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PHARMACOLOGY PAPER I - MODEL ANSWERS

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SECTION B (40 Marks)

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Q1. (2+4+4 = 10 Marks)

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1. Blocks voltage-gated Na+ channels - reduces repetitive neuronal firing
2. Blocks T-type Ca2+ channels (relevant in absence seizures)
3. Increases GABA concentration by inhibiting GABA transaminase (the enzyme degrading GABA) and stimulating glutamate decarboxylase (GABA synthesis)
4. May block NMDA-type glutamate receptors

• Drug of first choice for GTCS (as in this patient)
• First-line for absence seizures and myoclonic epilepsy (Juvenile Myoclonic Epilepsy - JME)
• Partial (focal) seizures
• Bipolar disorder (mood stabilizer)
• Migraine prophylaxis

• GI: nausea, vomiting, dyspepsia (most common; reduced with enteric-coated preparation)
• Hepatotoxicity (rare but fatal - especially in children under 2 years; idiosyncratic)
• Pancreatitis (rare)
• Teratogenicity: neural tube defects (spina bifida), fetal valproate syndrome - CONTRAINDICATED in pregnancy
• Weight gain, hair loss (alopecia)
• Thrombocytopenia, platelet dysfunction
• Tremor, sedation
• Hyperammonemic encephalopathy (especially with phenobarbitone co-administration)

• Inhibits CYP enzymes - increases plasma levels of phenobarbitone, phenytoin, lamotrigine, and carbamazepine-epoxide (toxic metabolite)
• Lamotrigine levels doubled by valproate - increases risk of toxic epidermal necrolysis
• Carbapenem antibiotics (e.g., meropenem) markedly reduce valproate levels
• Aspirin displaces valproate from plasma proteins
• Additive CNS depression with other CNS depressants

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• Secure airway, breathing, circulation (ABC)
• Lateral decubitus position, supplemental oxygen
• IV access, blood glucose check; if hypoglycemia - 50% dextrose IV
• Draw blood for CBC, electrolytes, drug levels, toxicology screen
• Lorazepam 0.1 mg/kg IV (or diazepam 0.15 mg/kg IV, or midazolam 0.2 mg/kg IM if no IV access)

• Fosphenytoin/Phenytoin 20 mg PE/kg IV (rate ≤50 mg/min - monitor cardiac)
• OR Levetiracetam 20-30 mg/kg IV
• OR Valproate 20-30 mg/kg IV

• Midazolam IV infusion 0.2 mg/kg bolus → 0.2-0.6 mg/kg/h
• OR Propofol 2 mg/kg bolus → 2-10 mg/kg/h
• Intubate and mechanically ventilate; continuous EEG monitoring

• Pentobarbital/Thiopental infusion
• Ketamine, isoflurane (volatile anaesthetic)
• Non-pharmacological: ketogenic diet, VNS, ECT, hypothermia, surgery

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Q2. Short Notes (4×5 = 20 Marks)

• Seven transmembrane (7-TM) alpha-helical domains
• Extracellular N-terminus (ligand binding site)
• Intracellular loops coupled to heterotrimeric G-proteins (Gα, Gβ, Gγ subunits)

1. Agonist binds → conformational change in receptor
2. Gα subunit exchanges GDP for GTP → active state
3. Gα dissociates from Gβγ → both can interact with effector proteins
4. Effectors: adenylyl cyclase (cAMP), phospholipase C (IP3 + DAG), ion channels
5. GTPase activity of Gα hydrolyzes GTP → GDP → inactivation (self-limiting)

• Drug targets: beta-blockers (β-AR), antihistamines (H1-AR), opioids (μ-receptor), muscarinic antagonists
• Desensitization (tachyphylaxis) occurs via GRK phosphorylation and β-arrestin binding

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• NSAIDs: Ibuprofen 400-800 mg, Naproxen 500-1000 mg
• Aspirin 900 mg + Metoclopramide 10 mg (anti-emetic + prokinetic)
• Paracetamol 1000 mg (less effective)

• Selective 5-HT1B/1D receptor agonists
• Drugs: Sumatriptan (6 mg SC / 50-100 mg oral), Rizatriptan 10 mg, Zolmitriptan 2.5-5 mg, Almotriptan, Eletriptan, Frovatriptan, Naratriptan
• Mechanism: cranial vasoconstriction + inhibit release of CGRP/substance P from trigeminal terminals
• Contraindications: ischemic heart disease, uncontrolled hypertension, basilar/hemiplegic migraine
• Side effects: "triptan sensations" - chest tightness, tingling; coronary vasospasm

• Non-selective 5-HT1 + alpha-adrenergic agonist
• Effective but side effects greater (nausea, peripheral vasospasm, ergotism)
• DHE nasal spray or IV preferred

• CGRP receptor antagonists (gepants): Ubrogepant, Rimegepant - used when triptans contraindicated
• Lasmiditan: 5-HT1F agonist (no vasoconstriction - safer in CVD)

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• Inducing agents bind to nuclear receptors (e.g., pregnane X receptor - PXR, constitutive androstane receptor - CAR)
• These receptors translocate to nucleus → upregulate transcription of CYP genes
• Takes 1-2 weeks to develop; reverses over weeks after discontinuation
• Mainly involves CYP3A4, CYP2C9, CYP2C19, CYP1A2

• Phenytoin, Phenobarbitone
• Carbamazepine
• Bacterial rifampicin (Rifampicin - strongest inducer)
• Ritonavir (also an inhibitor at low doses)
• Alcohol (chronic)
• St. John's Wort (herbal - contains hyperforin)
• Others: Griseofulvin, Nevirapine

1. Reduced efficacy of co-administered drugs: Rifampicin + Oral Contraceptive Pills (OCPs) → contraceptive failure; Carbamazepine + Warfarin → reduced anticoagulation (thrombosis risk)
2. Tolerance: Carbamazepine induces its own metabolism (autoinduction) → dose escalation needed over weeks
3. Increased toxic metabolite formation: Carbamazepine + Valproate → ↑ carbamazepine-10,11-epoxide (neurotoxic)
4. Post-induction effects: When inducer is stopped, levels of co-drug rise sharply → toxicity (e.g., stopping rifampicin in TB treatment → sudden ↑ warfarin effect → bleeding)

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• GI: nausea, diarrhea, cramping
• Uterine hypertonicity
• Bronchospasm (PGF2α - avoided in asthma)
• Hypotension (prostacyclin)
• With latanoprost: iris pigmentation, eyelash lengthening

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Q3. Very Short Answers (5×2 = 10 Marks)

1. Enalapril (ACE inhibitor prodrug) → hydrolyzed to enalaprilat (active) in the liver
2. Levodopa → decarboxylated to dopamine in the brain (dopamine cannot cross BBB; L-DOPA can)

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1. They mimic acetylcholine at nicotinic NMJ receptors - bind and cause prolonged depolarization
2. Initial transient fasciculations occur (brief muscle contractions)
3. The motor endplate remains persistently depolarized ("Phase I block" / depolarization block)
4. Since the plate is already depolarized, it cannot respond to further ACh release → flaccid paralysis
5. With continued exposure: Phase II block (desensitization block) - membrane repolarizes but is unresponsive

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1. Atropine is a muscarinic antagonist (anti-cholinergic drug)
2. It causes mydriasis (pupillary dilation) by blocking M3 receptors on the iris sphincter, allowing the iris dilator to dominate
3. In angle-closure (narrow-angle) glaucoma, the iridocorneal angle is already anatomically narrow
4. Mydriasis causes the iris to physically crowd into and further narrow/block this angle
5. This blocks the drainage of aqueous humor (through the trabecular meshwork into the canal of Schlemm)
6. Aqueous humor accumulates → acute rise in intraocular pressure (IOP) → acute angle-closure attack
7. Presents as severe eye pain, blurred vision, halos, headache, nausea - a medical emergency

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1. Beclomethasone dipropionate (BDP) - first ICS developed
2. Budesonide - high topical potency; safe in pregnancy
3. Fluticasone propionate (FP) - high lipophilicity, prolonged action
4. Fluticasone furoate
5. Mometasone furoate
6. Ciclesonide - prodrug (activated in lungs)
7. Triamcinolone acetonide

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• Mechanism: Agonist at mu (μ) and kappa (κ) opioid receptors in the cough center (nucleus tractus solitarius) in the medulla oblongata; raises the threshold for cough reflex; also has peripheral effect on afferent C-fibers in bronchi
• Dose for cough: 10-30 mg oral (lower than analgesic dose)

• Mechanism: NMDA receptor antagonist in the cough center; also weak sigma receptor agonist; suppresses central cough reflex without significant sedation or dependence
• Has no analgesic or addictive properties at therapeutic doses
• OTC preparation widely used

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SECTION C (40 Marks)

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Q1. (3+4+3 = 10 Marks)

• Muscarinic (M) receptors (Ps AND D - Parasympathetic + CNS)
• Nicotinic (N) receptors (NMJ + autonomic ganglia)

• DUMBELS: Diarrhea, Urination, Miosis, Bradycardia+Bronchospasm+Bronchorrhea, Emesis, Lacrimation, Salivation/Sweating
• Nicotinic effects: Muscle fasciculations → weakness → paralysis; tachycardia (ganglionic)
• CNS: Anxiety, seizures, coma

• Secure airway (suction secretions), intubate if needed
• IV access, O2 therapy
• Remove contaminated clothing (decontamination)
• Wash skin/eyes thoroughly
• For intubation: use rocuronium (non-depolarizing) - NOT succinylcholine (prolonged action due to AChE inhibition)

• Blocks muscarinic effects: dries secretions, bronchodilation, reverses bradycardia
• Dose: 1-3 mg IV q5 min, doubling each dose until "atropinized" (dry secretions, improved breathing, HR >80)
• May need 200-500 mg in severe cases
• Endpoint: drying of secretions (NOT pupil dilation or tachycardia)
• Does NOT reverse nicotinic effects (fasciculations, weakness)

• Reactivates AChE by breaking the OP-AChE bond if given EARLY (before "aging")
• Works at both muscarinic AND nicotinic sites (reverses muscle weakness)
• Dose: 1-2 g IV over 15-30 min, then infusion 200-500 mg/hr
• Must be given within 24-48 hours (before aging of OP-AChE complex)

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• Both inhibit acetylcholinesterase
• BUT the mechanism and reversibility differ:

1. Carbamates (e.g., carbaryl, physostigmine) carbamylate the AChE enzyme
2. The carbamate-AChE bond is spontaneously hydrolyzed rapidly (within 30 min - 4 hours)
3. AChE regenerates on its own - the inhibition is intrinsically reversible

1. Oximes (pralidoxime) work by nucleophilic attack on the OP-AChE complex to displace the organophosphate and restore AChE activity
2. In carbamate poisoning, the carbamyl-AChE complex spontaneously hydrolyzes faster than pralidoxime can act - making the oxime redundant
3. There is experimental evidence that pralidoxime may actually worsen outcomes in carbamate poisoning (possibly by inhibiting AChE directly)
4. Additionally, the clinical syndrome of carbamate poisoning is shorter and self-limiting due to rapid spontaneous reactivation of AChE

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Q2. (5×4 = 20 Marks)

• The patient is in severe pain, emotionally distressed ("tearfully"), and feels dismissed (doctor focused only on records, not on her suffering)
• Applying empathy:
  • Acknowledge her distress: "I can hear how much you are suffering. It must be incredibly frustrating to feel that your pain is not being taken seriously."
  • Validate her experience: Do not dismiss her subjective symptoms because inflammatory markers are stable
  • Non-verbal empathy: Maintain eye contact, lean forward, avoid distractions (phone/computer)
  • Ask open-ended questions: "Can you tell me more about how this is affecting your daily life?"
  • Avoid premature closure - do not schedule a review and leave without addressing emotional needs
  • Create a plan together (shared decision-making)

• N - Name the emotion: "I can see you are upset and in pain"
• U - Understand: "I understand this has taken a toll on your daily life"
• R - Respect/Admire: "I admire how you have coped with this"
• S - Support: "I want to support you in managing this better"
• E - Explore: "Tell me more about what is worrying you most"
• S - (Summarize/Silence): Allow the patient to speak; listen actively

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• Non-selective (β1+β2): Propranolol, Nadolol, Timolol, Sotalol
• Selective (β1 - cardioselective): Metoprolol, Atenolol, Bisoprolol, Esmolol (IV, ultra-short)
• α+β blockers (third generation): Carvedilol, Labetalol
• Intrinsic sympathomimetic activity (ISA): Pindolol, Acebutolol

• β1 blockade → ↓ heart rate (negative chronotropy), ↓ force of contraction (negative inotropy), ↓ renin release
• β2 blockade → bronchoconstriction, peripheral vasoconstriction, ↑ hypoglycemia risk

• Cardiovascular: ↓ BP (antihypertensive), ↓ HR, ↓ cardiac output, ↓ O2 demand
• Anti-arrhythmic (Class II - Vaughan Williams)
• Reduce tremor (β2 blockade in skeletal muscle)
• Reduce intraocular pressure (timolol eye drops - glaucoma)

• Hypertension, Angina pectoris (reduces O2 demand)
• Cardiac arrhythmias (SVT, AF rate control)
• Post-MI (reduces mortality, prevents sudden death)
• Heart failure (carvedilol, metoprolol, bisoprolol - reduce remodeling)
• Hyperthyroidism (symptom control)
• Pheochromocytoma (only after alpha blockade)
• Migraine prophylaxis (propranolol)
• Anxiety/performance anxiety, Essential tremor
• Glaucoma (timolol topical)

• Bradycardia, heart block
• Bronchoconstriction (non-selective - dangerous in asthma/COPD)
• Peripheral vasoconstriction → cold extremities, worsening Raynaud's
• Masking of hypoglycemia (tachycardia masked; sweating unaffected - noradrenergic)
• CNS: fatigue, depression, nightmares
• Rebound hypertension/angina on abrupt withdrawal

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• Primary: Non-competitive antagonist at NMDA (N-methyl-D-aspartate) receptor channels - blocks phencyclidine (PCP) site inside open channel
• Also: Opioid receptor agonism (μ, κ), sigma receptor agonism, muscarinic antagonism, monoamine reuptake inhibition
• Results in functional dissociation between thalamo-cortical and limbic systems

• Analgesia: Excellent, even at sub-anesthetic doses
• Anesthesia: Loss of consciousness at higher doses (1-2 mg/kg IV)
• Cardiovascular: Stimulatory - ↑ HR, ↑ BP, ↑ cardiac output (sympathomimetic - releases catecholamines). Useful in shock/hypovolemia
• Respiratory: Preserves respiratory drive and airway reflexes
• Bronchodilation: Useful in asthmatic patients requiring anesthesia
• CNS: ↑ ICP, ↑ IOP (disadvantage)

• Emergency anesthesia and procedural sedation (trauma, field conditions)
• Pediatric anesthesia and brief procedures
• Bronchospastic patients needing anesthesia
• Analgesia in burns, wound dressing changes
• Hemodynamically unstable patients
• Induction agent in rapid sequence intubation

• Emergence delirium, hallucinations, unpleasant dreams (reduced by benzodiazepine premedication)
• ↑ ICP (contraindicated in head injury)
• ↑ IOP (avoid in perforating eye injuries)
• Excessive secretions (pretreat with glycopyrrolate/atropine)
• Tachycardia and hypertension (avoid in hypertensive cardiovascular disease)

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Q3. Very Short Answers (5×2 = 10 Marks)

1. Dosing frequency: Drugs with short t½ (e.g., penicillin G ~30 min) need frequent dosing; long t½ (e.g., amlodipine ~35-50 hrs) allow once-daily dosing
2. Time to steady state: Achieved in ~4-5 half-lives; important for monitoring therapeutic levels
3. Duration of drug effect: Guides how long to continue or discontinue a drug
4. Drug accumulation: Drugs with long t½ accumulate with repeated dosing (e.g., digoxin, amiodarone)
5. Timing of drug interactions: Knowing when plasma levels decline helps anticipate interactions
6. Dose adjustment in organ failure: Prolonged t½ in renal/hepatic disease (e.g., digoxin in renal failure)
7. Withdrawal effects: Drugs with short t½ (benzodiazepines) cause acute withdrawal; those with long t½ (diazepam) cause gradual, milder withdrawal

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• PDE-4 is the predominant phosphodiesterase in immune cells (neutrophils, eosinophils, macrophages, T-lymphocytes)
• PDE-4 normally hydrolyzes cAMP → AMP (inactivation)
• Roflumilast inhibits PDE-4 → ↑ intracellular cAMP → activates PKA → anti-inflammatory effects:
  • Reduces neutrophil and eosinophil activity
  • Decreases release of cytokines (TNF-α, IL-6, IL-8), mediators, and enzymes
  • Reduces mucus hypersecretion
  • Bronchodilation (minor effect)

1. COPD (primary indication): Add-on treatment to bronchodilators in severe COPD (FEV1 <50% predicted) with chronic bronchitis and frequent exacerbations; reduces exacerbation frequency
2. Asthma: Investigated as add-on therapy for severe eosinophilic asthma

• GI: Nausea, diarrhea, abdominal pain (most common, usually transient)
• Weight loss (clinically significant - monitor BMI)
• Headache, insomnia
• Psychiatric effects: Depression, suicidal ideation (BLACK BOX WARNING - use with caution in depression/suicidal history)

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• GI: Gastric mucosal irritation, ulcers, bleeding (↓ PGE2 = ↓ mucus, ↓ bicarbonate, ↑ acid; also direct irritant); take with food/PPI
• Bleeding tendency: Antiplatelet effect (prolonged bleeding time)
• Reye's Syndrome: Severe hepatic failure + encephalopathy in children with viral illness (e.g., chickenpox, influenza) - AVOID in children <12 years
• Hypersensitivity: Aspirin-induced asthma (ASA triad/Samter's triad: asthma + nasal polyps + aspirin sensitivity) - due to shunting of arachidonic acid to leukotrienes
• Salicylism: Tinnitus, deafness, vertigo, nausea (early toxicity at high doses)
• Salicylate poisoning: Mixed respiratory alkalosis + metabolic acidosis; hyperthermia; hyperventilation
• Uric acid effects: Low dose → hyperuricemia; high dose → uricosuria
• Platelet dysfunction: Prolonged bleeding time after single dose (lasts 7-10 days)

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• Introduced by WHO in 1977 under Dr. Halfdan Mahler
• First list had 208 medicines
• Currently (~2023 edition): approximately 500 medicines (including vaccines, contraceptives, diagnostics)
• Updated every 2 years by the WHO Expert Committee

1. Relevance to the burden of disease in the population
2. Evidence of efficacy from well-designed clinical trials
3. Acceptable safety profile (benefit-risk ratio favorable)
4. Quality: availability of assured quality supply
5. Cost-effectiveness and affordability

• Guide national health systems in procuring and distributing medicines rationally
• Ensure universal availability of basic treatments
• Reduce irrational prescribing and unnecessary expenditure
• Used as template for National Essential Medicines Lists (NEMLs) by member states

• India adopted this concept and publishes its own NLEM
• Last updated: NLEM 2022 has 384 medicines
• Basis for price control (DPCO - Drug Price Control Order) by the government

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