions of the representational hemisphere have no effect on
speech; however, some patients lose the ability to tell stories or
jokes.
Other abnormalities in the higher functions

- Many abnormalities in the higher functions are studied in patients with
neurological lesions (e.g. strokes and head injuries). When a patient
presents with such abnormality, the fMRI and PET are used to localize the
site of the lesion.
- The following are examples of some these abnormalities:
Prosopagnosia “face blindness”
- Patients fail to recognize faces of familiar people (family and friends);
however they can recognize them by their voices.
- Due to lesion in the right inferior temporal lobe “fusiform gyrus” (but the
left is also involved in recognition of faces).
Acalculia
- Patients have difficulty in performing simple mathematical tasks, such as
adding, subtracting, multiplying and even simply stating which of two
numbers is larger.

- Due to lesion in the inferior portion of the left frontal lobe.
- Also caused by lesions affecting the left angular gyrus. Here the acalculia
is associated with “agraphia” (inability to write), “finger agnosia” (difficulty
in naming and differentiating among the fingers) and “left-right
disorientation” as in Gerstmann’s syndrome (a neurological disorder
associated with lesions in the dominant (usually left) side of the angular
and supramarginal gyri near the junction between the temporal and
parietal lobes).
Failure of navigation
- Failure to locate places is caused by lesions involving the right
hippocampus (concerned with learning locations of places) and the right
caudate nucleus (facilitates movement to the places).
- Men are better than women in spatial skills and navigation (may be
because they have larger number of brain cells and larger size of brain!).
Personality change & Lack of concern “Disinhibition”
- Anti-social behavior is a characteristic of frontal lobe lesions.
- Because these patients also do not bother about tensions and pain (=
lack of concern); prefrontal lobotomy was used for treatment of severe
intractable pain and incapacitating tensions associated with phobias,
delusions and compulsions.
Dementia
- Dementia is progressive decline in cognitive function of the brain; to a
degree above what is expected from normal aging.
- The affected areas in cognition (especially at the later stages of the
disease) include memory, attention, orientation, language and problem
solving.
- It is more common in the elderly population (senile dementia); however, it
may occur in younger age groups (pre-senile dementia).

Types of dementia
1- Cortical dementias
 Alzheimer disease
o The commonest cause of senile dementia (in the Western
countries).
o Characterized by progressive loss of short term memory followed
by general loss of cognitive function and eventually death.
o Atrophy of the hippocampus appears on the MRI before the onset
of symptoms.
o Pathological features: cytoplasmic neurofibrillary tangles
(abnormally phosphorylated tau protein that normally binds the
microtubules) and senile plaques (extracellular deposition of beta-
amyloid protein).
 Vascular dementia
o The next common cause of dementia in the elderly (in the Western
countries).
o Also known as multi-infarct dementia.
o Caused by poor circulation of blood to the brain (due to multiple tiny
strokes).
 Dementia with Lewy bodies
o Exhibits clinical overlap between Alzheimer's disease and
Parkinson's disease.
o Pathologically, it is characterized by development of abnormal
proteinaceous cytoplasmic inclusions, called Lewy bodies,
throughout the brain.
 Alcohol induced dementia
o Caused by long term excessive drinking of alcohol, resulting in
neurological damage and memory loss.

o May be associated with Wernicke’s encephalopathy and
Korsakoff’s psychosis.
o Wernicke’s encephalopathy is caused by acute thiamine deficiency
(vitamin B1) due to alcohol and Korsakoff’s psychosis is the chronic
complication of that deficiency.
o Signs of Wernicke’s encephalopathy:
 Aataxia
 Nystagmus
 Ophthalmoplegia
 Coma
o Signs of Korsakoff’s psychosis:
 Confusion
 Amnesia (anterograde and retrograde)
 Confabulation (description of events that never occurred)
2- Subcortical dementias
o Dementias due to Hypothyroidism, hypoglycemia, Parkinson’s
disease, Huntington’s disease, deficiency of vitamin B1, deficiency
of vitamin B12 & deficiency of folate.

1. Multiple spikes in the EEG are signs of:
a. Brain death
b. Head injury
c. Epilepsy
d. Sensory ataxia
e. Normal brain activity
2. A patient with sensory aphasia:
a. Cannot obey commands
b. Cannot speak in long sentences
c. Has normal wernicke’s area
d. Is unable to write words
e. Is unable to recognize objects by feeling them
3. Which of the following is true?
a. Hypotonia of sleep is more marked during the non rem type
b. Damage to the hippocampus results in impaired recent memory
c. Temporal lobe damage causes retrograde amnesia
d. Acoustic neuroma causes conductive deafness
e. Linear acceleration is detected by the semicircular canals
4. Eeg signs of stage iv sleep include:
a. Alpha waves
b. Dominance of sleep spindles
c. Beta waves
d. Delta waves
e. Spikes and waves
5. Long term memory:
a. Is lost in dementia
b. Formation requires the hippocampus
c. Is stored in the temporal lobe
d. Lasts for several hours
e. Formation requires mamillary bodies
6. The following is a fast eeg rhythm:
a. Beta waves
b. Delta waves
c. Alpha wave
d. Theta wave
7. Which of the following may show unilateral slowing of EEG activity:
a. Head injury
b. Epilepsy
c. Brain tumor
d. Meningitis
e. Parkinson’s disease
8. Sensory aphasia is caused by damage to:
a. Frontal lobe

b. Auditory pathway
c. Broca's area
d. Wernicke's area
e. Cerebellum
9. Dyslexia is caused by damage to:
a. The hippocampus
b. Temporal lobe
c. Broca's area
d. Wernicke's area
e. Visual association area
10. Motor aphasia is caused by damage to:
a. Frontal lobe
b. Auditory pathway
c. Broca's area
d. Wernicke's area
e. Cerebellum
11. Rapid eye movement sleep:
a. Constitutes 80% of sleep in adults
b. Decreases in duration as the subject becomes restful
c. Is dreamless
d. Is associated with profound hypotonia
e. Is associated with delta waves in EEG
12. Which of the following sleep disorders occur during REM sleep:
a. Sleep walking
b. Narcolepsy
c. Obstructive sleep apnoea
d. Nocturnal enuresis
e. Both b & c
13. Riding a bicycle is an example of:
a. Explicit memory
b. Implicit memory
c. Associative learning
d. Episodic memory
e. Sensitization
14. Inability to recognize objects by feeling their forms is:
a. Caused by lesions of dominat hemisphere
b. Known as apraxia
c. Known as asteriognosis
d. Explained by loss of sensation in the hands
e. Due to an abnormality in prefrontal cortex
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.
c a c d b A c d e c d
12. 13. 14.
e b c

FURTHER READING
1. Anderson PA, Bohlmann HH: Anterior decompression and arthrodesis

of the cervical spine: Long-term motor improvement: Improvement in
complete traumatic quadriplegia. J Bone Joint Surg 1992; 74:671-682.
2. Basran S, Frumento RJ, Cohen A, Lee S, Du Y, Nishanian E, Kaplan
HS, Stafford-Smith M, Bennett-Guerrero E. The association between
duration of storage of transfused red blood cells and morbidity and
mortality after reoperative cardiac surgery. Anesth Analg 2006;103:15-
20.
3. Benevento BT, Sipski ML. Spinal cord injury series. Phys Ther 2002;
82(6):601-612.
4. Brenda R. The Handbook of Cognitive Neuropsychology: What Deficits
Reveal about the Human Mind. Psychology Press; 2001.
5. Chandramouli R. Textbook of physiology. 2nd ed. New Delhi: Jaypee
brothers; 2003.
6. Cullen B, O'Neill B, Evans JJ, Coen RF, Lawlor BA. A review of
screening tests for cognitive impairment. J Neurol Neurosurg
Psychiatry 2007;78(8):790-9.
7. Dakin J, Kourteli E, Winter R. Making sense of lung function tests.
London: Arnold; 2003.
8. Despopoulos A, Silbernagl S. Color atlas of physiology. 4 th ed. New
York: Thieme; 1990.
9. Dudai Y. The Neurobiology of Memory: Concepts, Findings, Trends.
Oxford: Oxford University Press; 1989.
10. Easterbrook PJ. Basic medical sciences for MRCP part 1. London:
Churchil Livingstone; 1999.

11. Fine EJ, Ionita CC, Lohr L. The history of the development of the
cerebellar examination. Semin Neurol 2002; 22(4):375-84.
12. Ganong WF. Review of medical physiology. 21st ed. Lebanon:
McGraw-Hill; 2003.
13. Geeta Akhwaja. Plantar reflex. Journal Indian Academy of Clinical
Medicine “JIACM” 2005; 6(3):193-197.
14. Guyton AC. Human physiology and mechanisms of disease. 4 th ed.
Philadelphia: W.B. Saunders Company; 1987.
15. Hall JE. Pocket companion to Guyton and Hall textbook of medical
physiology. 2nd ed. Philadelphia: Elsevier; 2001.
16. Isselbacher KJ, Braunwald E, WilsonJD, Martin JB, Fauci AS, Kasper
DL. Harrison's principles of internal medicine. 13 th ed. New York:
McGraw-Hill; 1994.
17. Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science.
18. Keele CA, Neil E, Joels N. Samson Wright's Applied physiology. 13 th
ed. New York: Oxford university press; 1982.
19. Landrew BL. Experimental physiology. 9th ed. London: Churchill
Livingstone; 1972.
20. Luciano DS, Vander AJ, Sherman JH. Human anatomy and
physiology: structure and function. 2nd ed. New York: McGraw-Hill;
1983.
21. Marx SJ. Familial hypocalciuric hypercalcemia. In: Favus MJ ed.
Primer on the metabolic bone diseases and disorders of mineral
metabolism. 4th ed. Philadelphia: Lippincott, Williams & Wilkins, 1999.
22. McGeon JG. Physiology. Singapore: Churchil Livingstone; 1996.
23. Meister M, Berry MJ. The neural code of the retina. Neuron 1999;
22(3):435-50

24. Myers A. Respiratory system: Crash course. Philadelphia: Elsevier
Mospy; 2006.
25. Nolte J. The Human Brain: an introduction to its functional anatomy.
5th ed. St. Louis: Mosby; 2002.
26. Obayashi S. Possible mechanism for transfer of motor skill learning:
implication of the cerebellum. Cerebellum 2004; 3(4):204-11.
27. Sager M, Hermann B, La Rue A, Woodard J. Screening for dementia in
community-based memory clinics. WMJ 2006; 105(7):25-9.
28. Schulz HL, Goetz T, Kaschkoetoe J, Weber BH. The Retinome -
defining a reference transcriptome of the adult mammalian
retina/retinal pigment epithelium. BMC Genomics 2004; 5(1):50.
29. Siddall PJ, McClelland J. Non-painful sensory phenomena after spinal
cord injury. J Neurol Neurosurg Psychiatry 1999; 66:617-622.
30. Steensma DP, Hoyer JD, fairbanks VF. Hereditary red blood cell
disorders in middle eastern patients. Mayo Clin Proc 2001;76:285-293.
31. Weatheral DJ, L:edingham JG, Warrell DA. Oxford textbook of
medicine. 3rd ed, London: Oxford University Press;1996.
32. West JB. Respiratory physiology: the essentials. 4th ed. London:
Williams & Wilkins; 1993.
33. Willatts SM. Lecture notes on fluid and electrolyte balance. London:
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(‫)الحمد هلل الذى بنعمته تتم الصالحات‬

2010/548 :‫رقم االيداع‬

Core Human Physiology

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Core Human Physiology

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INTRODUCTION

The core of medical physiology (1) – 3rd edition Page 2

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Fig 2: The cell organelles

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Fig 2: Passive transport

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Fig 3: Active transport

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 Other transport mechanisms

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 Transport proteins "carriers, pumps & ion channels"

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Question 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

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Table1.1: % of TBW in males and females of different ages

 Body Fluid Compartments

The core of medical physiology (1) – 3rd edition Page 17

Table 1.2: Differences between ECF and ICF in a 70 kg adult male

Difference Extracellular fluid Intracellular fluid

Volume 15L 25L

Osmolarity 280-300 mOsm/L 280-300 mOsm/L

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Factors Affecting Body Fluid Compartments

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Osmolarity, Osmolality & Tonicity

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Fig 1.2: The osmotic pressure

Osmotic pressure prevents

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Table 1.3: Effects of I.V. solutions on volumes and osmolarities

Isotonic The same The same The same

- From the above table:

The core of medical physiology (1) – 3rd edition Page 25

B. From the Molarity

The core of medical physiology (1) – 3rd edition Page 26

Q: Calculate the osmolality of a solution containing 110 mmol NaCl,

The core of medical physiology (1) – 3rd edition Page 27

3- Gibbs Donnan equilibrium

The core of medical physiology (1) – 3rd edition Page 28

From the above relationships:

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Effects of Donnan equilibrium in the body:

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Table 1.2: Differences between plasma and ISF in an adult male

Difference Plasma Interstitial fluid

Volume 5% of body weight 15% of body weight

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- It accounts for 20-45% of the total metabolic energy expended by

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Fig 1.8: Starling's forces

- A filtration pressure of + 10 mmHg indicates that Starling’s forces

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