Department of Pharmacology & Therapeutics

Seth GSMC & KEM Hospital, Parel, Mumbai-12.

II MBBS (August 2013 batch)
Preliminary Examination
Paper-I
SECTION B & C
Date: 15/09/14
Total Marks: 32
Time: 1 hour 30 min
Roll no : ________
Brief Answer Questions: (Any 5 out of 6)
Marks: 20
1. Give pharmacological basis for using Tamsulosin in benign hypertrophy of
prostate.
Answer: In many elderly men, benign prostatic hyperplasia (BPH) produces symptomatic
urethral obstruction that leads to weak stream, urinary frequency, and nocturia. These
symptoms are due to a combination of mechanical pressure on the urethra due to the
increase in smooth muscle mass and the 1 receptormediated increase in smooth muscle
tone in the prostate and neck of the bladder. 1receptors in the trigone muscle of the
bladder and urethra contribute to the resistance to outflow of urine

(1 mark)

Administration of 1-selective antagonists cause relaxation of smooth muscle in the

bladder neck, prostate capsule, and prostatic urethra. There is growing evidence that the
predominant 1 receptor subtype expressed in the human prostate smooth muscle is the
1A receptor.Tamsulosinis auroselective blocker with more selectivity for1A and 1D
receptors than for the1B subtype. Hence tamsulosin has relatively greater potency in
inhibiting contraction in prostatesmooth muscle and causes a rapidimprovement in the
urinary flow when administered for BPH

(2marks)

Furthermore, compared with other antagonists, tamsulosin has less effect on standing
blood pressure in patients. This makes it a better toleratedand preferred 1 blocker for
benign prostatic hypertension.

( mark)

2. Explain any 4 therapeutic uses of anticholinesterases.

(1 Mark for each use. Any 4 uses can be explained)
Anti-ChE agents exert their action by preventing the hydrolysis of ACh by AChE at
sites of cholinergic transmission. Transmitter thus accumulates, enhancing the
response to ACh that is liberated by cholinergic impulses or that is spontaneously
released from the nerve ending.
1. Myasthenia gravis

Myasthenia gravis is caused by an autoimmune response primarily to the ACh

receptor at the post-junctional end plate. These antibodies reduce the number of
receptors.Pyridostigmine, neostigmine, and ambenonium are the standard anti-ChE
drugs used in the symptomatic treatment of myasthenia gravis. All can increase the
response of myasthenic muscle to repetitive nerve impulses, primarily by the
preservation of endogenous ACh. Edrophonium is sometimes used as a diagnostic
test for myasthenia. 2 mg of edrophonium chloride is injected rapidly intravenously,
followed 45 seconds later by an additional 8 mg if the first dose is without effect; a
positive response consists of brief improvement in strength.
2. Postoperative paralytic ileus and Atony of the Urinary Bladder
Neostigmine generally is preferred among the anti-ChE agents in the treatment of
postoperative ileus (atony or paralysis of the stomach or bowel following surgical
manipulation), urinary retention postoperatively or postpartum or secondary to spinal
cord injury or disease (neurogenic bladder). For paralytic ileus or atony of the urinary
bladder, neostigmine can be given subcutaneously in a dose of 0.51 mg.(oral dose is
15mg). Neostigmine should not be used when the intestine or urinary bladder is
obstructed, when peritonitis is present, when the viability of the bowel is doubtful, or
when bowel dysfunction results from inflammatory bowel disease.
3. Reversal of neuromuscular blockade due to skeletal muscle relaxants
Neuromuscular blockade is frequently produced as an adjunct to surgical anesthesia,
using nondepolarizing neuromuscular relaxants. After surgery, it is usually desirable
to reverse this pharmacologic paralysis promptly. This can be easily accomplished
with cholinesterase inhibitors; neostigmine and edrophonium are the drugs of choice.
They are given intravenously or intramuscularly for prompt effect.
4. Glaucoma
Glaucoma is a disease characterized by increased intraocular

pressure.

Anticholinesterases reduce intraocular pressure by causing contraction of the ciliary

body so as to facilitate outflow of aqueous humor and also by diminishing the rate of
its secretion.Since these agents produce transient blurring of far vision, limited visual
acuity in low light, and loss of vision at the margin when instilled in the eye,
adrenergic receptor antagonists, prostaglandin analogs, or carbonic anhydrase
inhibitors, have become the primary topical therapies for open-angle glaucoma. AChE
inhibitors are held in reserve when patients become refractory to the above agents.
Other uses: treatment of anticholinergic poisoning and alzheimers disease
3. State the mechanism of action and enlist therapeutic uses of warfarin.
Mechanism of Action

(1 mark)

Warfarin and other coumarin anticoagulants block the -carboxylation of several

glutamate residues in prothrombin and factors VII, IX, and X as well as the
endogenous anticoagulant proteins C and S. The blockade results in incomplete
coagulation factor molecules that are biologically inactive. The protein carboxylation
reaction is coupled to the oxidation of vitamin K. The vitamin must then be reduced to
reactivate it. Warfarin prevents reductive metabolism of the inactive vitaminK
epoxide back to its active hydroquinone form.Therapeutic doses of warfarin decrease
by 30-50% the total amount of each vitamin K-dependent coagulation factor made by
the liver; in addition, the secreted molecules are undercarboxylated, resulting in
diminished biological activity (10-40% of normal).
Diagrammatic representation : ----

( mark)

Therapeutic Uses
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.

(2 marks)

Deep vein thrombosis and pulmonary embolism

Myocardial infarction
Unstable angina
Prevention of stroke in trial fibrillation
Cerebral embolism
Vascular Surgery
Prosthetic heart valve
Retinal vessel thrombosis
Extracorporeal circulation
Hemodialysis
4. A 60 year old female patient diagnosed with carcinoma of cervix received an
antiemetic drug before chemotherapy. Identify the antiemetic drug she may have
received and describe its mechanism of action and therapeutic uses.
Various drugs such as 5HT3antagonists ,NK1 receptor antagonists, neuroleptics,
dexamethasone, aprepitant, metoclopramide etc., either alone or in combination are
used in the prevention and treatment of chemotherapy induced nausea and vomiting.
Of these 5HT3 antagonists like ondansetron and granisetron are most commonly
used .It is possible that the woman received ondansetron before chemotherapy.(1
Mark)
Ondansetron Mechanism of Action

(1 Mark)

Ondansetron, being a selective 5HT3receptor antagonist has potent antiemeticproperty

that is mediated mainly through blockade of peripheral 5HT3 receptors on extrinsic
intestinal vagal and spinal afferent nerves and in part through central 5HT3

receptorblockade in the vomiting center and chemoreceptor trigger zone. The

antiemeticaction of ondansetron is restricted to emesis attributable tovagal stimulation
(eg, postoperative) and chemotherapy; otheremetic stimuli such as motion sickness
are poorly controlled.
Therapeutic Uses

(2 Marks)

1. Chemotherapy-Induced Nausea and Vomiting

5-HT 3 -receptor antagonists like ondansetron are the primary agents for the
prevention of acute chemotherapy-induced nausea and emesis. When used alone,
it has little or no efficacy for the prevention of delayed nausea and vomiting (ie,
occurring >24 hours after chemotherapy). It is most effective when given as a
single dose by intravenous injection of 8 mg, 30 minutes prior to administration
of chemotherapy.

Its efficacy is enhanced by combination therapy with a

corticosteroid(dexamethasone) and NK 1 -receptor antagonist

2. Postoperative and Postradiation Nausea andVomiting
Ondansetron is also used to prevent or treat postoperativenausea and vomiting. It
is also effectivein the prevention and treatment of nausea and vomiting in
patientsundergoing radiation therapy to the whole body or abdomen.
5. Explain the rationale for using isosorbide dinitrate in the treatment of angina.
Mechanism of Smooth Muscle Relaxation by Isosorbite dinitrate

(1 Mark)

Isosorbite dinitrate is denitrated by glutathione S-transferase, aldehyde dehydrogenase

isoform 2 (ALDH2) and possibly isoform 3, ALDH3, in smooth muscles and other
cells. Free nitrite ion is released, which is then converted to nitric oxide. Nitric oxide
combines with the heme group of soluble guanylyl cyclase, activating that enzyme
and causing an increase in cGMP. Increase cGMP causes dephosphorylation of
myosin light chain kinase (MLCK) through a cGMP dependent protein kinase.
Reduced availability of phosphorylated (active) MLCK interferes with activation of
myosin. It fails to interact with actin to cause contraction. Consequently relaxation
occurs. Raised intracellular cGMP may also reduce Ca2+entry-contributing to
relaxation.
Rationale in classical angina

(2 Marks)

Decreased venous return to the heart and the resulting reduction of intracardiac
volume are important beneficial hemodynamiceffects of nitrates. Arterial pressure
also decreases. Decreased intraventricular pressure and left ventricular volume are

associatedwith decreased wall tension (Laplace relation) and decreased myocardial

oxygen requirement. Nitrates also lead to increased caliber of the large epicardial
coronary arteries except where blocked by concentric atheromas.Coronary arteriolar
resistance tends to decrease, though to a lesser extent. The reduction in oxygen
consumption is the major mechanism for the relief of effort angina.
Rationale in Variant Angina

(1 Mark)

Isosorbide dinitrate also benefits patients with variant angina by relaxing the smooth
muscle of the epicardial coronary arteries and relieving coronary artery spasm.
In both the types of angina, 2.5-5 mg tablet can used sublingually at the time of attack
as well as orally for chronic prophylaxis.
6. Discuss the consequences of microsomal enzyme induction.
Many drugs, insecticides and carcinogens interact with DNA and increase the
synthesis of microsomal enzyme protein, especially cytochrome P-450. As a result
rate of metabolism of inducing drug itself and/ or other drugs is increased. Enzyme
induction increases therate of metabolism by 2-4 fold. Induction takes 4-14 days to
reach its peak and is maintained tillthe inducing agent is being given. Thereafterthe
enzyme returns to their original value over1-3 weeks.
Microsomalenzyme induction may lead to following consequences:
1.
Decreased intensity and/ or duration of actionof drugs that are
inactivated by metabolism, e.g.failure of contraception with oral contraceptive
2.

and rifampicin.
Increased intensity ofaction of drugs that areactivated by metabolism.
Acute paracetamol toxicityis due to one of its metabolites N-acetyl-pbenzoquinone imine. Toxicity occursat lower doses in patients receiving

3.

enzymeinducers like phenytoin.

Tolerance: If the drug induces its ownmetabolism (autoinduction), e.g.

carbamazepine,rifampin.
4.
Some endogenous substrates (steroids, bilirubin)are also metabolized
faster due to enzyme induction. This phenomenon can be exploited
therapeutically by giving phenobarbitone in congenital nonhemolytic jaundice.
By same mechanism, phenytoin may reduce the manifestations of Cushings
5.

syndrome by enhancing degradation of adrenal steroids.

Enzyme inducing drugs are the most common triggering factor in
patients of acute intermittent porphyria. This is due to increased porphyrin
synthesis by delta-aminolevulenic acid synthetase.

6.

Intermittent use of an enzyme inducing agent may interferewith dose

adjustment

of

another

drug

prescribed.

e.g.

hypoglycaemics, antiepileptics, antihypertensives.

oral

anticoagulants,oral

SECTION C
Long Answer Questions: (Any 2 out of 3)

Marks: 12

1. A 55 year old male who is a known case of diabetes mellitus since last 10 years comes
to OPD for routine follow up. His blood pressure is found to be 152/98 mm of Hg. State
the antihypertensive you will prefer in this patient along with its rationale. Also give
other therapeutic uses of the same drug.
The antihypertensive that is preferred in this patient will be an ACE inhibitor e.g.
Enalapril for the following reasons:

(2 Marks)

Enalapril is an angiotension converting enzyme (ACE) inhibitor, which inhibits the

conversion of Ang I to Ang II and decreases the levels of Ang II.
Angiotensin II is an important regulator of cardiovascular function. It alters PVR by
direct vasoconstriction of precapillary arterioles and, to a lesser extent, postcapillary
venules, enhancement of peripheral nor adrenergic transmission, increased central
sympathetic discharge and release of catecholamines from the adrenal medulla.
Thus administration of Enalapril causes a fall in the total peripheral resistance. The
arterioles dilate and compliance of larger arteries is increased. Both systolic and diastolic
BP fall. It has no effect on cardiac output. Cardiovascular reflexes are not interfered with
and there is little dilatation of capacitance vessels. As such, postural hypotension is not a
problem. Reflex sympathetic stimulation does not occur despite vasodilatation. Moreover
the safety of ACE inhibitors like enalapril is proven in diabetic patients. It also has
protective effect against diabetic nephropathy and also slows progression if nephropathy
has already developed. Thus it is preferred in diabetic patients.
Other Therapeutic uses ( should be described briefly not just stated)

(4 Marks)

Congestive heart failure

Myocardial infarction
Prophylaxis in high cardiovascular risk subjects
Diabetic nephropathy
Scleroderma crisis

2. Classify drugs used in glaucoma. Discuss the mechanism of action and state adverse
effects of any 1 class of anti-glaucoma drugs.
Classification
Topical drugs:

(2 Marks)

1. Cholinergic agents e.g. pilocarpine, carbachol, demecarium bromide and

echothiophate iodide.
2. Adrenergic agonists e.g. epinephrine, dipivefrin, brimonidine and apraclonidine.
3. Beta blockers e.g. timolol, carteolol, betaxolol, levobunolol and metoprolol
4. Prostaglandin analogs e.g. PGF2a, latanoprost, unoprostone and PHXA-85.
5. Carbonic anhydrase inhibitors e.g. dorzolamide and brinzolamide.
Systemic drugs:
1. Carbonic anhydrase inhibitors e.g. acetazolamide and methazolamide.
2. Osmotic agents e.g. glycerine, mannitol and urea.
Beta blockers
Mechanism of Action
(2 Marks)
Topical Beta blockers like timolol, betaxolol, levobunalol lower i.o.t. by reducing
aqueous humor formation. This probably results from downregulation of
adenylylcyclase due to beta 2 receptorblockade in the ciliary epithelium and secondary
effect due to reduction in ocular blood flow.
Adverse effects

(2 Marks)

Topical beta blockers have both ocular and systemic side effects.
Ocular side effects include: Redness and dryness of eye, corneal hypoesthesia, allergic
blepharoconjunctivitis and blurred vision.
Systemic adverse effects are observed due to absorption through nasolacrimal duct and
include: life threatening bronchospasm in asthmatics, bradycardia, accentuation ofheart
block and CHF in elderly. Virtually all adverse effects of systemic beta blockers are
potentially possible with topical treatment also.
3. Define the terms drug synergism and drug antagonism. Explain the subtypes of drug
antagonism giving suitable examples.
Drug Synergism
(1 Mark)
When the action of one drug is facilitated or increased by the other, they are said to be
synergistic. In a synergistic pair, both the drugs can have action in the same direction or
given alone one may be inactive but still enhance the action of the other when given
together. Synergism can be additive (e.g. glibenclamide + metformin) or supraadditive
(e.g. levodopa + carbidopa).
Drug Antagonism

(1 Mark)

When one drug decreases or abolishes the action of another, they are said to be
antagonistic:
effect of drugs A + B < effect of drug A + effect of drug B
Explaination of subtypes of Antagonism with examples

(4 Marks)

Depending on the mechanism involved, antagonism may be:

1) Physical Antagonism
2) Chemical Antagonism
3) Physiological / Functional Antagonism
4) Receptor Antagonism
Physical Antagonism
Based on the physical property of the drugs, e.g. charcoal adsorbs alkaloids and can prevent
their absorption. Hence it is used in alkaloidal poisonings.
Chemical antagonism
The two drugs react chemically and form an inactive product, e.g.
Chelating agents like BAL (Dimercaprol) react chemically and form complex with toxic
metals like arsenic, mercury etc.
Nitrites form methaemoglobin which reacts with cyanide radical. Hence used in cyanide
poisoning.
Drugs may react chemically when mixed in the same syringe or infusion bottle, e.g.
Thiopentone sod. + succinylcholine chloride
Penicillin-G sod. + succinylcholine chloride
Physiological/functional antagonism
Thetwo drugs act on different receptors or by differentmechanisms, but have opposite effects
onthe same physiological function
Histamine and adrenaline on bronchialmuscles and BP.
Glucagon and insulin on blood sugar level.
Receptor antagonism
Antagonist drug blocks the receptor action of the other drug, which is agonist.This is a very
important mechanism of drug action because physiological signal molecules actthrough their
receptors, blockade of which canproduce specific and often profound pharmacologicaleffects.
Receptor antagonists are relatively selective, i.e. an anticholinergic will opposecontraction of
intestinal smooth muscle inducedby cholinergic agonists, but not that induced byhistamine or
5-HT.

Receptor antagonism can be either competitive or noncompetitive:

Competitive antagonism (equilibrium type)
Theantagonist is chemically similar to the agonist,competes with it and binds to thesame site
to the exclusion of the agonist molecules.Because the antagonist has affinity but nointrinsic
activity, no response isproduced and the log DRC of the agonist is shiftedto the right. Since
antagonist binding is reversibleand depends on the relative concentration of theagonist and
antagonist molecules, higher concentrationof the agonist progressivelyovercomes theblock-a
parallel shift of the agonist DRC withno suppression of maximal response is obtained. The
extent of shift is dependent onthe affinity and concentration of the antagonist.
A partial agonist, having affinityfor the same receptor, also competes with andantagonizes a
full agonist, while producing asubmaximal response of its own.
Competitive antagonism is the most common type e.g. naloxone on all opioid receptors.
Noncompetitive antagonism
The antagonist ischemically unrelated to the agonist, binds to adiifferent allosteric sitealtering
the receptor in such a way that it is unable to combine with the agonist, or unable to transduce
the response, so that the downstream chain of events are uncoupled. Because the agonist and
the antagonistare combining with different sites, there is no competition between them.
Hence, even high agonist concentration is unable to reverse the block completely. Increasing
concentrations of the antagonist progressively flatten the agonist DRC. Noncompetitive
antagonists in clinical use are very rare e.g. ketamine on NMDA receptor.
Nonequilibrium (competitive) antagonism
Certainantagonists bind to the receptor to the same site as agonist, but with strong(covalent)
bonds or dissociate from it slowly sothat agonist molecules are unable to reducereceptor
occupancy of the antagonist molecules, lawof mass actlon cannot apply-an irreversibleor
nonequilibrium antagonism is produced. Theagonist DRC is shifted to the right and
themaximal response is lowered (if spare receptorsare few). Phenoxybenzarnine is
anonequilibrium antagonist of adrenaline at the alphaadrenergic receptors.