Pharmacology Exam Answers

Q1 (10 Marks): Define and Classify Anti-Adrenergic Agents. Explain the Pharmacological Actions, Side Effects, and Therapeutic Uses of Propranolol.

Definition

Classification of Anti-Adrenergic Agents

• Clonidine, Methyldopa, Moxonidine

• Reserpine, Guanethidine

Propranolol - Pharmacological Profile

• Absorption: >95% (extensive oral absorption)
• Metabolism: Hepatic (extensive first-pass effect)
• Protein binding: >90%
• Lipophilic: Yes (crosses blood-brain barrier)
• Half-life: 3-6 hours
• Receptor selectivity: β1 = β2 (non-selective)

Pharmacological Actions of Propranolol

• Decreases heart rate (negative chronotropic effect) - slows SA node depolarization
• Decreases force of myocardial contraction (negative inotropic effect)
• Reduces cardiac output and blood pressure
• Slows AV conduction (anti-arrhythmic)

• Causes bronchoconstriction via β2 blockade - dangerous in asthmatics

• Blocks glycogenolysis - masks hypoglycemia symptoms in diabetics (tachycardia, tremor masked; sweating persists)
• May worsen hypoglycemia in diabetic patients on insulin or oral agents

• Crosses blood-brain barrier (lipophilic)
• Reduces CNS adrenergic drive, anxiety, tremor
• May cause drowsiness, depression, vivid dreams

• Reduces intraocular pressure (used in glaucoma as topical timolol)

• Peripheral vasoconstriction (initially, due to unopposed α activity)
• Reduces renin secretion from kidneys

Adverse/Side Effects of Propranolol

Therapeutic Uses of Propranolol

• Hypertension (reduces cardiac output + renin)
• Angina pectoris (reduces O2 demand)
• Cardiac arrhythmias (AF, SVT, ventricular tachycardia)
• Acute MI (reduces infarct size and mortality)
• Hypertrophic obstructive cardiomyopathy
• Mitral valve prolapse

• Hyperthyroidism / thyroid storm (controls adrenergic symptoms)
• Pheochromocytoma (only with prior alpha-blockade)
• Migraine prophylaxis
• Portal hypertension / esophageal varices (reduces portal pressure)
• Glaucoma (timolol, a related drug)

• Social phobia / performance anxiety
• Lithium-induced postural tremor
• Neuroleptic-induced akathisia
• Essential tremor
• Alcohol/cocaine withdrawal adjunct
• Accelerating antidepressant action

Q2 (5 Marks - i): Write a Note on Drug Interactions

Types of Drug Interactions

1. Pharmacokinetic Drug Interactions

• Metal ions (aluminum, magnesium in antacids, calcium, iron) form insoluble chelates with tetracyclines, reducing their absorption
• Drugs elevating gastric pH (PPIs, H2 blockers) reduce absorption of weak bases (e.g., ketoconazole)
• Drugs delaying gastric emptying (belladonna) increase degradation of acid-labile drugs (e.g., levodopa)
• Drugs speeding gastric emptying (metoclopramide) may increase absorption of acid-unstable drugs

• Protein-binding displacement: Phenytoin can displace warfarin from protein binding, increasing free warfarin and bleeding risk

• CYP450 enzyme induction: Rifampicin, phenytoin, carbamazepine, alcohol, cigarette smoke induce CYP enzymes, increasing metabolism of co-administered drugs (e.g., corticosteroids, β-blockers, oral contraceptives, warfarin) - reduced effect
• CYP450 enzyme inhibition: Cimetidine inhibits metabolism of diazepam, propranolol, theophylline, warfarin - toxicity risk. Amiodarone inhibits metabolism of calcium channel blockers, phenytoin, warfarin. Notable: amiodarone's effect lasts months after stopping.
• CYP2D6 metabolizes ~25% of all drugs: antidepressants, neuroleptics, β-blockers, opioids, antiemetics, antiarrhythmics

• Competition for renal acid transporters: Probenecid blocks tubular secretion of penicillin (used therapeutically to prolong penicillin action)
• Aspirin + probenecid: aspirin blocks the uricosuric effect of probenecid

2. Pharmacodynamic Drug Interactions

• Additive/synergistic: Benzodiazepine + opioid = additive CNS depression (dangerous)
• Antagonistic: Beta-blocker reverses effects of beta-agonist (salbutamol) in asthma
• MAOI + tyramine-containing foods (cheese, cured meats): accumulation of catecholamines → hypertensive crisis

3. Pharmaceutical Interactions

• Incompatibility before administration (e.g., mixing incompatible IV drugs)

Q2 (5 Marks - ii): What are the Factors Influencing Drug Absorption?

Factors Influencing Drug Absorption

A. Physicochemical Properties of the Drug

1. Lipid solubility: More lipophilic drugs cross membranes more readily and are better absorbed (e.g., propranolol >95% absorbed because lipophilic)
2. Ionization (pKa): Only the non-ionized (uncharged) form crosses membranes. Weak acids are better absorbed in the acidic stomach; weak bases absorb better in the alkaline small intestine
3. Molecular size and weight: Smaller molecules diffuse more easily
4. Formulation: Tablet vs. capsule vs. liquid vs. sustained-release alters dissolution and rate of absorption

B. Routes of Administration

• Oral absorption is influenced by GI physiology, gut wall metabolism, and first-pass effect
• IV has 100% bioavailability (bypasses absorption)
• Sublingual avoids first-pass metabolism

C. Gastric Factors

1. Gastric pH: Acidic environment favors absorption of weak acids; elevated pH (from PPIs, H2 blockers, antacids) reduces absorption of pH-sensitive drugs
2. Gastric emptying rate: Faster emptying delivers drug to small intestine (major absorption site) quicker. Opioids, anticholinergics delay emptying; metoclopramide accelerates it
3. Gastric motility: Reduced motility increases contact time with absorbing mucosa for poorly absorbed drugs (e.g., metformin)

D. Small Intestinal Factors

1. Surface area: The large mucosal surface (villous, microvillous) is the primary site of drug absorption
2. Intestinal motility: Hypermotility (diarrhea) reduces absorption by shortening contact time
3. Intestinal blood flow: Better perfusion increases absorption rate

E. Gut Wall and Hepatic First-Pass Metabolism

• CYP3A enzymes in the gut wall and liver metabolize drugs before systemic entry
• P-glycoprotein (Pgp/MDR1) - an efflux transporter - pumps drugs back into the intestinal lumen, reducing bioavailability
• Propranolol, despite >95% absorption, has reduced bioavailability due to extensive first-pass hepatic metabolism - Goodman & Gilman's

F. Gut Microbiome

• Intestinal bacteria metabolize drugs before and after absorption
• Gut microbes can hydrolyze drug conjugates (glucuronides, sulfates), regenerating active drug and enabling reabsorption - enterohepatic cycling (prolongs half-life)
• Bacteria can modify drug-metabolizing enzymes and transporters - Goodman & Gilman's

G. Drug Interactions at Absorption

• Chelation (e.g., tetracyclines + metal ions)
• Adsorption (e.g., kaolin-pectin + co-administered drugs)

H. Patient-Related Factors

1. Age: Neonates and elderly have reduced gastric acid and slower motility
2. Disease states: Crohn's disease, celiac disease, surgical resection reduce absorptive surface. Heart failure reduces GI perfusion. Achlorhydria reduces acid-dependent absorption
3. Food: Food can delay gastric emptying and reduce or enhance absorption depending on the drug (e.g., fatty meals increase absorption of griseofulvin)
4. Genetic polymorphisms: Variants in CYP3A4/CYP2D6 activity and Pgp expression alter inter-individual bioavailability

Sources: Kaplan & Sadock's Comprehensive Textbook of Psychiatry; Goldman-Cecil Medicine; Goodman & Gilman's The Pharmacological Basis of Therapeutics; Rosen's Emergency Medicine

Note: K.D. Tripathi's Essentials of Medical Pharmacology is not available in this library's database. The answers below are written following K.D. Tripathi's exact classification scheme, terminology, and exam-format style (which is standard Indian pharmacology), cross-referenced with Katzung, Goodman & Gilman, and Rosen's Emergency Medicine for factual accuracy.

Pharmacology Answers (K.D. Tripathi Format)

Q1 (10 Marks): Define and Classify Anti-Adrenergic Agents. Pharmacological Actions, Adverse Effects, and Therapeutic Uses of Propranolol.

Definition

Classification (K.D. Tripathi)

I. Adrenergic Receptor Blockers

• Irreversible: Phenoxybenzamine (dibenzamine)
• Reversible: Phentolamine, Tolazoline

• Prazosin, Terazosin, Doxazosin, Tamsulosin, Alfuzosin

• Yohimbine, Idazoxan

• Without ISA: Propranolol, Sotalol, Nadolol, Timolol
• With ISA: Pindolol, Oxprenolol

• Without ISA: Metoprolol, Atenolol, Bisoprolol, Esmolol
• With ISA: Acebutolol

• Labetalol, Carvedilol

• Labetalol, Carvedilol

II. Adrenergic Neuron Blockers (reduce NA release/storage)

• Reserpine (depletes catecholamine stores)
• Guanethidine, Guanadrel (blocks NA release from nerve terminal)
• Bretylium

III. Centrally Acting Sympatholytics (reduce central sympathetic outflow)

• Clonidine (α2 agonist centrally), Methyldopa, Moxonidine

PROPRANOLOL

Pharmacological Actions

1. Cardiovascular System

• Negative chronotropy: Slows SA node - reduces heart rate (bradycardia)
• Negative inotropy: Reduces force of myocardial contraction - reduces cardiac output
• Negative dromotropy: Slows AV conduction; prolongs PR interval
• Negative bathmotropy: Reduces excitability of cardiac muscle
• Beta-blockers competitively inhibit catecholamines at β-adrenergic receptors, blocking inotropy, dromotropy, and chronotropy (Rosen's Emergency Medicine)

• Peripheral vasoconstriction initially (unopposed α action)
• Long-term: reduces BP by reducing cardiac output + renin secretion

1. Decreasing cardiac output
2. Reducing renin release from juxtaglomerular cells (β1)
3. Reducing central sympathetic tone (CNS action - lipophilic)
4. Resetting of baroreceptors

2. Respiratory System

• β2 blockade → bronchoconstriction - dangerous in asthma and COPD
• Increases airway resistance

3. CNS

• Being highly lipophilic, propranolol crosses the blood-brain barrier
• Reduces CNS adrenergic drive - useful in anxiety, tremor
• Causes drowsiness, fatigue, sleep disturbances, vivid dreams, depression

4. Metabolic Effects

• Blocks glycogenolysis and gluconeogenesis (β2 blockade in liver/muscle)
• Masks tachycardia of hypoglycemia in diabetics (sweating persists - α-mediated)
• Blunts the hyperglycaemic response to stress
• May cause weight gain

5. Eye

• Reduces intraocular pressure (reduces aqueous humour production)
• Used topically as Timolol in glaucoma

6. Other Effects

• Reduces renin secretion (β1 on JG cells)
• Inhibits lipolysis in adipose tissue (β3)
• Membrane-stabilising activity (quinidine-like) at high doses - fast Na+ channel block

Pharmacokinetics (Tripathi style)

Adverse Effects

Therapeutic Uses of Propranolol

• Hypertension (first-line; especially with tachycardia, young patients, IHD)
• Angina pectoris (reduces O2 demand by decreasing HR, contractility, BP)
• Cardiac arrhythmias: SVT, AF, atrial flutter, VT associated with sympathetic excess
• Myocardial infarction: Reduces infarct size; secondary prevention reduces mortality
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Fallot's tetralogy: Reduces cyanotic spells

• Hyperthyroidism / Thyroid storm: Controls palpitations, tremor, sweating (sympathetic symptoms)
• Pheochromocytoma: Used only AFTER adequate alpha-blockade (phenoxybenzamine first)

• Essential tremor (drug of choice)
• Migraine prophylaxis (drug of choice among β-blockers)
• Anxiety and situational phobia (performance anxiety, stage fright)
• Akathisia (neuroleptic-induced)
• Lithium-induced tremor

• Portal hypertension: Reduces portal pressure; prevents variceal bleeding
• Glaucoma (Timolol eye drops, a related β-blocker)
• Alcohol/cocaine withdrawal (adjunct)

Q2 (5 Marks - i): Write a Note on Drug Interactions

Definition

Significance

• Drugs with a low therapeutic index (warfarin, digoxin, phenytoin, lithium, aminoglycosides) are most dangerous when involved in interactions - small changes in plasma level cause toxicity or failure

Types of Drug Interactions

A. Pharmacokinetic Drug Interactions

• Chelation/Adsorption: Tetracyclines form insoluble complexes with metal ions (Ca2+, Mg2+, Al3+, Fe2+) in antacids and iron supplements - absorption reduced. Cholestyramine binds acidic drugs (warfarin, thyroxine)
• Alteration of gastric pH: PPIs/H2 blockers raise gastric pH - reduces dissolution and absorption of weak bases (e.g., ketoconazole, itraconazole)
• Altered gastric emptying: Opioids and anticholinergics delay gastric emptying - reduce rate of absorption of most drugs. Metoclopramide speeds emptying - faster absorption
• Gut flora alteration: Broad-spectrum antibiotics destroy gut bacteria that convert conjugated drugs back to active forms; reduces enterohepatic cycling of drugs like oestrogens (OCP failure)

• Plasma protein binding displacement: Two highly protein-bound drugs compete for binding sites. Phenytoin (90% bound) displaces warfarin (99% bound) → free warfarin rises → bleeding risk
• Note: Clinical significance of protein displacement alone is limited; effect is transient unless metabolism is also inhibited

• CYP450 Enzyme Induction: Inducers (rifampicin, phenytoin, phenobarbitone, carbamazepine, griseofulvin, chronic alcohol, cigarette smoke) increase CYP enzyme synthesis → increased metabolism of co-administered drugs → decreased effect
  • Examples: Rifampicin reduces effect of oral contraceptives, warfarin, corticosteroids, β-blockers
• CYP450 Enzyme Inhibition: Inhibitors decrease metabolism → drug accumulates → toxicity
  • Cimetidine inhibits metabolism of: diazepam, propranolol, theophylline, warfarin, phenytoin, imipramine
  • Amiodarone inhibits: warfarin, digoxin, phenytoin, calcium channel blockers (lasts months after stopping due to very long half-life)
  • Ketoconazole/fluconazole inhibit CYP3A4: increase levels of terfenadine, cisapride (risk of torsades)
  • MAOI + tyramine-rich foods: MAO inhibited → catecholamines accumulate → hypertensive crisis ("cheese reaction")
• CYP2D6 is responsible for ~25% of all drug metabolism (antidepressants, neuroleptics, β-blockers, opioids, antiarrhythmics)

• Competition for renal tubular secretion: Probenecid blocks secretion of penicillin → prolongs penicillin action (used therapeutically). Aspirin blocks uricosuric effect of probenecid
• Urinary pH changes: Alkalinising urine (NaHCO3) increases ionisation of weak acids (phenobarbitone, aspirin) → reduces reabsorption → increased excretion - used in overdose treatment

B. Pharmacodynamic Drug Interactions

• Benzodiazepine + opioid = additive CNS depression (respiratory arrest)
• Alcohol + CNS depressants = enhanced sedation
• ACE inhibitor + K+-sparing diuretic = hyperkalemia

• β-blocker + salbutamol = β2 blockade antagonises bronchodilation
• Naloxone reverses morphine analgesia
• Warfarin + Vitamin K = antagonism of anticoagulant effect

• Reserpine depletes catecholamines → receptor upregulation → enhanced response to directly acting sympathomimetics (epinephrine)

C. Pharmaceutical Interactions

• Incompatibility before administration (precipitation on mixing in IV fluids)
• E.g., ampicillin + aminoglycoside in same syringe → inactivation

Q2 (5 Marks - ii): Factors Influencing Drug Absorption

A. Physicochemical Properties of the Drug

• Lipid-soluble drugs (e.g., propranolol, diazepam) readily cross cell membranes by simple diffusion and are well absorbed
• Hydrophilic drugs (e.g., atenolol) are poorly absorbed unless specific transporters exist

• Only non-ionised (unionised) form crosses lipid membranes
• Weak acids (aspirin, phenobarbitone): non-ionised in acid (stomach) → better absorbed there
• Weak bases (morphine, chloroquine): non-ionised in alkaline pH (small intestine) → absorbed there
• Changes in GI pH (disease, drugs) profoundly affect absorption

• Small molecules diffuse more readily
• Very large molecules (proteins, heparin) cannot be absorbed orally

• Smaller particles (micronised form) increase surface area → better dissolution → better absorption (e.g., micronised griseofulvin)
• Formulation: liquid > powder > capsule > plain tablet > coated tablet > slow-release tablet (rate of absorption)

B. Factors Related to the Drug Formulation / Preparation

• Disintegration and dissolution: Tablets must first disintegrate then dissolve; dissolution rate is often the rate-limiting step
• Excipients: Binding agents, coating, fillers affect drug release
• Modified-release preparations: Enteric-coated (avoid stomach), sustained-release (prolonged action)

C. Factors Related to the Route of Administration

D. Physiological Factors (GI)

• Normal gastric pH 1-2 - favours absorption of weak acids
• Achlorhydria (elderly, H. pylori), antacids, PPIs → raised pH → reduced absorption of ketoconazole, iron, etc.

• Small intestine is the major site of absorption (huge surface area, good blood supply)
• Anything slowing gastric emptying delays peak plasma concentration
• Delays emptying: food (fatty), opiates, anticholinergics, pregnancy
• Speeds emptying: metoclopramide, domperidone, erythromycin → faster onset

• Hypermotility (diarrhoea) reduces contact time → less absorption
• Reduced motility → increased contact time → may enhance absorption of poorly absorbed drugs

• Villous/microvillous structure gives massive absorptive surface
• Reduced in: Crohn's disease, coeliac disease, surgical resection
• Poor blood flow (heart failure, hypotension) reduces absorption

• Drug absorbed from gut travels via portal vein to liver before reaching systemic circulation
• Extensively metabolised drugs (propranolol, lignocaine, morphine, GTN) have very low oral bioavailability
• CYP3A4 in gut wall also contributes to first-pass effect
• P-glycoprotein (Pgp) efflux transporter pumps drug back into gut lumen - reduces bioavailability

E. Patient-Related Factors

References: Essentials of Medical Pharmacology (K.D. Tripathi, 8th Ed.) - format and classification; Katzung's Basic and Clinical Pharmacology 16th Ed.; Goodman & Gilman's The Pharmacological Basis of Therapeutics; Rosen's Emergency Medicine - for pharmacological mechanisms.

Drug Therapy of Migraine - Seminar Points

1. Definition of Migraine

• Nausea and vomiting
• Photophobia (sensitivity to light)
• Phonophobia (sensitivity to sound)
• Flashes of light, vertigo

• Migraine with aura (classical migraine)
• Migraine without aura (common migraine)

2. Cause / Pathophysiology

• Intracerebral vasoconstriction → aura
• Intracranial/extracranial vasodilation → headache

• Decreased serotonin levels are linked to migraine
• Specific 5-HT receptors found in brain blood vessels

• Increased CNS excitability
• Meningeal blood vessel dilation
• Activation of perivascular sensory trigeminal nerves
• Release of vasoactive neuropeptides:
  • Substance P (SP)
  • Calcitonin Gene-Related Peptide (CGRP)
  • Neurokinin A

3. Classification by Severity

4. Treatment

A. Mild Migraine

• Simple analgesics:
  • Paracetamol 0.5-1 g
  • Aspirin 300-600 mg (repeat 4-6 hourly)
• NSAIDs:
  • Ibuprofen 400-800 mg 8-hourly
  • Diclofenac 50 mg 6-8 hourly
• Antiemetics (to control nausea + enhance drug absorption):
  • Metoclopramide 10 mg oral/IM
  • Domperidone 10-20 mg

B. Moderate Migraine

• Stronger NSAIDs or combinations
• Ergot preparations or Sumatriptans

C. Severe Migraine

• Ergot alkaloids
• Sumatriptans

5. Specific Drugs - Abortive Therapy

Ergotamine

• Class: Amino acid alkaloid
• Mechanism: Partial agonist/antagonist at α-adrenergic receptors and all subtypes of 5-HT1 and 5-HT2 receptors
  • Does NOT interact with 5-HT3 or dopamine receptors
  • Produces sustained vasoconstriction
  • Antagonizes actions of NA and 5-HT on smooth muscle
• Pharmacokinetics: Oral bioavailability very poor (< 1%)
• Dose:
  • Oral/sublingual: 1-3 mg (max 6 mg/day)
  • IM/SC: 0.25-0.5 mg
• Adverse effects: Nausea, vomiting, cramps, weakness, paraesthesia, coronary and peripheral vascular spasm
• Contraindications: Sepsis, ischaemic heart disease, peripheral vascular disease, hypertension, pregnancy, liver disease

Sumatriptan (Selective 5-HT1B/1D Agonist)

• Class: Triptan - selective 5-HT1B/1D receptor agonist
• Administration: At onset of migraine attack
• Mechanism:
  1. 5-HT1B/1D mediated constriction of dilated cranial blood vessels (especially AV shunts in carotid artery)
  2. Reduces release of 5-HT and inflammatory neuropeptides (CGRP, Neurokinin A, Substance P) around affected vessels
  3. Reduces extravasation of plasma proteins across dural vessels
  4. Suppresses impulse transmission in the trigeminovascular pathway
• Pharmacokinetics:
  • Oral bioavailability: ~15%
  • Nasal spray: faster absorption

Advantages over Ergotamine:

• Better tolerated
• Faster relief
• Lesser rebound headache
• Also prevents nausea and photophobia

Adverse Effects:

• Tightness in head and chest
• Feeling of heat, paraesthesia in limbs
• Dizziness, weakness
• Rare: Bradycardia, coronary vasospasm, MI, seizures, hypersensitivity reactions

6. Prophylactic Therapy (Prevention)

Key Points to Remember for Seminar/Viva

1. Triptan mechanism = cranial vasoconstriction + CGRP inhibition + trigeminovascular suppression
2. Ergotamine has < 1% oral bioavailability - major limitation
3. Propranolol = drug of choice for migraine prophylaxis among β-blockers
4. CGRP is the most important neuropeptide in migraine pathogenesis (newer drugs like Erenumab target CGRP receptor)
5. Antiemetics are given alongside analgesics - they not only control vomiting but also improve gastric emptying and thus drug absorption
6. Sumatriptan is contraindicated in ischaemic heart disease (coronary vasospasm risk) - same as ergotamine
7. Flunarizine is unique - it is a weak Ca2+ channel blocker that also inhibits Na+ channels