INTRODUCING

PHARMACOKINETICS AND
PHARMACODYNAMICS
Kinanti Narulita D
Pharmacology Department
FACULTY OF MEDICINE UNISSULA

LEARNING OUTCOMES

Define and discuss pharmacokinetic factors

Discuss the factors that affect absorption,
distribution, metabolism and excretion-how
they affect drug therapy
Define and discuss pharmacodynamic
mechanisms of drug actions
Apply
pharmacokinetic
and
pharmacodynamic concepts to patient
scenarios.
2

PHARMACOKINETIC

PHARMACOKINETICS :
CONSIDERING SUCH TERMS AS

Route
Absorption
Distribution
Protein Binding
Hepatic Metabolism
Metabolic products
Renal Excretion
Half-life
Toxicity

Route : oral, parenteral, inhalation, rectal,

transdermal, injection.
Absorption entry into body-acidity and solubility.
First-pass-metabolic change due to liver enzymes :
patients with liver disease poor metabolism
toxicity.
Distribution extent of protein binding important as
only free (unbound) drug can have effect. Penicillin is
highly protein bound. Two drug co-administered,
degree of protein binding can be altered, displaced?
Toxicity?
Excretion removal or clearance of drug from body.
Half-life how long does it take the plasma
concentration of drugs to go down to 50%.
Toxicity consider the pharmacological routes to
adverse drug effects.

PHARMACOKINETIC

Pharmacokinetics is what the body does to

the drugs (THE BODIES RESPONSE TO
MEDICATION), pharmacokinetics refers to the
handling of a drug within the body.
For almost all drugs the magnitude of
pharmacological effect depends on its
concentration at its site of action.
To achieve the pharmacological response
desired, the drug must first be in an available
and suitable form and then administrated by an
appropriate route.
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Absorption
Distribution
Metabolism
Excretion
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Absorption

Distribution

Route

Enteral
oral

Parenteral
IV

sublingual

Topical
transdermal

Absorption

inhalation

Absorption

Systemic circulation

ABSORPTION

Process of drug movement from the

administration site to the systemic circulation.
The amount and rate of absorption are determined
by several factors :
Drug characteristics that affect absorption /
physical nature of the dosage form : molecular
weight, ionization, solubility, & formulation

ABSORPTION

Disintegration and dissolution of the released

drug into the correct part of the GI tract is
required for the drug to be absorbed. Drugs in
liquid dose form require no disintigration and
often dissolution are already accomplished and
therefore absorb more rapidly with faster effects.

10

ABSORPTION

Food effect on some drugs affects the

bioavailability.
GI motility effects the thorough mixing in the GI
tract which increases the efficacy in which the
drug makes contact with surfaces that are
available to engage absorption.
Drug absorption is mainly in the upper small
intestine that is facilitated by the large surface
area of villi and the rich blood supply.
11

ABSORPTION

The level of mesenteric blood flow directly

affects the rate of removal of the drug from the
site of absorption.
Alteration in the rate of gastric emptying will
result in corresponding alterations in the rate of
absorption, as in diarrhoea and vomiting can
affect whether therapeutic levels achieved. E.g :
oral contraceptives, migraine reduced rate of
gastric motility = delayed response to oral
analgesia. Delay can be lessened by use of
metoclopramide that increases gastric emptying.
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ABSORPTION

KEYNOTE Factors affecting drug

absorption related to patients :
Route of administration
Gastric or intestinal pH
Contents / composition of GI tract
Presence or absence of food in the
stomach
Mesenteric blood flow
Concurrent administration with other drugs

13

BIOAVAILABILITY

Bioavailability is the proportion of the administered

dose that reaches the systemic circulation. = refers
to the amount and the rate of appearance of the
drug in the blood after administration in its initial
dose form.
Orally administered drug bioavailability is directly
related to the individual solubility in body fluids.
Poor solubility = low bioavailability
To become affective i.e. produce a therapeutic
effect, a drug must reach an adequate concentration
in the blood. Drugs administered by the IV route are
bioavailable in 100% of cases as it is administered
directly into the blood.

14

BIOAVAILABILITY

Some drugs with the same active principle, made by

different manufacturers may differ in the
bioavailability, dependant on the degree of
compression or nature of excipients (added
substances), that may affect the disintigration and
dissolution of the drug.
Drugs licensed for use in the UK (including parallel
imports) the manufacturing processes are controlled
to ensure bioavailability across drug production is
consistent.
Brand vs generic prescribing. Bioequivalence
should be similar with a few exceptions.

15

concentration

Time to Peak Concentration

100
90
80
70
60
50
40
30
20
10
0

IV
Oral
Rectal

10

20

30

minutes

60

120

180

EFFECT OF FOOD ON THE

ABSORPTION OF DRUGS

Bioavailability of some drugs is affected by the

presence of food. E.g : penicillin, erythromycin,
rifampicin, thyroxine.
Some drugs are taken before meals to allow
time for drug to act before food is taken.
Gastric irritation can be caused by drugs taken
on an empty stomach.

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FIRST PASS EFFECT

Drugs that are absorbed via the GIT are
circulated to the liver first via
the hepatic portal vein
Liver then acts as a filter
Only part of the drug is
circulated systemically
The combination of
processes is termed
the First Pass effect

18

FIRST PASS EFFECT

All drugs taken orally that are absorbed pass by

the hepatic portal vein. This is a defence
mechanism to detoxify substances coming into
the body.
The liver protects the body from systemically
circulating toxins that are absorbed via the GIT by
filtering drugs through a range of detoxification
mechanisms seeking for natural toxins.
As a result only part of the administered drug
reaches the systemic circulation via the hepatic
artery.
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Absorption

Distribution

Metabolism

Factors affecting

Low albumin

Problems with:
Heart
Circulation
Diabetes

Bound drugs are pharmacologically inactive because the drugprotein complex is unable to cross cell membranes.

20

DISTRIBUTION

Membrane permeability

Plasma protein binding

bound drugs do not cross membranes

malnutrition = albumin = free drug

Lipophilicity of drug

cross membranes to site of action

lipophilic drugs accumulate in adipose tissue

Volume of distribution

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PLASMA PROTEINS

Low Affinity, high capacity binding Proteins :

Albumin (e.g. phenytoin)
1-acid glycoprotein (cationic lidocaine)
Lipoproteins
Specific binding Proteins (high affinity low
capacity) : cortisol binding globulin, thyroid
binding globulin

IKATAN OBAT PROTEIN

PLASMA
Protein

Berat Molekul
(Da)

Konsentrasi
(g/L)

Obat yang
mengikat

Albumin

65,000

3.55.0

Acid drugs (large variety of

drug)

1- acid
glycoprotein

44,000

0.04 0.1

Basic drug : propranolol,

imipramine and lidocaine.
Globulins : corticosteroids.

Lipoproteins

200,000
3,400,000

.003-.007

Basic lipophilic drug :

chlorpromazine

1 globulin

59000

.015-.06

2 globulin

13400

Steroid, thyroxine,
Cynocobalamine,
Vit. A,D,E,K

PENYAKIT DAN
PROTEIN BINDING
Protein Binding (Ikatan Obat Protein) Menurun Pada Kondisi :
PENYAKIT LIVER
Dapsone
Diazepam
Morphine
Phenytoin
Prednisolone
Quinidine
Tolbutamide
Triamterene

PENYAKIT RENAL
Barbiturates
Cardiac Glycosides
Chlordiazepoxide
Clofibrate
Diazepam
Diazoxide
Furosemide
Morphine
Phenylbutazone
Phenytoin

Salicylates
Sulfonamides
Triamterene

Warferin
binding
site

DRUG BINDING SITE

ON HSA

Beberapa obat mampu

berikatan dgn HAS lebih satu
binding site :
- Flucoxacillin, flurbiprofen,
ketoprofen, tamoxifen dan
dicoumarol berikatan dgn
2 binding site
- Indomethacin berikatan
dengan 3 binding site.
AAG mempunyai kapasitas
terbatas.
AAG
hanya
mempunyai
binding site 1
untuk lidocaine.

Site 1
Site 2

Diazapam
binding
site

HSA
Site 3
site4

Digitoxin
binding site

Tamoxifen
binding site

METABOLISM
Drugs are metabolised in the liver, lungs, kidneys,
blood and intestines.
In order for drugs to pass across the lipid cell
membrane they must be lipophilic. Lipophilic
means fat soluble. Hydrophilic means water
soluble.
The higher the solubility in lipids compared to
water, the more rapid the tissue entry.
Metabolic rate determines the duration of the
action of the drugs.
The primary metabolic site is the liver. If enzyme
function is inadequate the metabolic effect can be
compromised and cause toxicity.
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METABOLISM

Eg : liver disease, very young and very old who

have diminished hepatic microsomal enzyme
activity.
Body works to convert drugs to less active forms
and increase water solubility (hydrophilic than
lipophilic) to enhance elimination / excretion.
The speed with which a drug is metabolised will
determine the duration of the action of the drug.
This in turn will determine how often the drug is
administered.
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PHASE 1 REACTIONS

Cytochrome P450 system

Located within the endoplasmic reticulum
of hepatocytes
Through electron transport chain, a drug
bound to the CYP450 system undergoes
oxidation or reduction
Enzyme induction
Drug interactions

PHASE 1 REACTIONS

Hydrolysis
Oxidation
Reduction
Demethylation
Methylation
Alcohol dehydrogenase metabolism

PHASE 2 REACTIONS

Polar group is conjugated to the drug

Results in increased polarity of the drug
Types of reactions
Glycine conjugation
Glucuronide conjugation
Sulfate conjugation

EXCRETION / EXCRETION

Pulmonary = expired in the air

Bile = excreted in feces
enterohepatic circulation
Renal
glomerular filtration
tubular reabsorption
tubular secretion

EXCRETION / EXCRETION
Drugs are primarily excreted by the kidneys
In order for drugs to be excreted they need to
become hydrophilic
Excretion of drugs can be affected by the
urinary pH
How the drug is excreted can influence
prescribing decisions
The excretion rate varies from hours to weeks
and on the condition of the kidneys

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EXCRETION / EXCRETION

Aging patient with reduced renal capacity

more prone to build up (toxicity) of drugs
excreted renally, more of problem with drugs
narrow therapeutic range e. g digoxin. some
beta blockers (celiprolol, sotaolol) etc.
Excretion and prescribing influence. Eg
ampicillin is excreted in high concentrations
in bile, so is a good chioce for biliary tract
infection.
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EXCRETION / EXCRETION

When lipid soluble drugs pass through the

kidneys they are re-absorbed in the distal
tubule and return to the plasma. In order to
be excreted they need to become more
hydrophilic. This occurs in the Bowmans
capsule, converted to less active metabolites
more easily excreted.

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EXCRETION / EXCRETION

Steady State : the amount of drug

administered is equal to the amount of drug
eliminated within one dosing interval resulting
in a plateau or constant serum drug level.
Drugs with short half-life reach steady state
rapidly; drugs with long half-life take days to
weeks to reach steady state.

HALF LIFE OF DRUGS

Drug excretion is commonly expressed in terms

of half life (t1/2)
This is the time required for the concentration of
the drug in the plasma to decrease by one-half
of its initial value
Drug half life is variable and can be long or short
Subsequent doses are given to raise the
concentration levels to a peak
In theory, the optimal dosage interval between
drug administration is equal to the half-life of
the drug
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HALF LIFE OF DRUGS

Eg. half life of drugs aspirin 6 hours,

metronidazole 9 hours, digoxin 36 hours.
Half-life is affected by :
Short half life : extensive tissue uptake, rapid
metabolism, rapid excretion.
Long half life : extensive protein binding, slow
metabolism, poor excretion.
Concentration falls after metabolism and
excretion. If dose interval is too long, effect is not
achieved, too short an interval leads to toxicity.
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LOADING DOSES

Are used when the medical condition

demands high concentrations very quickly
This is achieved by an initial dose that is
twice the maintenance dose
Example :
Acute infections : use stat dose of
antibiotic, 2 times the next dose.
Digoxin loading dose.
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LOADING DOSES

Loading doses
allow rapid
achievement of
therapeutic serum
levels
Same loading dose
used regardless of
metabolism /
elimination
dysfunction

40
35
30
25
20
15
10
5
0

w/ bolus
w/o
bolus

SPECIAL PATIENT
POPULATIONS

Renal Disease : same hepatic metabolism,

same / increased volume of distribution and
prolonged elimination dosing interval
Hepatic Disease : same renal elimination,
same / increased volume of distribution, slower
rate of enzyme metabolism dosage,
dosing interval
Cystic Fibrosis Patients :
increased
metabolism / elimination, and larger volume of
distribution dosage, dosage interval

PHARMACODYNAMIC

PHARMACODYNAMICS
Pharmacodynamics : study of the biochemical
and physiologic processes underlying drug action
what the drug does to the body or mode of
action of drugs in the body, ideally including how
drugs exert their effect at a general, cellular level
or the molecular mechanism by which the drug
acts.
Mechanism of drug action
Drug-receptor interaction
Efficacy
Safety profile
43

PHARMACODYNAMICS

Understanding the pharmacodynamics of

drugs will enable you to predict drug
interactions and toxicities.
The pharmacology of a drug is not always
known-but where it is, it would be nice if you
had a handle on how the drugs you will be
prescribing exert their effect

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CONSIDERING

Receptors

Ion channels

Ion channels-gating of
intracellular ions

Enzymes

Receptors-agonist, partial
agonist and antagonist

Enzymes-drugs act to inhibit or

potentiate

Carrier molecules

Carrier molecules-allow
molecules not lipid soluble to
cross cell membrane

45

CONSIDERING

Chemotherapy
Chemotherapeutic agents
Drug tolerance / dependence
Effects of pathological state and biological
variability

46

TYPES OF RECEPTORS

G-protein-couple receptors. G protein receptors

work in seconds, e.g. muscarinic ACh receptors,
adrenoceptors, histamine receptors. Proteins or
glycoproteins :
Present on cell surface, on an organelle within the
cell, or in the cytoplasm
Finite number of receptors in a given cell
Kinase linked receptors. Kinase (enzyme) linked
receptors can take hours, e.g. Insulin, Growth factor.
Nuclear intracellullar receptors, e.g. steroid, thyroid
hormone.
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48

DRUG RECEPTORS

Action occurs when drug binds to receptor and

this action may be :
Ion channel is opened or closed
Second messenger is activated :
cAMP, cGMP, Ca++, inositol phosphates,
etc.
Initiates a series of chemical reactions
Normal cellular function is physically inhibited
Cellular function is turned on

DRUG RECEPTORS

Affinity
Refers to the strength of binding between a
drug and receptor
Number of occupied receptors is a function
of a balance between bound and free drug

RECEPTORS
Receptors are a target molecule that
a drug molecule has to combine with
to produce a specific effect
Receptors must be compatible like 2
pieces of a jigsaw e.g.
neurotransmission
Main types of action at receptor :
Receptor agonists
Receptor antagonists

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DRUG RECEPTORS

AGONIST
Drugs which alter the physiology of a cell by
binding to plasma membrane or intracellular
receptors.
Full agonist is isoproterenol, which mimics
the
action
of
adrenaline
at
adrenoreceptors. Morphine, which mimics
the actions of endorphins at -opioid
receptors throughout the CNS.

DRUG RECEPTORS

PARTIAL AGONIST
A drug which does not produce maximal
effect even when all of the receptors are
occupied. E.g : Clomiphene & Tamoxifen
partial agonist at estrogen receptor.
Buprenorphine partial agonist at opioid receptors throughout the CNS.

DRUG RECEPTORS

ANTAGONISTS
Inhibit or block responses caused by
agonists. Physiological antagonist =
opposing physiological actions, but act
at different receptors. They are sometimes
called blockers; examples include : blockers, -blockers, CCB.

DRUG RECEPTORS

COMPETITIVE ANTAGONIST
Competes with an agonist for receptors. High
doses of an agonist can generally overcome
antagonist.
Naloxone is used to reverse opioid
overdose caused by heroin / morphine.
Flumazenil vs benzodiazepines.
Competitive antagonists combine with the
same receptor as an endogenous agonist
(e.g. ranitidine at histamine H2-receptors).

DRUG RECEPTORS

NONCOMPETITIVE ANTAGONIST
Binds to a site other than the agonist-binding
domain. Induces a conformation change in the
receptor such that the agonist no longer
recognizes the agonist binding site. High doses
of an agonist do not overcome the antagonist in
this situation.
Histamine arterial pressure through vasodilatation at the H1 receptor, while adrenaline
arterial pressure through vasoconstriction
mediated by -adrenergic receptor activation.

DRUG RECEPTORS

IRREVERSIBLE ANTAGONIST
Bind permanently to the receptor binding site
by forming a covalent bond to the active site
/ just by binding so tightly, therefore they can
not be overcome with agonis.
Irreversible enzyme inhibitors that act
similarly are clinically used and include drugs
such aspirin, omeprazol and monoamine
oxidase inhibitors.

ION CHANNELS

Drugs act to affect cellular gating mechanism

in cell wall. Ligand-gated ion channels work in
milliseconds
e.g GABA benzodiazepines,
Nicotinic Ach.
Some ion channels are gated by receptor
(open only when receptor is occupied by an
agonist) while other are voltage-gated-drugas
affect the permage or flow of for example,
potassioum, sodium or calcium in and out of
the cell.
58

ION CHANNELS

Drugs acting at ion channels include :

Benzodiazepines
that act at GABA
(gamma amino butyric acid receptor)
chloride channel return over excitable
receptor to constitutive (normal) level of
activation
Calcium channel blockers prevent diffusion
of calcium through cell membrane
Nicorandil acts at potassium channels

59

ION CHANNELS

Another examples of this drugs :

Loop
diuretics which inhibit sodium,
potassium and chlorine passage in the lop
of Henle
Another
example omeprazole inhibits
proton pump in the gastric mucosa
Tricyclics inhibit noradrenaline uptake
60

CARRIER MOLECULES

Carrier molecules allow transport of small

organic molecules that are too polar not
sufficiently lipid soluble to penetrate cell
membranes on their own. Drugs act on
carrier transporters which allow molecules
eg. glucose and amino acids.

61

ENZYME INHIBITORS

An enzyme is a protein that can promote or

accelerate a biochemical reaction with a
substrate
When the enzyme mistakes the drug for a
substrate, a drug-enzyme interaction occurs
This interaction could increase or decrease
the rate of the biochemical reaction

62

ENZYME INHIBITORS

Many drugs target enzymes acting as false

substrates to competitively inhibit either
reversibly e.g.neostigmine or irreversibly e.g
Aspirin
Simvastatin inhibits HMG CoA REDUCTASE

63

64

ENZYME INHIBITORS

The cell is ruptured arachidonic acid is

released this is a precurser, or building
block to prostaglandins, which lead to
inflammation and escalate the sensation of
pain.
COX enzymes (cyclo-oxygenase) converts
arachidonic acid to prostaglandins
All NSAIDs inhibit COX enzymes
65

CHEMOTHERAPEUTIC
AGENTS

Cytotoxic drugs act by interfering with cell

growth and division at different stages of the
cycle
Anti-infective drugs

66

CHEMOTHERAPEUTIC
AGENTS
Examples :
Folic acid is required for DNA synthesis.
Methotrexate inhibits the formation of folic
acid.
Penicillins
and
cephalosporins
inhibit
synthesis of bacterial cell walls.
Nyastatin acts by increasing the permeability
of of cell membranes of invading organisms.
Erythromycin
inhibits bacterial protein
synthesis.
67

Bacterial Cell
Cell wall

Cell membrane

DNA

Metabolism of bacterial cell

Amino
acids

Class 3 reactions

Class 2 reactions

Class 1 reactions

Glucose

Precursor
molecules

Nucleotides

Proteins
RNA
DNA

68

CHEMOTHERAPEUTIC
AGENTS

Chemotherapy-exploiting the differences

between host and bacteria.
Class 1 reactions are not good targets for
chemotherapy no marked difference in the
way humans and bacteria obtain energy from
glucose.
Class 2 are better targets as some pathways
converting precursor molecules to amino
acids occur in bacteria but not in human.
69

CHEMOTHERAPEUTIC
AGENTS

E.g. man cannot manufacture own folate

(needed for DNA synthesis) and needs to
take from diet. Bacteria make their own folate
and cannot transport into cell from
environment.
Class 3 reactions are excellent target for
chemotherapy because every cell makes its
own macromolecules,
e.g. needed for
manufacture of bacterial cell wall, different
from human cells.
70

DEFINITIONS

EFFICACY
Degree to which a drug is able to produce
the desired response
POTENCY
Amount of drug required to produce 50% of
the maximal response the drug is capable
of inducing
Used
to compare compounds within
classes of drugs

DEFINITIONS

EFFECTIVE CONCENTRATION 50% (ED50)

Concentration of the drug which induces a specified
clinical effect in 50% of subjects.
LETHAL DOSE 50% (LD50)
Concentration of the drug which induces death in
50% of subjects.
THERAPEUTIC INDEX
Measure of the safety of a drug.
Calculation : LD50/ED50
MARGIN OF SAFETY
Margin between the therapeutic and lethal doses of a
drug.

DOSE-RESPONSE
RELATIONSHIP

Drug induced responses are not an all or

none phenomenon.
Increase in dose may :
Increase therapeutic response
Increase risk of toxicity

PHYSIOLOGICAL
VARIABILITY

Liver disease / damage of liver cells

Chronic alcoholism
Induces microsomal oxidation enzymes
that participate in metabolism of certain
drugs e.g. theophyline. If given in normal
doses more rapid metabolism due to higher
level of enzymes. This will result in
inadequate plasma levels and doses need
to be altered accordingly.
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PHYSIOLOGICAL
VARIABILITY

Reduced hepatic blood flow

Renal disease
Potential to reduce the elimination of drugs
if eliminated largely by the kidneys. This
could lengthen the half life of drugs if the
metabolites are pharmacologically active.
Dosage adjustments are required
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PHYSIOLOGICAL
VARIABILITY

Allergy
Allergy incidence is increasing with multiple
drug therapy. Penicillin groups most
commonly involved.
Initial
reaction is the formation of
antibodies. Subsequent exposure causes
chemicals to be releases e.g. histamine
that causes the allergic response
Decreased plasma proteins
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REMEMBER
No drug produces
a single effect!!!