Department of Pharmacology & TherapeuticsSeth GSMC & KEM Hospital, Parel, Mumbai-12.II MBBS (August 2013 batch)Preliminary ExaminationPaper-ISECTION B & CDate: 15/09/14 Total Marks: 32Time: 1 hour 30 min Roll no : ________ Brief Answer Questions: (Any 5 out of 6) Marks: 201. 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 gravisMyasthenia 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 BladderNeostigmine 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 relaxantsNeuromuscular 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. GlaucomaGlaucoma 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(2 marks)1. Deep vein thrombosis and pulmonary embolism2. Myocardial infarction3. Unstable angina4. Prevention of stroke in trial fibrillation5. Cerebral embolism6. Vascular Surgery7. Prosthetic heart valve8. Retinal vessel thrombosis9. Extracorporeal circulation10. Hemodialysis4. 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 Vomiting5-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 andVomitingOndansetron 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 Relaxationby 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 and rifampicin.2. Increased intensity ofaction of drugs that areactivated by metabolism. Acute paracetamol toxicityis due to one of its metabolites N-acetyl-p-benzoquinone imine. Toxicity occursat lower doses in patients receiving enzymeinducers like phenytoin.3. 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 syndrome by enhancing degradation of adrenal steroids.5. 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. oral anticoagulants,oral hypoglycaemics, antiepileptics, antihypertensives.

SECTION CLong Answer Questions: (Any 2 out of 3) Marks: 121. 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(2 Marks)Topical drugs: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 metoprolol4. 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 BExplaination of subtypes of Antagonism with examples(4 Marks)Depending on the mechanism involved, antagonism may be:1) Physical Antagonism2) Chemical Antagonism3) Physiological / Functional Antagonism4) Receptor AntagonismPhysical AntagonismBased 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 antagonismThe 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 antagonismThetwo 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 antagonismAntagonist 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 antagonismThe 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) antagonismCertainantagonists 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.