BASIC PRINCIPLES OF PHARMACOLOGY
Describe how drugs are metabolized
1. Differentiate pharmacokinetics from pharmacodynamics
Pharmacokinetics - describes the effect of the body on
drugs (example: absorption, excretion)
Pharmacodynamics: -denotes the actions of the drug on the
body (example: mechanism of action. toxic effects)
2. List and discuss the common routes of drug
administration and excretion
OP
The most important organ for drug metabolism is the liver
Elimination of Drugs: Usually through the kidneys
3.
A. Drug Metabolism as a Mechanism of Activation or
Termination of Drug Action
Conversion to an inactive metabolite is a form of elimination.
In contrast, prodrugs (eg, levodopa, minoxidil) are inactive
as administered and must be metabolized in the body to become
active. Many drugs are active as administered and have active
metabolites as well (eg, morphine, some benzodiazepines).
B. Drug Elimination Without Metabolism
Some drugs (eg, lithium, many others) are not modified by
the body; they continue to act until they are excreted.
Phase I Reactions: Oxidation, Reduction, Deamination
and Hydrolysis
75% of drugs are metabolized by the enzymes CYP3A4 and
CYP2D6.
Phase II Reaction: addition (conjugation) of subgroups to —
OH, —NH2, and —SH, Glucuronidation, Acetylation,
Glutathione conjugation, Glycine conjugation, Sulfation,
Methylation
4. Differentiate first-order elimination from zero-order
elimination.
A. First-Order Elimination
The term first-order elimination indicates that the rate of
elimination is proportional to the concentration (ie, the higher
the concentration, the greater the amount of drug eliminated per
unit time). The result is that the drug’s concentration in plasma
decreases exponentially with time. Drugs with first-order elimination
have a characteristic half-life of elimination that is constant
regardless of the amount of drug in the body. The concentration of
such a drug in the blood will decrease by 50% for every half-life. Most
drugs in clinical use demonstrate first-order kinetics.
B. Zero-Order Elimination
The term zero-order elimination implies that the rate of
elimination is constant regardless of concentration. This occurs
with drugs that saturate their elimination mechanisms at
concentrations of clinical interest. As a result, the
concentrations of these drugs in plasma decrease in a linear
fashion over time.
Such drugs do not have a constant half-life. This is typical of
ethanol (over most of its plasma concentration range) and of
phenytoin and aspirin at high therapeutic or toxic
concentrations.
FIGURE: Comparison of first-order and zero-order elimination. For drugs with first-
order kinetics (left), rate of elimination (units per
hour) is proportional to concentration; this is the more common process. In the case of
zero-order elimination (right), the rate is constant and
independent of concentration.

BLOOD & GOUT DRUGS
1. Name the 2 most common types of nutritional anemia,
and, for each, describe the most likely biochemical
causes.
Iron deficiency and vitamin deficiency anemia
- Microcytic hypochromic anemia
- Caused by iron deficiency
- Most common type of anemia
Pernicious anemia
-The most common type of vitamin B12 deficiency anemia
-Caused by a defect in the synthesis of intrinsic factor, a
protein required for efficient absorption of dietary vitamin
B12, or by surgical removal of that part of the stomach that
secretes intrinsic factor.
2. Identify the iron and folic acid requirements for
pregnant women.
30 mg to 60 mg of elemental iron and
400 µg (0.4 mg) folic acid
3. Explain how folic acid and B12 deficiency affects the body and how
they can be treated.
Folic acid
- folic acid is required for normal DNA synthesis, and its
deficiency usually presents as megaloblastic anemia.
- In addition, deficiency of folic acid during pregnancy
increases the risk of neural tube defects in the fetus
- Anemia resulting from folic acid deficiency is readily treated
by oral folic acid supplementation.
- Because maternal folic acid deficiency is associated with
increased risk of neural tube defects in the fetus, folic acid
supplementation is recommended before and during
pregnancy.
Vitamin B12 (cobalamin)
- a cobalt-containing molecule, is, along with folic acid, a
cofactor in the transfer of 1-carbon units, a step necessary for
the synthesis of DNA.
- Impairment of DNA synthesis affects all cells, but because red
blood cells must be produced continuously, deficiency of
either vitamin B12 or folic acid usually manifests first as
anemia.
In addition, vitamin B12 deficiency can cause neurologic
defects, which may become irreversible if not treated
promptly
- However, the exogenous folic acid does not correct the
neurologic defects of vitamin B12 deficiency
- Administration of folic acid to patients with vitamin B12
deficiency helps refill the tetrahydrofolate pool and partially or
fully corrects the anemia.
- However, the exogenous folic acid does not correct the
neurologic defects of vitamin B12 deficiency.
- The 2 available forms of vitamin B12— hydroxocobalamin
and cyanocobalamin—have equivalent effects.
- The major application is in the treatment of naturally
occurring pernicious anemia and anemia caused by gastric
resection.
- Because vitamin B12 deficiency anemia is almost always
caused by inadequate absorption, therapy should be by
replacement of vitamin B12, using parenteral therapy.
4. Name 3 types of anticoagulants and describe their
mechanisms of action.
Heparin
acts by binding to endogenous antithrombin III via a key
pentasaccharide sequence; the resulting complex irreversibly
inactivates thrombin and factor Xa.
In the presence of heparin, ATIII proteolyzes thrombin and
factor Xa approximately 1000-fold faster than in its absence
Direct Thrombin Inhibitors
Parenteral: Lepirudin, desirudin, bivalirudin, argatroban
Oral: Dabigatran
- The protein analogs of lepirudin bind simultaneously to the
active site of thrombin and to thrombin substrates.
- Argatroban binds solely to the thrombin- active site.
- Unlike the heparins, these drugs inhibit both soluble
thrombin and the thrombin enmeshed within developing
clots.
- Bivalirudin also inhibits platelet activation.
Rivaroxaban and apixaban; Rapid onset of action and shorter
half-lives than warfarin. These drugs are given as fixed oral
doses and do not require monitoring
- These small molecules directly bind to and inhibit both free
factor Xa and factor Xa bound in the clotting complex.
Warfarin
-acts by interfering with the normal post- translational
modification of clotting factors in the liver, a process that
depends on an adequate supply of reduced vitamin K.
The drugs inhibit vitamin K epoxide reductase (VKOR), which
normally converts vitamin K epoxide to reduced vitamin K.
The vitamin K-dependent factors include thrombin and factors
VII, IX, and X.
5. Compare the pharmacokinetics, clinical uses, and toxicities of such as omeprazole and esomeprazole, should not be
the major antiplatelet drugs. administered concurrently with clopidogrel. Antagonists of
A. Aspirin ADP receptors: clopidogrel
Pharmacokinetics: When given orally, aspirin is absorbed by
passive diffusion and quickly hydrolyzed to salicylic acid in the
liver. Salicylic acid is further metabolized in the liver, and some Therapeutic use: Clopidogrel is approved for prevention of
is excreted unchanged in the urine. The half-life of aspirin atherosclerotic events in patients with a recent MI or stroke
ranges from 15 to 20 minutes and for salicylic acid is 3 to 12 and in those with established peripheral arterial disease. It is
hours. Aspirin, an IRREVERSIBLE COX inhibitor also approved for prophylaxis of thrombotic events in acute
coronary syndromes (unstable angina or non–ST-elevation MI).
Therapeutic use: Aspirin is used in the prophylactic treatment
Additionally, clopidogrel is used to prevent thrombotic events
of transient cerebral ischemia, to reduce the incidence of
associated with percutaneous coronary intervention (PCI) with
recurrent MI, and to decrease mortality in the setting of
or without coronary stenting. Ticlopidine is similar in structure
primary and secondary prevention of MI. Complete
to clopidogrel. It is indicated for the prevention of transient
inactivation of platelets occurs with 75 mg of aspirin given
ischemic attacks (TIA) and strokes in patients with a prior
daily. The recommended dose of aspirin ranges from 50 to 325
cerebral thrombotic event. However, due to life-threatening
mg daily. Aspirin is used to prevent further infarcts in persons
hematologic adverse reactions, ticlopidine is generally
who have had 1 or more myocardial infarcts
reserved for patients who are intolerant to other therapies.
Adverse effects: Higher doses of aspirin increase drug-related Prasugrel is approved to decrease thrombotic cardiovascular
toxicities as well as the probability that aspirin may also inhibit events in patients with acute coronary syndromes (unstable
prostacyclin production. Bleeding time is prolonged by aspirin angina, non–ST-elevation MI, and ST-elevation MI managed
treatment, causing complications that include an increased with PCI). Ticagrelor is approved for the prevention of arterial
incidence of hemorrhagic stroke and gastrointestinal (GI) thromboembolism in patients with unstable angina and acute
bleeding, especially at higher doses of the drug. Nonsteroidal MI, including those undergoing PCI.
anti-inflammatory drugs, such as ibuprofen, inhibit COX-1 by
Adverse effects: These agents can cause prolonged bleeding
transiently competing at the catalytic site. Ibuprofen, if taken
for which there is no antidote. Ticlopidine is associated with
within the 2 hours prior to aspirin, can obstruct the access of
severe hematologic reactions that limit its use, such as
aspirin to the serine residue and, thereby, antagonize platelet
agranulocytosis, thrombotic thrombocytopenic purpura (TTP),
inhibition by aspirin. Therefore, immediate release aspirin
and aplastic anemia. Clopidogrel causes fewer adverse
should be taken at least 60 minutes before or at least 8 hours
reactions, and the incidence of neutropenia is lower. However,
after ibuprofen. Although celecoxib (a selective COX-2
TTP has been reported as an adverse effect for both
inhibitor, see Chapter 36) does not interfere with the
clopidogrel and prasugrel (but not for ticagrelor). Prasugrel is
antiaggregation activity of aspirin, there is some evidence that
contraindicated in patients with history of TIA or stroke.
it may contribute to cardiovascular events by shifting the
Prasugrel and ticagrelor carry black box warnings for bleeding.
balance of chemical mediators in favor of thromboxane A2.
Additionally, ticagrelor carries a black box warning for
B. Ticlopidine, clopidogrel, prasugrel, and ticagrelor diminished effectiveness with concomitant use of aspirin doses
above 100 mg.
Pharmacokinetics: These agents require loading doses for
quicker antiplatelet effect. Food interferes with the absorption C. Abciximab, eptifibatide, and tirofiban
of ticlopidine but not with the other agents. After oral Pharmacokinetics: Abciximab is given by IV bolus, followed by
ingestion, the drugs are extensively bound to plasma proteins. IV infusion, achieving peak platelet inhibition within 30
They undergo hepatic metabolism by the cytochrome P450 minutes. The metabolism of abciximab is unknown. After
(CYP) system to active metabolites. Elimination of the drugs cessation of abciximab infusion, platelet function gradually
and metabolites occurs by both the renal and fecal routes. returns to normal, with the antiplatelet effect persisting for 24
Clopidogrel is a prodrug, and its therapeutic efficacy relies to 48 hours. When IV infusion of eptifibatide or tirofiban is
entirely on its active metabolite, which is produced via stopped, both agents are rapidly cleared from the plasma.
metabolism by CYP 2C19. Genetic polymorphism of CYP 2C19 Eptifibatide and its metabolites are excreted by the kidney.
leads to a reduced clinical response in patients who are “poor Tirofiban is excreted largely unchanged by the kidney and in
metabolizers” of clopidogrel. Tests are currently available to the feces. Glycoprotein IIb/IIIa receptor inhibitors: abciximab,
identify poor metabolizers, and it is recommended that other tirofiban, and eptifibatide
antiplatelet agents (prasugrel or ticagrelor) be prescribed for Therapeutic use: These agents are given intravenously, along
these patients. In addition, other drugs that inhibit CYP 2C19, with heparin and aspirin, as an adjunct to PCI for the
 prevention of cardiac ischemic complications. Abciximab is also
approved for patients with unstable angina not responding to
CARDIOVASCULAR DRUGS
conventional medical therapy when PCI is planned within 24 Drugs Used in Hypertension
hours. The glycoprotein IIb/IIIa inhibitors prevent restenosis 1. List the 4 major groups of antihypertensive drugs, and give
after coronary angioplasty and are used in acute coronary examples of drugs in each group. (Renin inhibitors are not
syndromes (eg, unstable angina and non-Q-wave acute considered an independent major group; can you name
myocardial infarction). the drug that acts by this mechanism?)

Adverse effects: The major adverse effect of these agents is

bleeding, especially if used with anticoagulants

D. Dipyridamole

Dipyridamole, a coronary vasodilator, increases intracellular

levels of cAMP by inhibiting cyclic nucleotide
phosphodiesterase, thereby resulting in decreased
thromboxane A2 synthesis. The drug may potentiate the effect
of prostacyclin to antagonize platelet stickiness and, therefore,
decrease platelet adhesion to thrombogenic surfaces.
Dipyridamole is used for stroke prevention and is usually given
in combination with aspirin. Dipyridamole has variable
bioavailability following oral administration. It is highly protein
bound. The drug undergoes hepatic metabolism, as well as
glucuronidation, and is excreted mainly in the feces. Patients
with unstable angina should not use dipyridamole because of
its vasodilating properties, which may worsen ischemia
(coronary steal phenomenon). Dipyridamole commonly causes
headache and can lead to orthostatic hypotension (especially if
administered IV).

E. Cilostazol

Cilostazol is an oral antiplatelet agent that also has vasodilating

activity. Cilostazol and its active metabolites inhibit
phosphodiesterase type III, which prevents the degradation of
cAMP, thereby increasing levels of cAMP in platelets and
vascular tissues. The increase in cAMP levels in platelets and
the vasculature prevents platelet aggregation and promotes
vasodilation of blood vessels, respectively. Cilostazol favorably
alters the lipid profile, causing a decrease in plasma
triglycerides and an increase in high-density lipoprotein
cholesterol. The drug is approved to reduce the symptoms of
intermittent claudication. Cilostazol is extensively metabolized
in the liver by the CYP 3A4, 2C19, and 1A2 isoenzymes. As
such, this agent has many drug interactions that require dose
modification. The primary route of elimination is via the
kidney. Headache and GI side effects (diarrhea, abnormal
stools, dyspepsia, and abdominal pain) are the most common
adverse effects observed with cilostazol. Phosphodiesterase
type III inhibitors have been shown to increase mortality in
patients with advanced heart failure. As such, cilostazol is
contraindicated in patients with heart failure.
Inhibitors of phosphodiesterase 3: dipyridamole and cilostazol
NOTE: READ THE LECTURE NOTE
 Low-dose thiazide diuretics are often used as first-line agents
• Induce hypokalemia and hyperuricemia in 70 percent of
patients and hyperglycemia in 10 percent of patients
Renin Inhibitors: Aliskiren
The newest drug in the antihypertensive group
Directly inhibits renin’s action on its substrate,
angiotensinogen.
It thus reduces the formation of angiotensin I and, in
consequence, angiotensin II
It lowers blood pressure about as effectively as ARBs, ACE
inhibitors, and thiazides.
It does not appear to cause cough
It does not show reproductive toxicity in animals but is
considered to be contraindicated in pregnancy because of the
toxicity of ACE inhibitors and ARBs.
Note: Aliskiren (newest drug) – does not cause cough
Captopril (old drugs) – cause cough
Losartan – lower cough incidence
All 3 are contraindicated in pregnancy
2. List the 4 mechanisms of action of vasodilator drugs.
- release of nitric oxide
- opening of potassium channels (which leads to
hyperpolarization)
- blockade of calcium channels
- activation of D1 dopamine receptors (causing vasodilation)
3. List the major antihypertensive vasodilator drugs and
describe their effects.
HYDRALAZINE
Acts through the release of nitric oxide from endothelial cells
Used to treat moderately severe hypertension
Rarely used at high dosage because of its toxicity
Hydralazine-induced lupus erythematosus with high dosage
-reversible upon stopping the drug
-lupus is uncommon at dosages below 200 mg/d.
MINOXIDIL
Reserved for severe hypertension
a prodrug; its metabolite, minoxidil sulfate, is a potassium
channel opener that hyperpolarizes and relaxes vascular
smooth muscle.
Because it can cause hirsutism, minoxidil is also available as a
topical agent for the treatment of baldness.
Calcium-Channel Blockers
Moderately effective vasodilators
Suitable for chronic use in hypertension of any severity
Intracellular concentration of calcium helps maintains the tone
of smooth muscle and contraction of the myocardium.
Calcium enters muscle cells through special voltage-sensitive
calcium channels triggers release of calcium from the
sarcoplasmic reticulum and mitochondria ↑ cytosolic level of
calcium
Drug binds to L-type calcium channels in the heart and in
smooth muscle of the coronary and peripheral vasculature
block the inward movement of calcium vascular smooth
muscle relax dilation mainly of arterioles
Nicardipine
Also used in hypertensive emergencies
Can be given as an intravenous infusion
Major limitation of nicardipine in treating hypertensive
emergency: long half-time (approximately 8 hours), which
precludes rapid titration.
May have unique benefits in cerebrovascular disease: crosses
the blood-brain barrier and acts to vasorelax cerebrovascular
smooth muscle
NITROPRUSSIDE
Release of nitric oxide (from the drug molecule itself) 
stimulates guanylyl cyclase  ↑ cyclic guanine
monophosphate (cGMP) concentration in smooth muscle 
prompt vasodilation with reflex tachycardia
The drug has little effect outside the vascular system, acting
equally on arterial and venous smooth muscle.
Note: Because nitroprusside also acts on the veins, it can
reduce cardiac preload
4. Describe the differences between the 2 types of
angiotensin antagonists.
Angiotensin Converting Enzyme (ACE) Inhibitors
– Captopril (benazepril, enalapril)
- Decrease Angiotensin II and increase bradykinin =
vasodilation
 ↓ angiotensin II levels, ACE inhibitors  ↓ secretion of
aldosterone  ↓ sodium and water retention
Useful in heart failure and diabetes as well as in hypertension
Slow the progression of diabetic nephropathy
ACE inhibitors are also effective in the management of patients
with chronic heart failure.
ACE inhibitors are a standard in the care of a patient following
a myocardial infarction. Therapy is started 24 hours after the
end of the infarction.
- Reduce peripheral resistance w/o increasing cardiac output
- TOXICITY: Cough, Renal damage in renal disease patient and
Fetus, and Fetal renal toxicity -Contraindicated in pregnancy
Angiotensin II Receptor Blockers (ARBs) – Losartan
(valsartan,irbesartan)
Competitively inhibit angiotensin II at its AT1 receptor site
Appear to be as effective in lowering blood pressure as the
ACE inhibitors
Also produce arteriolar and venous dilation and block
aldosterone secretion  ↓ blood pressure and ↓ salt and
water retention
TOXICITY: Fetal renal toxicity – contraindicated in pregnancy
5. List the major toxicities of the prototype
antihypertensive agents.
Thiazide – hypokalemia, hypovolemia, hyperuricemia and
hyperglycemia, INSULIN RESISTANCE, INCREASED
CHOLESTEROL
Furosemide – hypokalemia, hypovolemia and ototoxicity
Prazosin (alpha 1 blocker) – orthostatic hypotension
especially with the first few doses.
Propranolol (beta blocker) – bronchospasm in asthma
patients, cardiac depression and sexual dysfunction
• Bradycardia
• CNS side effects: fatigue, lethargy, insomnia, and
hallucinations
• Hypotension
• Decreased libido
• Impotence
Clonidine and methyldopa (CNS agonist/ alpha2 seletive
agonists) – rebound hypertension due to Sudden
discontinuation (drug should therefore be withdrawn slowly)
Most common SE: drowsiness
Methyldopa: Cardiac output is not decreased. Used in
hypertensive pregnant patients and in px with renal
insufficiency
Captopril – feto renal toxicity
Drugs Used in the Treatment of Angina Pectoris
Nitrate (Nitroglycerin)
- 10 – 20min Short duration of action (sublingual
administration; for Acute angina)
- 8 – 10 hours Long duration of action (transdermal; for
prophylaxis of angina)
- Intermediate duration of action (oral; for prophylaxis of
angina)
Atherosclerotic Angina is relieved within 5–10 min by rest
and/or sublingual nitroglycerin
- Nitrate also treats acute coronary syndrome
- MOA: Nitrates release nitric oxide (NO) within smooth
muscle cells which stimulate Guanylyl cyclase and then
increase cGMP (secondary messenger)
cGMP induces smooth muscle relaxation.
Smooth muscle relaxation  venodilation  reduced
preload  reduced cardiac size and cardiac output
Venodilation leads to decreased diastolic heart size and
fiber tension.
Relaxation of arterial smooth muscle  increase flow
through partially occluded epicardial coronary vessels.
Reduced afterload, from arteriolar dilation of resistance
vessels  increase in ejection and a further decrease in
cardiac size.
Arteriolar dilation leads to reduced peripheral resistance
and blood pressure.
- Toxicities: tachycardia, orthostatic hypotension, flushing,
throbbing headache, convert the ferrous iron in hemoglobin
to the ferric form, yielding methemoglobin. significant reflex
tachycardia and increased force of contraction
Beta blockers
Used only for prophylactic therapy of angina
They are of no value in an acute attack
Effective in preventing exercise-induced angina
Ineffective against the vasospastic form
The combination of β blockers and nitrates is useful because
the adverse undesirable compensatory effects evoked by the
nitrates (tachycardia and increased cardiac force) are
prevented or reduced by β blockade.
Calcium blockers
Calcium influx is increased in ischemia because of the
membrane depolarization that hypoxia produces
 promotes the activity of several adenosine
triphosphate-consuming enzymes  depleting energy
stores and worsening the ischemia
The calcium-channel blockers protect the tissue by inhibiting
the entrance of calcium into cardiac and smooth muscle cells of
the coronary and systemic arterial beds
- All are arteriolar vasodilators
 - Reduce blood pressure
- Verapamil – affects myocardium (Decrease BP, heart rate,
contractility and oxygen demand). Avoided in patients with
congestive heart failure
- Nifedipine – affects peripheral vasculature (minimal effect on
cardiac conduction and heart rate)
- Diltiazepine – is intermediate in its action
Relieve coronary artery spasm (variant angina)
Antiarrhythmic Drugs
1. Enumerate the 4 major types of antiarrhythmic drugs and list
2-3 important drugs under each group.
Group 1A agents (prototype procainamide) prolong the AP.
Group 1B drugs (prototype lidocaine) shorten the AP in some
cardiac tissues.
Group 1C drugs (prototype flecainide) have no effect on AP
duration.
All group 1 drugs slow conduction in ischemic and depolarized
cells and slow or abolish abnormal pacemakers wherever these
processes depend on sodium channels.
GROUP 2 / BETA BLOCKERS (Propranolol and esmolol) are
prototypic antiarrhythmic β blockers.
Their mechanism in arrhythmias is primarily cardiac β-
adrenoceptor blockade and reduction in cAMP, which results
in the reduction of both sodium and calcium currents and the
suppression of abnormal pacemakers.
The AV node is particularly sensitive to β blockers and the PR
interval is usually prolonged by group 2 drugs.
GROUP 3 ANTIARRHYTHMICS/ POTASSIUM IK CHANNEL
BLOCKERS prolong the duration of the action potential
without altering Phase 0 of depolarization or the resting
membrane potential
Instead, they prolong the effective refractory period.
All Class III drugs have the potential to induce arrhythmias.
DOFETILIDE and IBUTILIDE are typical group 3 drugs.
SOTALOL is a chiral compound
Amiodarone is usually classified as a group 3 drug because it
blocks the same K channels and markedly prolongs AP duration
as well as blocking sodium channels
DRONEDARONE is a new drug, similar to amiodarone but less
efficacious and less toxic.
hallmark of group 3 drugs is prolongation of the AP
duration
GROUP 4 ANTIARRHYTHMICS/CALCIUM L-TYPE CHANNEL
BLOCKERS They decrease the inward current carried by
calcium, resulting in a decreased rate of Phase 4 spontaneous
depolarization.
Major effect of calcium-channel blockers is on vascular
smooth muscle and the heart
- Verapamil is the prototype.
- Diltiazem is also an effective antiarrhythmic drug
- AV conduction velocity is decreased, and effective
refractory period and PR interval are increased by
these drugs
List the major toxicities of those drugs
Class I (Na channel blockers)
IA – procainamide, quinidine: hypotension, lupus
erythematosus (procainamide)
torsades de pointes and cinchonism – headache, vertigo,
tinnitus (quinidine)
IB – lidocaine: convulsions and cardiovascular depression, may
precipitate, hyperkalemia increase cardiotoxicity
IC – flecainide: greater mortality and hyperkalemia increase
cardiotoxicity
Class III (K channel blockers)
Amiodarone - interstitial pulmonary fibrosis, gastrointestinal
tract intolerance, tremor, ataxia, dizziness, hyper- or
hypothyroidism, liver toxicity, Photosensitivity, Neuropathy,
muscle weakness, blue skin & corneal discoloration
caused by iodine accumulation
 Class IV (Ca channel blockers) excessive depression of o Inc. ventricular ejection
cardiac contractility, AV conduction, and blood pressure. o Dec. end-systolic and end- diastolic size
These agents should be avoided in ventricular o Inc. cardiac output
tachycardias. o Inc. renal perfusion
- ECG effects:
o Increases PR interval
o Flattening of the T wave

Drugs Used in Heart Failure - Toxicity:

o Increased automacity caused by intracellular calcium
1. Describe the strategies and list the major drug groups overload
used in the treatment of acute heart failure and o Extrasystoles, tachycardia, fibrillation
chronic failure. o Extrasystoles are recognized as premature ventricular
Therapeutic strategies: beats
- Removal of retained salt and water with diuretics
o Chronic: abnormal automaticity and arrhythmias
- Reduction of afterload and salt and water retention by
means of ACE inhibitors o Severe, acute: cardiac depression leading to cardiac
- Reduction of excessive sympathetic stimulation by arrest rather than tachycardia or fibrillation
means of B blockers
- Reduction of preload or afterload with vasodilators Digitalis is no longer considered as the first line therapy for
- Systolic failure: direct augmentation of depressed cardiac chronic heart failure because too much inhibition of Na/K
contractility with positive inotropic drugs such as digitalis glycosides ATPase can cause dysrhythmias. Moreover, careful clinical
studies indicate that while digitalis may improve functional
Therapeutic strategies: acute heart failure status (reducing symptoms), it does not prolong life.
- Loop diuretics
- Very severe HF: a prompt acting positive inotropic agent such as B
agonist or phosphodiesterase inhibitor, and vasodilators should be
used as required to optimize filling pressures and blood pressure. CNS DRUGS
- Nesiritide
- recombinant form of brain natriuretic peptide Sedative-Hypnotics Drugs
- Has vasodilating and diuretic properties
Benzodiazepine:
Therapeutic strategies: chronic heart failure
Alprazolam
- Best treated with diuretics (often a loop agent plus spironolactone)
plus an ACE inhibitor and if tolerated, a B blocker Chlordiazepoxide
- Digitalis may be helpful id systolic dysfunction is Clorazepate
prominent. Flurazepam
Midazolam
2. Describe the mechanism of action of digitalis and its major effects. Clonazepam (Longacting)
Indicate why digitalis is no longer considered a first-line therapy for
chronic heart failure.
Diazepam (LA)
Digitalis- inhibition of Na/K ATPase of the cell membrane Lorazepam (LA)
Free cytosolic calcium concentrations at the end of
contraction must be ↓ for cardiac muscle to relax. MOA: Bind GABA-a receptor subunits to facilitate chloride
The Na+/Ca2+-exchanger plays an important role in this channel opening and increase frequency (which leads to an
process by extruding Ca2+ from the myocyte in exchange increase in chloride conductance)
for Na+ •membrane hyperpolarization
Inhibition of Na+/K+ ATPase  small ↑ in intracellular Na Therapeutic uses:
 alters the driving force for Na-Ca exchange by the -Anxiety disorders - useful in treating the anxiety that
exchanger, NCX  less calcium is removed from the cell accompanies some forms of depression and schizophrenia
↑intracellular calcium is stored in the sarcoplasmic -Reserved for continued severe anxiety, and then should only
reticulum and upon release increases contractile force be used for short periods of time because of their addiction
potential.
Increases force of contraction of the heart\ Increase in
contractility results in:
-panic disorders, alprazolam is effective for short- and
long-term treatment
-Diazepam is useful in the treatment of skeletal muscle
spasms. DOC terminating grand mal epileptic seizures.
-Midazolam is an injectable-only benzodiazepine also used
for the induction of anesthesia
-Diazepam and lorazepam are the drugs of choice in
terminating grand mal epileptic seizures and status
epilepticus
-chlordiazepoxide, clorazepate, diazepam, and oxazepam are
useful in the acute treatment of alcohol withdrawal and
reducing the risk of withdrawal-related seizures
Adverse effects
-Drowsiness and confusion: The two most common side
effects of the benzodiazepines
-Ataxia occurs at high doses, don’t drive
-Cognitive impairment (decreased long-term recall and
acquisition of new knowledge)
-Triazolam, with the most rapid elimination, often shows a Abrupt withdrawal from barbiturates may cause tremors,
rapid development of tolerance, early morning insomnia, and anxiety, weakness, restlessness, nausea and vomiting,
daytime anxiety, along with amnesia and confusion.
-Avoid in patients with acute narrow-angle glaucoma
-Alcohol and other CNS depressants enhance the sedative-
hypnotic effects
Benzodiazepine Antagonist (Management
for Overdose):
Flumazenil:
A GABA-receptor antagonist that can rapidly reverse the
effects of benzodiazepines (“olam”)
Buspirone
- treatment of generalized anxiety disorder
MOA: mediated by serotonin (5-HT1A) receptors
Causes hypothermia and Can increase prolactin and growth
hormone. Advantage of minimal sedation.
Adverse effect: Most common effects: headaches, dizziness,
nervousness, and light-headedness
Barbiturates
Amobarbital
Butabarbital
Pentobarbital
Phenobarbital
Secobarbital
Thiopental
MOA:
Bind to GABA-a receptor sites (distinct from benzodiazepines)
• facilitate chloride channel opening and increase duration
• Can block excitatory glutamate receptors
• Anesthetic concentrations of pentobarbital also block high-
frequency sodium channels.
Therapeutic uses
Anesthesia: thiopental, are used intravenously
Anxiety: barbiturates have been used as mild sedatives to
relieve anxiety, nervous tension, and insomnia.
when used as hypnotics, they suppress REM sleep more than
other stages.
Adverse effects
CNS: drowsiness, impaired concentration, and mental and
physical sluggishness
Drug hangover - occasionally, nausea and dizziness occur
induce the P450 system and, therefore, may decrease the
duration of action of drugs
increase porphyrin synthesis  contraindicated in patients
with acute intermittent porphyria.
seizures, delirium, and cardiac arrest.
Zolpidem
- acts on a subset of the benzodiazepine receptor family, BZ1.
- shows few withdrawal effects, and exhibits minimal rebound
insomnia, and little or no tolerance occurs with prolonged use
- Adverse effects of zolpidem include nightmares, agitation,
headache, gastrointestinal upset, dizziness, and daytime
drowsiness.
Ramelteon
Novel hypnotic drug that activates melatonin receptors in
the suprachiasmatic nuclei of the CNS decreases the latency of
sleep onset with minimal rebound insomnia or withdrawal
symptoms.
adverse effects of the drug include dizziness, fatigue, and
endocrine changes including decreased testosterone and
increased prolactin.

Alcohol
1. RELATE BLOOD ALCOHOL LEVEL IN A NONTOLERANT
PERSON TO CNS DEPRESSANT EFFECTS OF ACUTE ALCOHOL
INGESTION
In nontolerant persons, impairment of driving ability is thought to
occur at ethanol blood levels 60 and 80 mg/dL. (i.e from 60mg/L
Liver microsomal mixed function oxidase system is active)
Blood levels of 120 to 160 mg/dL are usually associated with gross
drunkenness.
Levels greater than 300 mg/dL may lead to loss of
consciousness, anesthesia, and coma sometimes with fatal
respiratory and cardiovascular depression.
Blood levels higher than 500 mg/dL are usually lethal.
4. Describe Fetal alcohol syndrome
Fetal alcohol syndrome: Ethanol use in pregnancy is associated
with teratogenic effects that include mental retardation (most
common), growth deficiencies, microcephaly, and a
characteristic underdevelopment of the midface region (facial
abnormalities)
ANTISEIZURE DRUGS
1. LiSt the drugS of choice for partial SeizureS,
generalized tonic-clonic SeizureS, absence
and myoclonic SeizureS, and Statu epilepticus

2. Identify the toxic effects of chronic ethanol ingestion

1. Tolerance and dependence: Tolerance occurs mainly as a

result of CNS adaptation and to a lesser extent by an
increased rate of ethanol metabolism

2. Liver: Liver disease is the most common medical complication

of chronic alcohol abuse.
3. Gastrointestinal system: Irritation, inflammation, bleeding,
and scarring of the gut wall occur after chronic heavy use of Phenytoin ,Carbamazipine and Valporic Acid
ethanol - is the DOC Generalize Tonic-Clonic seizure
4. CNS: Peripheral neuropathy is the most common neurologic Phenytoin, Carbamazipine and Lamotrigine
abnormality in chronic alcohol abuse. DOC for Partial Seizure
More rarely, thiamine deficiency, along with alcohol abuse, Ethosuximide or Valproic acid
leads to Wernicke-Korsakoff syndrome, which is characterized - DOC for Absence Seizure
by ataxia, confusion, and paralysis of the extraocular muscles. Diazepam or Lorazepam
- DOC for Status Epilepticus
5. Endocrine system: Gynecomastia, testicular atrophy, and salt
retention can occur, partly because of altered steroid 2. Describe the main pharmacokinetic features, and list
metabolism in the cirrhotic liver the adverse effects of carbamazepine, phenytoin, and
6. Cardiovascular system: Excessive chronic ethanol use is valproic acid
associated with an increased incidence of hypertension,
Subclass Pharmacokinetics Adverse Effect
anemia, and dilated cardiomyopathy.
Phenytoin Variable absorption, Variable absorption,
Methanol is metabolized to formaldehyde and formic acid, dose-dependent dose- dependent
which causes severe acidosis, retinal damage, and blindness elimina- tion; elimina- tion; protein
protein binding; binding; many
3. Describe the Treatment for Ethanol overdosage many drug drug interactions
Treatment for Ethanol interactions
long-acting benzodiazepine (eg, diazepam, chlordiazepoxide) is
preferred unless the patient has compromised liver function, in
which case a short-acting benzodiazepine with less complex
Carbamazepine Well absorbed, Ataxia, diplopia,
metabolism (eg, lorazepam) is preferred active headache, nauseav
- Naltrexone metabolite • many
Nonselective competitive antagonist of opioid receptors drug
- Acamprosate interactions
Poorly understood NMDA receptor antagonist and GABAA Valproate Extensive protein Nausea, alopecia,
agonist effects binding and weight gain,
- Disulfiram metabolism; many teratogenic
drug interactions
Inhibits aldehyde dehydrogenase • causes aldehyde accumulation
during ethanol ingestion. Drug for treat chronic alcohol abuse
 DRUGS OF ABUSE withdrawal from opioids is rarely fatal (unlike withdrawal from
sedative-hypnotics). Treatment involves replacement of the
1. IDENTIFY THE MAJOR DRUGS THAT ARE COMMONLY ABUSED illicit drug with a pharmacologically equivalent agent (eg,
methadone), followed by slow dose reduction.
sedative-hypnotic drugs: are responsible for many cases of Buprenorphine, a partial agonist at μ opioid receptors and a
drug abuse includes ethanol, barbiturates, and longer acting opioid (half-life >40 h), is also used to suppress
benzodiazepines. withdrawal symptoms and as substitution therapy for opioid
addicts. The administration of naloxone to a person who is
Opioids analgesics: most commonly abused drugs in this using strong opioids (but not overdosing) may cause more
group are heroin, morphine, codeine, oxycodone, and among rapid and more intense symptoms of withdrawal (precipitated
health professionals,meperidine and fentanyl withdrawal). Neonates born to mothers physiologically
dependent on opioids require special management of
Stimulants: Caffeine (in beverages) and nicotine (in tobacco withdrawal symptoms.
products), Amphetamines, Cocaine

Hallucinogens: phencyclidine
sedative-hypnotics
Marijuana: Marijuana (“grass”), Cannabis sativa (hemp),
Hashish, cannabinoids
2. Describe the signs and symptoms of overdose with, and
withdrawal from, CNS stimulants, opioid analgesics, and
sedative-hypnotics, including ethanol.
3. ..
4. ..
CNS stimulants
Toxicity—Acute toxicity from overdosage of caffeine or
nicotine includes excessive CNS stimulation with tremor,
insomnia, and nervousness; cardiac stimulation and
arrhythmias; and, in the case of nicotine, respiratory paralysis. Withdrawal
Severe toxicity has been reported in small children who ingest Physiologic dependence occurs with continued use of
discarded nicotine gum or nicotine patches, which are used as
substitutes for tobacco products.
Withdrawal—Withdrawal from caffeine is accompanied by
lethargy, irritability, and headache. The anxiety and mental
discomfort experienced from discontinuing nicotine are major
impediments to quitting the habit. Varenicline, a partial
agonist at the α4β2 subtype nicotinic receptors, which
occludes the rewarding effects of nicotine, is used for smoking
cessation. Rimonabant, an agonist at cannabinoid receptors,
approved for use in obesity, is also used off-label in smoking
cessation.
opioid analgesics
Overdose of opioids leads to respiratory depression
progressing to coma and death. Overdose is managed with
intravenous naloxone or nalmefene and ventilatory support.
Withdrawal
Deprivation of opioids in physiologically dependent individuals discontinuance of sedative-hypnotics after long-term
leads to an abstinence syndrome that includes lacrimation,
rhinorrhea, yawning, sweating, weakness, gooseflesh (“cold
turkey”), nausea and vomiting, tremor, muscle jerks (“kicking
the habit”), and hyperpnea. Although extremely unpleasant
Acute overdoses commonly result in death through
depression of the medullary respiratory and cardiovascular
centers. Management of overdose includes maintenance of a
patent airway plus ventilatory support. Flumazenil can be used
to reverse the CNS depressant effects of benzodiazepines,
but there is no antidote for barbiturates or ethanol.
Flunitrazepam (Rohypnol), a potent rapid-onset
benzodiazepine with marked amnestic properties, has been
used in “date rape.” Added to alcoholic beverages, chloral
hydrate or f-hydroxybutyrate (GHB; sodium oxybate) also
renders the victim incapable of resisting rape. The latter
compound, a minor metabolite of GABA, binds to GABAB
receptors in the CNS. When used as a “club drug,” GHB causes
euphoria, enhanced sensory perception, and amnesia.
sedativehypnotics; the signs and symptoms of the withdrawal
(abstinence) syndrome are most pronounced with drugs that
have a half-life of less than 24 h (eg, ethanol, secobarbital,
methaqualone). However, physiologic dependence may occur
with any sedativehypnotic, including the longer acting
benzodiazepines. The most important signs of withdrawal
derive from excessive CNS stimulation and include anxiety,
tremor, nausea and vomiting, delirium, and hallucinations.
Seizures are not uncommon and may be life-threatening.
Treatment of sedative-hypnotic withdrawal involves
administration of a long acting sedative-hypnotic (eg,
chlordiazepoxide or diazepam) to suppress the acute
withdrawal syndrome, followed by gradual dose reduction.
Clonidine or propranolol may also be of value to suppress
sympathetic overactivity. The opioid receptor antagonist
naltrexone, and acamprosate, an antagonist at N-methyl-d-
aspartate (NMDA) glutamate receptors, are both used in the
treatment of alcoholism.
A syndrome of therapeutic withdrawal has occurred on
therapeutic administration. In addition to the symptoms of
classic withdrawal presented, this syndrome includes weight
loss, paresthesias, and headache.
 DERMATOLOGICAL
PHARMACOLOGY
1. EXPLAIN THE USE GLUCOCORTICOIDS IN
DERMATOLOGIC DISEASES AND THEIR TOXICITY.
Glucocorticoids (triamcinolone acetonide and triamcinolone
hexacetonide) are prescribed frequently for their
immunosuppressive and anti-inflammatory properties.
MOA include a) apoptosis of lymphocytes, b) inhibitory effects
on the arachidonic acid cascade c) depression of production of
many cytokines, and d) myriad effects on inflammatory cells.
With the development of appropriate vehicles, these agents
rapidly became the mainstay of therapy for many
inflammatory skin diseases. more potent drugs have a
fluorinated hydrocortisone backbone.
Toxicity & Monitoring
Chronic use of class I topical glucocorticoids can cause skin
atrophy, striae, telangiectasias, purpura, and acneiform
eruptions.
Because perioral dermatitis and rosacea can develop after the documented. Clinically, this translates to modest attenuation
use of fluorinated compounds on the face, they should not be of fine and coarse wrinkling, smoother texture, increased
used in this site
Systemic Glucocorticoids
Systemic glucocorticoid therapy is used for severe
dermatological illnesses.
In general, it is best to reserve this method for allergic contact
dermatitis to plants (e.g., poison ivy) and for life-threatening
vesiculobullous dermatoses such as pemphigus vulgaris and
bullous pemphigoid.
Chronic administration of oral glucocorticoids is problematic,
given the side effects associated with their long-term use.
Daily morning dosing with prednisone generally is preferred,
although divided doses are used occasionally to enhance
efficacy.
Fewer side effects are seen with alternate-day dosing, and if
required for chronic therapy, prednisone is tapered to every
other day as soon as it is practical.
Pulse therapy using large intravenous doses of
methylprednisolone sodium succinate is an option for
severe resistant pyoderma gangrenosum, pemphigus
vulgaris, systemic lupus erythematosus with multisystem
disease, and dermatomyositis.
Toxicity & Monitoring
Oral glucocorticoids have numerous systemic effects.
Most side effects are dose-dependent.
Long-term use is associated with a number of complications,
including psychiatric problems, cataracts, myopathy,
osteoporosis, avascular bone necrosis, glucose intolerance or
overt diabetes mellitus, and hypertension.
2. ENUMERATE IMPORTANT RETINOIDS USED IN
DERMATOLOGICAL DISEASES.
3. DESCRIBE THEIR (RETINOID) MECHANISM OF ACTIONS,
CLINICAL USE, AND TOXICITIES.
Tretinoin
- Approved for the treatment of acne vulgaris and as an
adjunctive agent for treating photoaging
Reduce the hyperkeratinization that leads to microcomedone
formation, the initial lesion in acne
- Epidermal effects include increased epidermal and granular
layer thickness, decreased melanocytic activity, and increased
secretion of a glycosaminoglycan- like substance into the
intercellular space.
- In the dermis, blood vessel vasodilation and angiogenesis and
increased papillary dermal collagen synthesis have been
pinkness, and diminished hyperpigmentation.
- Nightly application produces maximum response within 1
year, and application one to three times weekly is said to
maintain improvement.
- Treatment must be combined with a rigorous program of
photoprotection, including sunscreens, sun avoidance, and
photoprotective clothing
ADAPALENE
Adapalene has similar efficacy to tretinoin, but unlike tretinoin,
it is stable in sunlight and tends to be less irritating
Tazarotene
- Treatment of psoriasis and acne vulgaris.
- May be used as monotherapy or in combination with other
medications, such as topical corticosteroids, for the treatment
of localized plaque psoriasis.
- Side effects of burning, itching, and skin irritation are
relatively common, and patients should avoid sun exposure
Isotretinoin
- Oral isotretinoin is approved for the treatment of severe
nodulocystic acne vulgaris (numerous papules and pustules
distributed on the whole facial area, along with developing
inflamed nodules)
- normalizes keratinization in the sebaceous follicle, reduces
sebocyte number with decreased sebum synthesis, and
reduces Propionibacterium acnes, the anaerobic, gram-
positive bacteria that produces inflammation in acne
prescribed for:
 ✓severe, recalcitrant nodular acne
✓moderate acne unresponsive to oral antibiotics
✓acne that produces scarring
It also is used commonly for other related disorders, such as
G(-) folliculitis, acne rosacea, and hidradenitis suppurativa
- Toxicity & Monitoring: cheilitis/inflamed lip, mucous
membrane dryness,Epistaxis/nosebleeds, dry eyes,
blepharoconjunctivitis, erythematous eruptions, and
xerosis/dry skin are all Side effects Retinoids
-Systemic side effects: Transitory elevations in serum
transaminases occur rarely. Hyperlipidemia (25%), Myalgia
and arthralgia are common complaints for Isotretinoin
- Headaches occur and rarely are a symptom of pseudotumor
cerebri.
- Long-term therapy may produce skeletal side effects, and
premature epiphyseal closure in children.
- Teratogenicity is a major problem; it occurs if the drug is
given within the first 3 weeks of gestation and is not dose-
related.
- Pregnancy is an absolute contraindication to the use of
isotretinoin.
- Females of childbearing potential should initiate therapy at
the beginning of a normal menstrual period after giving
informed consent and obtaining two negative pregnancy
tests.
6. EXPLAIN HOW TINEA CAPITIS AND TINEA PEDIS ARE
TREATED.
TINEA CAPITIS
Systemic therapy is necessary for the treatment of tinea
capitis.
• Oral griseofulvin has been the traditional medication for
treatment of tinea capitis.
• Oral terbinafine is a safe and effective alternative to
griseofulvin in treating tinea capitis in children.
TINEA PEDIS
Topical therapy with the azoles and allylamines is effective for
tinea pedis.
• Macerated toe web disease may require the addition of
antibacterial therapy. Econazole nitrate, which has a limited
antibacterial spectrum, can be useful in this situation.
• Systemic therapy with griseofulvin, terbinafine, or
itraconazole is used for more extensive tinea pedis. It should
be recognized that long-term topical therapy may be necessary
in some patients after courses of systemic antifungal therapy

4. DESCRIBE THE TYPES OF UV RADIATION AND THEIR

EFFECTS
UVB (290 to 320 nm)
• The most erythrogenic and melanogenic type of radiation.
• It is the major action spectrum for sunburn, tanning, skin
cancer, and photoaging.
UVA: A-I (320 to 340 nm), and A-II (340 to 400 nm)
• The longer wavelengths of UVA are a thousand times less
erythrogenic than UVB
• However, they penetrate more deeply into the skin and
contribute substantially to photoaging and photosensitivity
diseases.
• They also enhance UVB-induced erythema and increase the
risk of skin carcinogenesis.
Psoriasis, Vitiligo – to repigment (PUVA = psoralen capsule
followed by UVA), Cutaneous T-cell lymphoma (PUVA)
• Nonmelanoma skin cancers = Photodynamic therapy
(photosensitizing drugs + visible light)

5. EXPLAIN THE CLINICAL USE OF AZOLES

The azoles miconazole and econazole and the
allylamines naftifine (gel) and terbinafine are effective
topical agents for the treatment of localized tinea
corporis (“ringworm”) and uncomplicated tinea pedis
(“athlete’s foot).
Topical therapy with the azoles is preferred for localized
cutaneous candidiasis and tinea versicolor.