---

Assignment Questions - 15/07/2026

---

Q1. 5-HT Receptor Agonists and Antagonists: Examples and Therapeutic Uses

Classification of 5-HT (Serotonin) Receptors

---

5-HT Agonists

A. Non-selective Agonists

• Serotonin (5-HT) itself - no therapeutic use due to multiple actions

B. 5-HT1A Agonists (Azapirones)

• Buspirone - Partial agonist at 5-HT1A
  • Therapeutic use: Generalized anxiety disorder (GAD) - no sedation, no dependence, no withdrawal
  • Onset of action: 2-3 weeks
  • Does NOT interact with benzodiazepine receptors

C. 5-HT1B/1D Agonists (Triptans) - "Selective Serotonin Receptor Agonists"

• Sumatriptan (first generation, subcutaneous/oral/nasal)
• Zolmitriptan, Naratriptan, Rizatriptan, Almotriptan, Eletriptan, Frovatriptan (second generation, oral only)

• Acute migraine attacks (drug of choice for moderate-to-severe migraine)
• Cluster headache (sumatriptan subcutaneous)

D. 5-HT3 Agonists

• 2-Methyl-5-HT - experimental only (no therapeutic use)

E. 5-HT4 Agonists (Prokinetics)

• Metoclopramide - also D2 blocker
• Cisapride - withdrawn due to cardiac arrhythmias
• Mosapride, Tegaserod

---

5-HT Antagonists

A. 5-HT2 Antagonists

• Potent 5-HT2 antagonist
• Therapeutic use: Prophylaxis of migraine and cluster headaches; carcinoid syndrome
• Adverse effect (major): Retroperitoneal fibrosis, pleuropulmonary fibrosis, endocardial fibrosis with long-term use → "drug holiday" after every 6 months

• 5-HT2 + H1 blocker; also anticholinergic
• Therapeutic uses:
  • Allergic conditions (urticaria, rhinitis)
  • Migraine prophylaxis (children)
  • Carcinoid syndrome
  • Appetite stimulant (weight gain in anorexia)
  • Cold urticaria

• 5-HT2A + alpha-1 blocker
• Therapeutic use: Hypertension (not widely used now)

• 5-HT2A + D2 blockers
• Therapeutic use: Schizophrenia, bipolar disorder

B. 5-HT3 Antagonists (Setrons - Gold Standard Antiemetics)

• Chemotherapy-induced nausea and vomiting (CINV) - most effective for acute phase
• Radiotherapy-induced nausea/vomiting
• Post-operative nausea and vomiting (PONV)
• Note: Palonosetron also covers delayed CINV

C. Ergotamine (5-HT1 partial agonist/antagonist + alpha-agonist)

• Ergotamine and methylergide are ergot alkaloids with complex receptor actions
• Use: Acute migraine (oral/sublingual), cluster headache prophylaxis
• ADR: Ergotism (gangrene, vasospasm), nausea, retroperitoneal fibrosis (methylergide)

---

Q2. Drug Therapy of Migraine Including Prophylaxis

Pathophysiology (Brief)

---

A. Treatment of Acute Migraine Attack

Step 1 - Mild to Moderate Attack

• Analgesics: Aspirin 600-900 mg, Paracetamol 1g, Ibuprofen 400-800 mg
• Antiemetics (also prokinetic - improve absorption): Metoclopramide 10 mg, Domperidone 10 mg - given 20 min before analgesic

Step 2 - Moderate to Severe Attack (Drug of Choice)

• Sumatriptan - Oral 50-100 mg; SC 6 mg (fastest onset, used for severe attacks); Nasal spray 20 mg
• Rizatriptan - 10 mg oral (fast acting, preferred by many)
• Zolmitriptan - 2.5-5 mg oral/nasal
• Naratriptan - 2.5 mg (longer half-life, fewer recurrences, milder but slower)
• Eletriptan, Almotriptan, Frovatriptan - oral

Step 3 - Ergot Alkaloids (second line)

• Ergotamine tartrate 1-2 mg oral/sublingual at onset; can repeat up to 6 mg/attack
• Dihydroergotamine (DHE) 1 mg IM/IV; DHE nasal spray 0.5 mg/nostril
• Partial agonist at 5-HT1, alpha-adrenergic agonist
• Causes intense vasoconstriction - limited by ergotism and nausea
• Contraindicated in pregnancy, IHD, peripheral vascular disease, HTN

Adjuncts

• Chlorpromazine/prochlorperazine - IV for severe refractory attacks in ER
• Dexamethasone - IV for prolonged migraine (status migrainosus)
• Opioids - last resort; risk of medication overuse headache (MOH)

---

B. Prophylaxis of Migraine

• ≥4 attacks per month
• Attacks lasting >48 hours
• Attacks significantly impairing quality of life
• Contraindication to acute drugs
• Failure of acute treatment
• Risk of neurological sequelae (hemiplegic migraine)

1. Beta-Blockers (First-line)

• Propranolol 80-240 mg/day (most evidence) - mechanism unknown; possibly reduces vasomotor reactivity, inhibits 5-HT2 receptors
• Metoprolol, Atenolol, Nadolol, Timolol
• Contraindicated in: Asthma, heart block, diabetes (masks hypoglycemia symptoms)

2. Antidepressants

• Amitriptyline (TCA) 10-75 mg at night - most used for migraine prophylaxis, especially with comorbid depression/insomnia
• Venlafaxine (SNRI) - also effective
• Mechanism: 5-HT2 blockade, NE enhancement, sodium channel blockade

3. Antiepileptics (Anticonvulsants)

• Valproic acid / Sodium valproate 500-1500 mg/day - FDA approved; increases GABA; very effective
  • ADR: Weight gain, teratogenicity (neural tube defects - avoid in women of childbearing age), hepatotoxicity, tremor
• Topiramate 25-100 mg/day - FDA approved; blocks sodium channels, AMPA/kainate receptors, enhances GABA
  • ADR: Cognitive slowing ("dopamax"), weight loss, renal stones, metabolic acidosis

4. Calcium Channel Blockers

• Flunarizine 5-10 mg at night - most commonly used CCB for migraine prophylaxis in India
  • ADR: Weight gain, sedation, depression, extrapyramidal symptoms (with long-term use)
• Verapamil - especially for cluster headache prophylaxis
• Nimodipine - used in some centers

5. Ergot Derivatives

• Methysergide 2-6 mg/day - potent 5-HT2 antagonist; highly effective but limited by retroperitoneal fibrosis (drug holiday every 6 months mandatory)

6. 5-HT2 Antagonists

• Cyproheptadine - especially in children
• Pizotifen (pizotyline) - 5-HT2 + H1 blocker; used in Europe

7. Newer - CGRP Antagonists (Gepants and Monoclonal Antibodies)

• Erenumab, Fremanezumab, Galcanezumab - anti-CGRP monoclonal antibodies (monthly SC injections) - highly effective prophylaxis with minimal side effects; mentioned in newer editions of KDT

8. Botulinum Toxin Type A (Botox)

• For chronic migraine (≥15 headache days/month) - injected into pericranial/cervical muscles every 12 weeks

---

Summary Table - Migraine Prophylaxis Drugs

---

Q3. Prostaglandin Analogues: Classification, Pharmacological Actions, Therapeutic Uses, Adverse Effects, and Contraindications

Introduction

---

Classification of Prostaglandin Analogues

Group I - PGE2 Analogues

• Dinoprostone (PGE2) - natural
• Misoprostol (PGE1 analogue - synthetic, stable, orally active)
• Sulprostone - PGE2 analogue

Group II - PGE1 Analogues

• Alprostadil (PGE1 - natural)
• Misoprostol (synthetic PGE1 analogue)

Group III - PGF2α Analogues (used primarily in ophthalmology as IOP-lowering agents)

• Latanoprost (FP receptor agonist)
• Bimatoprost (prostamide analogue - acts on FP receptors)
• Travoprost
• Tafluprost
• Unoprostone

Group IV - PGI2 (Prostacyclin) Analogues

• Epoprostenol (prostacyclin itself - IV)
• Iloprost (oral/inhaled/IV)
• Treprostinil (SC/IV/inhaled)
• Beraprost (oral)

Group V - Thromboxane A2 (TXA2) - Note: TXA2 is NOT used therapeutically; aspirin inhibits its synthesis

---

Pharmacological Actions

PGE2 and PGE1 (Dinoprostone, Misoprostol, Alprostadil)

1. Uterus: Stimulate uterine contractions (both pregnant and non-pregnant); sensitize uterus to oxytocin; PGE2 especially potent on cervical ripening
2. GIT: Cytoprotective effect on gastric mucosa (↑mucus, ↑bicarbonate secretion, ↓acid secretion); stimulate intestinal motility → diarrhea
3. Vasculature: PGE1 causes vasodilation; lowers blood pressure
4. Bronchi: PGE1 and PGE2 cause bronchodilation at EP2 receptors (but paradoxically bronchoconstriction via EP3 in some situations)
5. Inflammation: Sensitize pain receptors (hyperalgesia); cause fever via action on hypothalamus

PGF2α Analogues (Latanoprost, Bimatoprost, Travoprost)

1. Eye: Increase uveoscleral outflow of aqueous humor → lower IOP
2. Uterus: Cause powerful uterine contractions (used for abortion and induction)
3. Bronchi: PGF2α causes bronchoconstriction

PGI2 (Prostacyclin) Analogues (Epoprostenol, Iloprost, Treprostinil)

1. Platelets: Potent inhibitor of platelet aggregation (elevate cAMP in platelets)
2. Vasculature: Potent vasodilator (especially pulmonary vasculature)
3. Bronchi: Bronchodilation

---

Therapeutic Uses

1. Obstetrics and Gynecology

• 250 mcg IM for refractory PPH not responding to oxytocin/ergometrine
• Contraindicated in asthma (causes bronchoconstriction)

2. Gastroenterology

• Misoprostol - Prevention of NSAID-induced peptic ulcers
  • Used with NSAIDs in patients at high GI risk
  • Reduces gastric acid secretion + cytoprotective effect
  • Now largely replaced by PPIs in clinical practice
• Alprostadil (PGE1) - cytoprotective, rarely used for ulcers now

3. Ophthalmology - Glaucoma (First-line treatment)

• Latanoprost 0.005% eye drops - once daily at night (most used)
• Bimatoprost 0.01-0.03% - once daily
• Travoprost 0.004% - once daily
• Tafluprost - preservative-free, for sensitive eyes

• Iris hyperpigmentation (increased melanin in iris stromal melanocytes) - permanent
• Eyelash changes (longer, thicker, more pigmented - hypertrichosis)
• Periorbital fat atrophy (prostaglandin-associated periorbitopathy - PAP)
• Conjunctival hyperemia (redness)
• Uveitis, macular edema (rare)

4. Pulmonary Arterial Hypertension (PAH)

• Epoprostenol IV - continuous IV infusion; potent but short half-life (3-5 min)
• Iloprost - inhaled 6-9 times/day; also IV
• Treprostinil - SC or IV infusion; inhaled form available
• Beraprost - oral (less potent)

5. Erectile Dysfunction

• Alprostadil (PGE1):
  • Intracavernosal injection (Caverject) 5-20 mcg
  • Intraurethral suppository (MUSE) 125-1000 mcg
  • Causes corporal smooth muscle relaxation → penile erection
  • ADR: Penile pain, priapism, local fibrosis

6. Patent Ductus Arteriosus (PDA)

• Alprostadil (PGE1) IV infusion - maintains PDA open in neonates with duct-dependent congenital heart disease (e.g., pulmonary atresia, coarctation of aorta, hypoplastic left heart) until surgery
• Indomethacin / Ibuprofen (COX inhibitors) - used to CLOSE PDA (opposite purpose)

7. Peripheral Vascular Disease

• Alprostadil, Iloprost - IV for critical limb ischemia, Buerger's disease, Raynaud's phenomenon

---

Adverse Effects (Common to PG Analogues)

1. GIT: Nausea, vomiting, diarrhea, abdominal cramping (most common with misoprostol)
2. Uterus: Uterine hyperstimulation, uterine rupture (especially with misoprostol in previous uterine scar)
3. Cardiovascular: Hypotension, flushing, tachycardia
4. Bronchospasm: With PGF2α analogues (carboprost) → dangerous in asthmatics
5. Fever and chills (especially carboprost)
6. Local effects (eye drops): iris hyperpigmentation, eyelash hypertrichosis, PAP

---

Contraindications

---

Q4. Role of Leukotrienes and Leukotriene Antagonists

Biosynthesis of Leukotrienes

• Arachidonic acid is released from membrane phospholipids by phospholipase A2
• 5-Lipoxygenase (5-LOX) + 5-LOX activating protein (FLAP) converts arachidonic acid → 5-HPETE → Leukotriene A4 (LTA4)
• LTA4 → LTB4 (via LTA4 hydrolase) or LTC4 (via LTC4 synthase, adds glutathione)
• LTC4 → LTD4 → LTE4 (sequential loss of amino acids)

---

Physiological and Pathological Roles of Leukotrienes

LTB4 (acts on BLT receptors)

• Potent chemotactic agent for neutrophils and eosinophils
• Stimulates neutrophil adherence, aggregation, and superoxide production
• Roles in: Psoriasis, IBD, rheumatoid arthritis, COPD
• Does NOT cause bronchoconstriction

Cysteinyl Leukotrienes - LTC4, LTD4, LTE4 (act on CysLT1 and CysLT2 receptors)

1. Bronchospasm: 100-1000x more potent than histamine; cause prolonged bronchoconstriction (major mediators of asthma)
2. Mucus hypersecretion in airways
3. Mucosal edema (increased vascular permeability)
4. Eosinophil recruitment to airways
5. Nasal congestion in allergic rhinitis
6. Cardiovascular: Decrease cardiac contractility, cause coronary vasoconstriction
7. Role in anaphylaxis - contribute to bronchoconstriction and hypotension

• Asthma (especially aspirin-exacerbated asthma / Samter's triad)
• Allergic rhinitis
• Urticaria
• Anaphylaxis
• Exercise-induced bronchoconstriction
• Aspirin-sensitive asthma (aspirin blocks COX → shunts arachidonic acid to 5-LOX pathway → excess LT production)

---

Leukotriene Antagonists (Antileukotrienes)

Classification

• Montelukast (most used - once daily oral)
• Zafirlukast (twice daily; has more drug interactions)
• Pranlukast (used in Japan/Asia)

• Zileuton - inhibits 5-LOX enzyme → blocks ALL leukotriene synthesis (LTB4 + cysteinyl LTs)
  • ADR: Hepatotoxicity (liver function monitoring required)
  • Drug interactions: warfarin, theophylline, propranolol

---

Pharmacology of Montelukast (KDT Focus)

1. Prophylaxis of bronchial asthma (especially mild persistent; add-on in moderate asthma)
2. Aspirin-exacerbated asthma (most effective here - drug of choice)
3. Exercise-induced bronchoconstriction (prophylaxis - single dose 2 hours before exercise)
4. Allergic rhinitis (seasonal and perennial) - reduces congestion, sneezing, rhinorrhea
5. Urticaria (especially chronic)
6. Eosinophilic esophagitis (emerging use)

• Oral (no technique issues)
• No systemic steroid side effects
• Anti-inflammatory + bronchodilator effect
• Effective for both upper and lower airway disease
• Suitable for children (chewable tablets for 2-5 years; granules for 6 months-5 years)

• Generally well tolerated
• GI disturbances (mild)
• Headache, dizziness
• Elevated liver enzymes (rare)
• Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis) - rare, may be "unmasking" phenomenon when steroids are reduced
• Neuropsychiatric effects (FDA black box warning 2020): agitation, aggression, anxiety, depression, suicidal ideation - especially in children/adolescents; patients should be counselled

---

---

Assignment Questions - 16/07/2026

---

Q1. Aspirin: Pharmacological Actions, Therapeutic Uses, Adverse Effects, Contraindications, and Poisoning

Introduction

---

Mechanism of Action

• Irreversibly inhibits COX-1 and COX-2 by acetylation of Ser-529 of COX-1 and Ser-516 of COX-2
• This blocks the conversion of arachidonic acid to PGG2 → PGH2 → prostaglandins, thromboxane A2, and prostacyclin
• Platelets: Lack nucleus → cannot synthesize new COX → TXA2 synthesis inhibited for entire platelet lifespan (7-10 days) → antiplatelet effect is permanent
• Endothelium: Can synthesize new COX → PGI2 synthesis resumes; aspirin's antiplatelet effect outlasts anticoagulant effect

---

Pharmacological Actions

1. Analgesic Action

• Peripheral: Inhibit PG synthesis at site of injury → reduce sensitization of nociceptors
• Central: Inhibit PG synthesis in CNS (hypothalamus, spinal cord)
• Effective for: Headache, myalgia, arthralgia, dysmenorrhea, toothache
• NOT effective for visceral pain (unlike opioids)

2. Antipyretic Action

• Inhibit PG synthesis (especially PGE2) in the hypothalamus → reset thermostat to normal
• Enhance heat loss (vasodilation, sweating)
• Do NOT lower normal body temperature
• Contraindicated in children with viral fever (risk of Reye's syndrome)

3. Anti-inflammatory Action

• Inhibit PG synthesis + reduce leukocyte migration, prevent kinin release
• High doses (3-5 g/day) required for anti-inflammatory effect
• Used in rheumatoid arthritis, acute rheumatic fever

4. Antiplatelet Action (Unique among NSAIDs)

• Irreversible inhibition of platelet COX-1 → ↓ TXA2 → inhibits platelet aggregation
• Low dose (75-150 mg/day) is sufficient and safer
• Duration: Lasts for life of platelet (7-10 days)

5. Uricosuric Action

• Dose-dependent, paradoxical:
  • Low dose (< 1 g/day): Inhibit tubular secretion of uric acid → uric acid RETENTION (hyperuricemia)
  • High dose (> 3 g/day): Inhibit tubular reabsorption of uric acid → uricosuric (uric acid excretion increases)
  • Intermediate dose: Neither beneficial

6. Other Actions

• Respiration: Stimulate respiration (at toxic doses - direct stimulation of respiratory center)
• Metabolic: High doses uncouple oxidative phosphorylation → ↑ O2 consumption, ↑ CO2 production, hyperthermia
• Glucose metabolism: High doses cause hypoglycemia (increase peripheral utilization)

---

Therapeutic Uses

---

Adverse Effects

1. GI Effects (Most Common)

• Gastric irritation, nausea, vomiting (direct local + systemic: ↓ PG → ↓ mucus/bicarbonate + ↓ blood flow)
• Peptic ulcer disease, gastric bleeding (occult blood loss ~2-6 mL/day)
• GI bleeding - major risk at any dose
• Reduced by: Enteric-coated aspirin, proton pump inhibitors (PPIs), food intake

2. Bleeding

• Prolonged bleeding time (platelet COX inhibition)
• GI bleeding, hemoptysis, postoperative bleeding
• Intracranial hemorrhage (rare but serious)

3. Hypersensitivity / Aspirin Sensitivity (Aspirin-Exacerbated Respiratory Disease - AERD)

• Aspirin triad (Samter's triad): Asthma + nasal polyps + aspirin sensitivity
• Manifestations: Urticaria, angioedema, bronchospasm (within 30 min - 3 hours of ingestion)
• Mechanism: Inhibit COX-1 → shunt arachidonic acid to 5-LOX → excess leukotrienes
• Cross-reactive with all COX-1 inhibiting NSAIDs

4. Reye's Syndrome

• Rare but potentially fatal complication in children (< 12 years) with viral infection (varicella, influenza)
• Features: Acute encephalopathy + fatty liver degeneration after aspirin use
• Aspirin is contraindicated in children < 12 years with febrile illness

5. Salicylism (Chronic Toxicity at High Doses)

• Tinnitus, deafness, headache, dizziness, nausea, vomiting, mental confusion
• Reversible on dose reduction

6. Renal Effects

• High doses: Inhibit PG-mediated vasodilation in kidney → acute renal failure (especially in patients with pre-existing renal impairment, heart failure, liver cirrhosis, dehydration)
• Sodium and water retention → edema

7. Hepatotoxicity

• At high doses (especially chronic use in connective tissue disorders)

8. Urate Retention

• Low doses (< 1 g/day) → precipitate/worsen gout

9. Pregnancy

• First trimester: Risk of miscarriage (high doses)
• Third trimester: Premature closure of ductus arteriosus, inhibition of uterine contractions → prolonged labor, increased bleeding
• Low-dose aspirin (75-150 mg) is safe and used in pre-eclampsia prevention

---

Contraindications

1. Children < 12 years with viral fevers (Reye's syndrome)
2. Active peptic ulcer / GI bleeding
3. Hemophilia and other bleeding disorders
4. Hypersensitivity to aspirin (Samter's triad/AERD)
5. Severe hepatic dysfunction
6. Severe renal failure (GFR < 10 mL/min)
7. Third trimester pregnancy (premature ductus arteriosus closure)
8. Concurrent anticoagulant therapy (risk of serious bleeding) - relative contraindication
9. Gout (low doses worsen hyperuricemia)
10. Pre-operatively (stop 7-10 days before major surgery)

---

Aspirin Poisoning (Salicylate Toxicity)

Toxic Dose

• Therapeutic dose: 300-600 mg
• Toxic dose: > 150 mg/kg body weight
• Fatal dose (adults): ~20-30 g

Pathophysiology / Mechanism of Toxicity

• Salicylate directly stimulates medullary respiratory center → hyperventilation → CO2 washout → respiratory alkalosis
• Most prominent in adults with acute poisoning

• Uncoupling of oxidative phosphorylation → accumulation of organic acids (pyruvate, lactate, ketoacids)
• Inhibition of Krebs cycle enzymes
• High doses block carbohydrate and fat metabolism
• Children develop metabolic acidosis early (CNS vulnerable)

• Uncoupling → hyperthermia
• Inhibit platelet function → bleeding
• Stimulate chemoreceptor trigger zone → vomiting
• Pulmonary edema (noncardiogenic)

Clinical Features

• Nausea, vomiting
• Tinnitus, deafness
• Vertigo, dizziness
• Hyperventilation
• Diaphoresis (sweating)

• Above features
• Hyperthermia
• Confusion, disorientation
• Dehydration
• Metabolic disturbances

• Convulsions
• Coma
• Pulmonary edema
• Cardiovascular collapse
• Renal failure
• Hypoglycemia (especially children)
• Death from respiratory/cardiovascular failure

Diagnosis

• Serum salicylate levels (Done nomogram - Rumack-Matthew)
• Blood gas: Mixed respiratory alkalosis + metabolic acidosis
• Urine: Ferric chloride test (purple color with salicylates)
• Urinalysis, electrolytes, blood glucose

Treatment of Aspirin Poisoning

• Activated charcoal 1 g/kg oral (if within 1-2 hours and patient alert)
• Gastric lavage (if large ingestion, early presentation, unable to take charcoal)
• Do NOT induce vomiting (risk of aspiration)

• Monitor vital signs, urine output, blood glucose
• IV fluids: Normal saline or D5W + saline (correct dehydration and hypoglycemia)
• Control hyperthermia: cooling measures (NOT more aspirin)
• Diazepam for convulsions

• IV Sodium bicarbonate (1-2 mEq/kg bolus, then infusion to maintain urine pH 7.5-8.0)
• Mechanism: Alkaline urine ionizes salicylic acid (pKa 3.5) → ionized form cannot be reabsorbed by tubules → "ion trapping" → enhanced renal excretion
• Target: Urine pH > 7.5, serum pH 7.45-7.55
• Also correct hypokalemia (required for urinary alkalinization to work)

• Indications:
  • Serum salicylate > 100 mg/dL (acute) or > 60 mg/dL (chronic)
  • Renal failure
  • Pulmonary edema
  • Severe metabolic acidosis unresponsive to treatment
  • Neurological deterioration (coma, seizures)
  • Hemodynamic instability

---

Q2. Paracetamol (Acetaminophen): MOA, Adverse Effects, Acute Poisoning, Treatment, and Clinical Uses

Introduction

---

Mechanism of Action (MOA)

• Paracetamol is a weak inhibitor of COX-1 and COX-2 in peripheral tissues (insufficient to be anti-inflammatory at normal plasma concentrations)
• CNS-selective action: At therapeutic doses, paracetamol preferentially inhibits COX in the CNS (particularly in the hypothalamus and spinal cord) where peroxide concentrations are low
• Unlike classic NSAIDs, paracetamol cannot inhibit COX in inflamed tissues (high peroxide environment → paracetamol is oxidized, loses its COX-inhibiting ability)

• Paracetamol preferentially inhibits a splice variant of COX-1 called COX-3 found mainly in CNS (brain and spinal cord) → central analgesia and antipyresis
• This hypothesis explains CNS selectivity (not universally accepted)

• Paracetamol → deacylated to AM404 (paracetamol-arachidonic acid conjugate) in CNS
• AM404 inhibits anandamide (endocannabinoid) reuptake and activates TRPV1 receptors
• Also activates cannabinoid CB1 receptors → central analgesia

• Paracetamol activates descending serotonergic (5-HT) pain inhibitory pathways in the spinal cord → contributes to central analgesia

• Inhibits N-methyl-D-aspartate (NMDA) receptor-mediated NO synthesis → reduces central sensitization

---

Clinical Uses

1. Mild to moderate pain:
   • Headache, myalgia, back pain, arthralgia, post-operative pain
   • Drug of choice for analgesia in: Peptic ulcer patients, patients on anticoagulants, renal impairment, gout, elderly
2. Fever (antipyretic): Drug of choice in children (safe, no Reye's syndrome risk)
3. Osteoarthritis: First-line analgesic (Step 1 WHO ladder)
4. Cancer pain: Step 1 (WHO analgesic ladder)
5. Post-vaccination fever in children (preferred over aspirin)
6. Migraine (1g oral - for mild attacks)
7. Combination products: With tramadol, codeine, or NSAIDs

• Adults: 325-1000 mg every 4-6 hours; maximum 4 g/day (3 g/day in elderly or chronic alcohol use)
• Children: 10-15 mg/kg every 4-6 hours

---

Advantages Over Aspirin

• No GI irritation / ulceration
• No antiplatelet effect → safe perioperatively
• No effect on uric acid → safe in gout
• Safe in asthma (no COX-1 inhibition peripherally)
• Safe in children with fever
• No Reye's syndrome risk
• Safe in patients on anticoagulants

---

Adverse Effects (at Therapeutic Doses)

1. Generally very well tolerated at therapeutic doses
2. Rare: Skin rash, urticaria, fixed drug eruption (very rare - contains para-amino group)
3. Hepatotoxicity - rare at therapeutic doses unless:
   • Chronic alcoholism (induced CYP2E1 → more NAPQI production)
   • Prolonged use at high therapeutic doses
   • Malnutrition (depleted glutathione)
4. Renal papillary necrosis - with chronic high-dose use (analgesic nephropathy - usually in combination with aspirin)
5. Methemoglobinemia - very rare
6. Thrombocytopenia, neutropenia - extremely rare

---

Acute Paracetamol Poisoning

Hepatotoxic Dose

• Toxic dose (adults): > 150 mg/kg or > 7.5-10 g (single ingestion)
• Fatal dose: > 15-25 g (without treatment)

Mechanism of Hepatotoxicity (Critical for Exam)

• ~90-95% paracetamol conjugated to sulfate and glucuronide → non-toxic, excreted in urine
• ~5-10% oxidized by CYP2E1 (and CYP3A4) → highly reactive intermediate NAPQI (N-acetyl-p-benzoquinoneimine)
• NAPQI rapidly detoxified by conjugation with glutathione (GSH) → mercaptopuric acid → excreted

• Sulfation and glucuronidation pathways become saturated
• More paracetamol is shunted to CYP2E1 → excess NAPQI formation
• Glutathione stores become depleted (to <30% of normal)
• Excess NAPQI binds covalently to hepatocyte proteins (sulfhydryl groups) → hepatocellular necrosis
• Centrilobular (zone 3) necrosis - highest CYP2E1 activity in zone 3

• Chronic alcoholism (induced CYP2E1)
• Enzyme-inducing drugs (rifampicin, phenytoin, carbamazepine, phenobarbitone)
• Fasting / malnutrition (depleted glutathione)
• Liver disease

Clinical Stages of Paracetamol Poisoning

• Nausea, vomiting, malaise, diaphoresis, pallor
• May appear well (deceptively mild)

• Right upper quadrant pain (hepatic tenderness)
• Rise in liver enzymes (AST, ALT, bilirubin)
• Prothrombin time prolonged
• Oliguria (renal involvement begins)

• Peak hepatic damage (highest AST/ALT)
• Fulminant hepatic failure
• Jaundice, coagulopathy, encephalopathy
• Renal failure (acute tubular necrosis)
• Lactic acidosis
• Death most likely at this stage (from hepatic failure)

• Patients who survive begin to recover
• Hepatic regeneration (complete recovery possible even after severe damage)
• No permanent damage in survivors

Risk Assessment Tools

• Rumack-Matthew nomogram: Plot serum paracetamol concentration vs. time after ingestion → predicts hepatotoxicity risk; treatment line at 150 mcg/mL at 4 hours post-ingestion (in UK, line is lower at 100 mcg/mL)

---

Treatment of Acute Paracetamol Poisoning

1. Gastric Decontamination (if within 1-2 hours)

• Activated charcoal 1 g/kg oral (most effective within 1 hour)
• Gastric lavage - rarely used now (charcoal preferred)

2. Specific Antidote - N-Acetylcysteine (NAC) - MOST IMPORTANT

• Acts as a glutathione precursor → replenishes hepatic glutathione stores → NAPQI detoxified
• Direct scavenger of NAPQI
• Also increases sulfate availability (sulfation pathway)

• Loading dose: 150 mg/kg IV in 200 mL 5% dextrose over 15-60 min
• 2nd dose: 50 mg/kg IV in 500 mL 5% dextrose over 4 hours
• 3rd dose: 100 mg/kg IV in 1000 mL 5% dextrose over 16 hours
• Total dose: 300 mg/kg over 21 hours

• Most effective if given within 8-10 hours of ingestion
• Still beneficial up to 24 hours (reduces severity of hepatic injury)
• May be beneficial even after 24 hours in severe cases

3. Methionine (oral)

• Alternative to NAC if NAC not available
• Also replenishes glutathione
• 2.5 g orally every 4 hours for 4 doses (total 10 g)

4. Supportive Care

• IV fluids, electrolyte correction
• Monitor LFTs, PT/INR, creatinine, glucose
• Treat hypoglycemia (IV dextrose)
• Vitamin K for coagulopathy
• FFP / cryoprecipitate if bleeding
• Dialysis for renal failure

5. Liver Transplant

• For fulminant hepatic failure meeting King's College Criteria:
  • Arterial pH < 7.30 (despite resuscitation), OR
  • PT > 100 seconds + creatinine > 300 μmol/L + Grade III/IV encephalopathy

---

Q3. Pharmacological Management of Rheumatoid Arthritis

Introduction

---

Classification of Drugs for RA (KDT)

• Conventional synthetic DMARDs (csDMARDs)
• Biologic DMARDs (bDMARDs)
• Targeted synthetic DMARDs (tsDMARDs - JAK inhibitors)

---

A. Symptom-Modifying Drugs

1. NSAIDs (First-line for symptomatic relief)

• Diclofenac, Naproxen, Ibuprofen, Indomethacin, Piroxicam
• COX-2 selective: Celecoxib, Etoricoxib (fewer GI side effects)
• Aspirin (high dose 3-5 g/day) - historical, now largely replaced
• Role: Provide analgesia and reduce inflammation; do NOT slow disease progression
• ADR: GI ulceration, renal dysfunction, cardiovascular effects (COX-2 selective >> non-selective)

2. Corticosteroids

• Prednisolone (low dose: 5-10 mg/day)
• Methylprednisolone (IV pulse - 1 g/day for 3 days for severe flares)
• Intraarticular triamcinolone/methylprednisolone (for 1-3 inflamed joints)
• Role:
  • "Bridge therapy" until DMARDs take effect (3-6 months lag time)
  • Short-term flare management
  • Low-dose maintenance in refractory disease
• ADR: Osteoporosis, infection, diabetes, hypertension, cushingoid features, adrenal suppression
• Always give with calcium + vitamin D supplementation; consider bisphosphonate

---

B. Disease-Modifying Antirheumatic Drugs (DMARDs)

KDT Principle: "DMARD therapy should be started EARLY (within 3 months of diagnosis) to prevent irreversible joint damage"

1. Conventional Synthetic DMARDs (csDMARDs)

• Mechanism: Inhibits dihydrofolate reductase → blocks purine/pyrimidine synthesis → antiproliferative + anti-inflammatory; also inhibits AICAR transformylase → adenosine release → anti-inflammatory
• Dose: 7.5-25 mg orally once weekly (not daily!)
• Folic acid 5 mg/week (same day or next day) - reduces toxicity without reducing efficacy
• Onset: 4-8 weeks
• ADR:
  • Hepatotoxicity (fatty liver, fibrosis, cirrhosis with long-term use)
  • Pulmonary toxicity (interstitial lung disease - MTX pneumonitis)
  • Bone marrow suppression (leucopenia, thrombocytopenia, megaloblastic anemia)
  • Mucositis, nausea, vomiting
  • Teratogenicity (Category X - stop 3 months before conception)
• Monitoring: LFTs, CBC every 4-8 weeks
• Contraindications: Pregnancy, severe hepatic disease, renal failure, immunodeficiency, alcoholism, pre-existing lung disease (relative)

• Mechanism: Inhibits NF-kB signaling, adenosine release, inhibits dihydropteroate synthetase
• Dose: 1-3 g/day (built up gradually)
• Onset: 4-8 weeks
• ADR: GI upset, reversible sperm abnormalities, hepatotoxicity, bone marrow suppression, skin rash, reversible reduced sperm count
• Monitoring: CBC, LFTs periodically
• Contraindications: Sulfonamide allergy, G6PD deficiency

• Mechanism: Unclear; possibly inhibit TLR signaling, reduce antigen presentation, inhibit lysosomal function
• Dose: Hydroxychloroquine 200-400 mg/day; Chloroquine 250 mg/day
• Onset: 3-6 months (slowest of all DMARDs)
• Most gentle DMARD; mildest ADR profile
• ADR:
  • Retinal toxicity (chloroquine retinopathy) - rare but irreversible; more with chloroquine than HCQ
  • Annual ophthalmological screening needed
  • GI upset, headache, skin rash
• Contraindications: Pre-existing retinopathy, G6PD deficiency (chloroquine)

• Mechanism: Inhibits dihydroorotate dehydrogenase → blocks pyrimidine de novo synthesis → inhibits T and B lymphocyte proliferation
• Prodrug: Converted to active metabolite teriflunomide (A77 1726)
• Dose: 10-20 mg/day (loading dose 100 mg/day for 3 days sometimes used)
• Efficacy similar to MTX
• ADR: Hepatotoxicity, diarrhea, nausea, hypertension, alopecia, rash, teratogenicity
• Long half-life (active metabolite t½ = 2 weeks; enterohepatic circulation)
• Drug washout with cholestyramine 8 g TDS for 11 days if pregnancy desired or serious ADR
• Contraindications: Pregnancy (teratogenic), severe hepatic disease

• Historical use; now largely abandoned due to ADR profile
• ADR: Nephrotoxicity (membranous nephropathy), dermatitis, stomatitis, thrombocytopenia, "chrysiasis" (gold deposits in skin)

• Mechanism: Immunomodulatory; rarely used now
• ADR: Nephrotic syndrome, pemphigus, myasthenia gravis, aplastic anemia
• Now largely obsolete

• Purine analogue; inhibits T and B cell proliferation
• Used in severe RA with extra-articular manifestations
• ADR: Bone marrow suppression, hepatotoxicity, increased infection risk

---

2. Biologic DMARDs (bDMARDs)

A. Anti-TNF-α Agents (most used biologics)

• Serious infections (TB reactivation - tuberculin test / IGRA mandatory before starting)
• Opportunistic infections
• Injection site reactions / infusion reactions
• Demyelination (rare - contraindicated in MS)
• Heart failure worsening (infliximab at high doses)
• Lymphoma (controversial, may be due to underlying RA not the drug)
• Autoimmune syndromes (drug-induced lupus - etanercept)

B. Anti-IL-6 Agents

• Tocilizumab - anti-IL-6 receptor mAb (IV monthly or SC weekly)
• Sarilumab - anti-IL-6 receptor mAb (SC every 2 weeks)
• ADR: Neutropenia, elevated cholesterol, GI perforations, elevated LFTs

C. Anti-IL-1 Agents

• Anakinra (IL-1 receptor antagonist) - SC daily; less used for RA now
• Canakinumab - anti-IL-1β mAb; mainly for SJIA, gout flares

D. Anti-CD20 (B-cell depleter)

• Rituximab - chimeric anti-CD20 mAb (IV infusion, 2 doses 2 weeks apart, repeated every 6-12 months)
• Used for RA not responding to anti-TNF agents
• ADR: Infusion reactions, severe infections (PML with JC virus - rare), hypogammaglobulinemia

E. T-cell Costimulation Blocker

• Abatacept (CTLA4-Ig fusion protein) - blocks CD28-CD80/86 costimulation → inhibits T-cell activation
• IV monthly or SC weekly
• ADR: Infections, headache; lower infection risk than anti-TNF

F. Anti-CD52

• Alemtuzumab - rare use in RA

---

3. Targeted Synthetic DMARDs - JAK Inhibitors

• Serious infections (herpes zoster reactivation especially), TB
• Thromboembolism (VTE, PE) - particularly tofacitinib at high doses
• MACE (cardiovascular events) - FDA warning
• Malignancy (lymphoma) - FDA black box warning
• Anemia, neutropenia
• Dyslipidemia

---

Treatment Strategy for RA (KDT / ACR/EULAR Approach)

• Methotrexate (first-choice csDMARD) ± HCQ ± Sulfasalazine (triple therapy)

• Alternative if anti-TNF fails: Try second anti-TNF OR switch class (abatacept, tocilizumab, rituximab)

---

Q4. Drugs Used in Gout: Classification and Management of Acute and Chronic Gout

Introduction (KDT)

---

Classification of Drugs Used in Gout (KDT)

Group I - Drugs for Acute Gout (Anti-inflammatory, reduce acute attack)

1. NSAIDs - Indomethacin, Naproxen, Etoricoxib, Diclofenac
2. Colchicine - Highly specific for gout
3. Corticosteroids - Systemic (prednisolone) or intraarticular
4. IL-1 Inhibitors - Anakinra, Canakinumab (for refractory attacks)

Group II - Drugs for Chronic Gout (Urate-lowering therapy, ULT)

• Probenecid
• Sulfinpyrazone
• Benzbromarone
• (Note: High-dose aspirin > 3 g/day is also uricosuric, but low doses are uricosuric. Losartan has mild uricosuric effect)

• Allopurinol (non-selective inhibitor)
• Febuxostat (selective, non-purine XO inhibitor)

• Rasburicase (recombinant uricase - for tumor lysis syndrome)
• Pegloticase (PEGylated recombinant uricase - for refractory chronic tophaceous gout)

---

Management of Acute Gout Attack

1. NSAIDs (Drug of Choice for Acute Gout - KDT)

• 50 mg TDS for 2-3 days, then taper
• Most potent anti-inflammatory NSAID

• Naproxen 500-750 mg initially, then 250-500 mg TDS (well-tolerated)
• Etoricoxib 120 mg once daily (COX-2 selective; preferred in patients with GI risk)
• Diclofenac 50 mg TDS

2. Colchicine

• Loading dose: 1 mg oral
• Then: 0.5 mg 1 hour later
• Subsequently: 0.5-1 mg BD (for prophylaxis)
• Old high-dose regimen (now ABANDONED): 0.5-1 mg every 2 hours until relief or GI side effects - caused severe diarrhea, nausea

• GI toxicity (most common): Nausea, vomiting, diarrhea, abdominal cramps (dose-limiting)
• Bone marrow suppression: Leukopenia, thrombocytopenia, agranulocytosis (with high doses/long-term use)
• Myopathy/neuropathy: Proximal muscle weakness, elevated CPK (especially with long-term use or renal failure)
• Alopecia (with prolonged use)
• Azoospermia (reversible, with prolonged use)
• Teratogenicity (avoid in pregnancy)

• Cyclosporine, clarithromycin, ketoconazole (P-glycoprotein inhibitors and CYP3A4 inhibitors) → dramatically increase colchicine levels → severe toxicity (fatal cases reported)
• Statins (risk of myopathy)

• Familial Mediterranean Fever (FMF) - prophylaxis (0.5-1 mg/day; drug of choice)
• Pericarditis - acute and recurrent (reduces recurrence)
• Behcet's disease
• Primary biliary cholangitis

3. Corticosteroids

• Prednisolone 30-40 mg/day orally for 3-5 days, then taper
• Methylprednisolone IV for severe attacks (40-125 mg)
• Intraarticular triamcinolone 40 mg - for monoarticular gout
• Used when NSAIDs and colchicine are contraindicated (renal failure, GI intolerance)
• Rapid response

---

Management of Chronic Gout (Urate-Lowering Therapy - ULT)

• ≥2 attacks per year
• Presence of tophi
• Chronic gouty arthropathy
• Renal stones (uric acid)
• Renal impairment due to gout
• Very high serum uric acid (> 9 mg/dL) even asymptomatic in some guidelines

---

1. Allopurinol (Drug of Choice for Chronic Gout)

• Structural analogue of hypoxanthine
• Competitive inhibitor of xanthine oxidase (XO) - enzyme that converts hypoxanthine → xanthine → uric acid
• Active metabolite oxypurinol is a non-competitive XO inhibitor (longer-acting)
• Result: Hypoxanthine and xanthine accumulate (more soluble than uric acid) and are excreted in urine; uric acid synthesis ↓ by 60-70%

• Acute gout flares (at initiation - due to mobilization of urate)
• Allopurinol hypersensitivity syndrome (AHS): Severe rash (SJS/TEN), fever, hepatitis, eosinophilia, renal failure; fatal in ~20-25% of cases
  • Associated with HLA-B*5801 allele (common in Han Chinese, Thai, Korean populations) - genetic testing recommended in these populations before starting allopurinol
• Skin rash (maculopapular - 2-3%; may escalate to AHS - stop immediately)
• GI disturbances: Nausea, diarrhea
• Hepatotoxicity (transient elevation of liver enzymes)
• Peripheral neuropathy (rare)

• 6-Mercaptopurine (6-MP) and Azathioprine - allopurinol inhibits XO → 6-MP metabolism blocked → accumulation → severe bone marrow toxicity. Dose reduction of 6-MP/AZA by 75% required if combined.
• Ampicillin - increases incidence of rash
• Warfarin - enhanced anticoagulant effect (inhibits warfarin metabolism)
• Cyclosporine - increased cyclosporine levels
• Theophylline - increased theophylline levels

---

2. Febuxostat (KDT 8th Ed)

• No dose adjustment needed in mild-moderate renal impairment (metabolized hepatically)
• Does not interact with 6-MP/azathioprine (at standard doses)
• Alternative in patients who cannot tolerate or are allergic to allopurinol

• Acute gout flares (at initiation)
• GI disturbances
• Liver function abnormalities
• Cardiovascular events (FDA black box warning 2019 - increased risk of cardiovascular death compared to allopurinol in patients with established CVD - CARES trial)
• Skin rash

---

3. Probenecid (Uricosuric)

• GI disturbances (nausea, vomiting)
• Nephrolithiasis (uric acid stones due to increased urinary uric acid - prevent by adequate hydration and urine alkalinization)
• Hypersensitivity (rash)
• Salicylate interaction (aspirin even low-dose abolishes uricosuric effect)

• Aspirin (even 1-2 g/day) blocks uricosuric effect of probenecid → avoid combination
• Probenecid inhibits tubular secretion of: penicillins, cephalosporins, indomethacin, methotrexate, zidovudine → increases their plasma levels
• Penicillin + probenecid: Classic combination used historically to increase penicillin levels

• Renal stones (uric acid)
• Renal impairment (GFR < 30-50 mL/min) - ineffective
• Acute gout attack (at initiation)
• Patient on salicylates (aspirin)

---

4. Benzbromarone

• More potent uricosuric than probenecid
• Used when probenecid fails or is not tolerated
• ADR: Severe hepatotoxicity (serious - drug restricted in many countries)
• Available in India

---

5. Rasburicase

• Recombinant uricase (urate oxidase) - converts uric acid to allantoin (more water-soluble)
• IV infusion
• Used for: Tumor lysis syndrome (prevention/treatment in cancer patients receiving chemotherapy)
• Contraindicated in G6PD deficiency (allantoin oxidation generates H2O2 → hemolysis)
• Short-term use only; not for chronic gout maintenance

---

6. Pegloticase

• PEGylated recombinant uricase
• IV infusion every 2 weeks
• For refractory chronic tophaceous gout not responding to allopurinol/febuxostat
• ADR: Infusion reactions, gout flares, immunogenicity

---

Summary Table: Acute vs Chronic Gout Management

---

Specific Clinical Situations (KDT)

---