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Botany 3% exam weight

Topic 7

Part of the INI CET (AIIMS PG) study roadmap. Botany topic pharma-007 of Botany.

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NSAIDs and Anti-inflammatory Drugs covers NSAIDs and anti-inflammatory drugs for INI CET (AIIMS PG).

Arachidonic Acid Pathway: Phospholipase A₂ (from cell membrane phospholipids) → Arachidonic acid

  • COX pathway (cyclooxygenase): → Prostaglandins (PGs) → PGE₂, PGI₂ (prostacyclin), TXA₂
  • LOX pathway (lipoxygenase): → Leukotrienes (LTs) → LTB₄, LTC₄, LTD₄, LTE₄

Prostaglandins — Key Effects:

  • PGE₂ & PGI₂: Vasodilation, protective gastric mucosa (↑mucus/bicarbonate secretion), renal blood flow, fever (pyrogenic)
  • TXA₂: Platelet aggregation, vasoconstriction (produced by platelets)
  • PGs + Pain: Sensitize nociceptors to pain (hyperalgesia) — lower pain threshold

NSAIDs — Mechanism:

  • Non-selective NSAIDs: Inhibit both COX-1 and COX-2 → ↓ prostaglandin synthesis
  • COX-1: Constitutive (always present) — gastric mucosa protection, platelet TXA₂, renal blood flow
  • COX-2: Inducible (inflammation activates it) — mediates pain, fever, inflammation
  • COXIBs (COX-2 selective): Celecoxib, Etoricoxib — ↓ inflammation with theoretically fewer GI effects

NSAID Side Effects (crucial for INI CET (AIIMS PG)):

  1. GI toxicity (most common — COX-1 inhibition): Gastric ulcers, bleeding — PGE₂ is gastroprotective
  2. Renal toxicity: ↓ prostaglandins → ↓ renal blood flow → acute kidney injury, interstitial nephritis (especially with chronic use)
  3. Bleeding (non-selective NSAIDs): ↓ platelet aggregation → ↑ bleeding time (COX-1 inhibition in platelets → ↓TXA₂)
  4. CV risk (COX-2 selective): ↑ thrombotic events (COX-2 inhibition → ↓ PGI₂ without ↓TXA₂ → net prothrombotic state) — Vioxx (rofecoxib) withdrawn for ↑MI risk
  5. Asthma exacerbation: Some patients (especially with nasal polyps) — cross-sensitivity with aspirin (leukotrienes path not blocked)
  6. Aplastic anemia: Phenylbutazone (withdrawn) — bone marrow suppression

Specific NSAIDs:

  • Aspirin (Acetylsalicylic acid): Irreversible COX inhibition (acetylates serine residue) → ↓TXA₂ (antiplatelet) + ↓PGs; low dose (75mg) for cardiovascular prophylaxis; high dose for anti-inflammatory; Reye syndrome in children (avoid in viral illness)
  • Ibuprofen: Reversible COX inhibition; antipyretic, analgesic, anti-inflammatory
  • Diclofenac: Potent NSAID; hepatotoxic (black box warning)
  • Indomethacin: Very potent; used in gout (excretion of urate), patent ductus arteriosus (PDA) closure; significant CNS side effects
  • Naproxen: Long half-life; similar to ibuprofen but longer duration
  • Celecoxib: COX-2 selective; less GI toxicity but ↑CV risk

Paracetamol (Acetaminophen):

  • Analgesic + antipyretic but MINIMAL anti-inflammatory activity
  • Mechanism: Inhibits COX-3 (splice variant of COX-1) in CNS; also inhibits peroxidase activity of COX-1/COX-2 at low concentrations
  • Metabolism: Glucuronidation + sulfation (safe); CYP2E1 → NAPQI (toxic — glutathione normally detoxifies)
  • Overdose: Depleted glutathione → NAPQI accumulates → hepatic necrosis (centrilobular)
  • Antidote: N-acetylcysteine (NAC) — replenishes glutathione; most effective within 8–10 hours
  • Does NOT cause GI toxicity or platelet dysfunction — safe in peptic ulcer disease, bleeding risk, asthma

⚡ Exam Tip for INI CET (AIIMS PG): Aspirin is CONTRAINDICATED in children with viral illness (Reye syndrome — hepatic encephalopathy). Aspirin is also CONTRAINDICATED in last trimester of pregnancy (premature closure of ductus arteriosus).