Which of the following is the primary mechanism by which NSAIDs cause gastric ulceration?

Explanation

## NSAID-Induced Gastric Ulceration: Mechanism **Key Point:** NSAIDs cause gastric ulcers primarily by inhibiting COX-1 in gastric mucosa, which reduces protective prostaglandin (PGE₂ and PGI₂) synthesis. This leads to decreased mucus and bicarbonate secretion, compromising the mucosal barrier. ### Protective Role of Prostaglandins in Gastric Mucosa 1. **PGE₂ and PGI₂ stimulate:** - Mucus secretion (forms protective layer) - Bicarbonate secretion (neutralizes acid) - Mucosal blood flow (maintains integrity) - Epithelial cell proliferation and repair 2. **When NSAIDs block COX-1:** - Prostaglandin production ↓ - Mucus barrier ↓ - Bicarbonate secretion ↓ - Mucosal blood flow ↓ - Result: **ulcer formation** ### COX-1 vs COX-2 Selectivity and GI Risk | NSAID Type | COX-1 Inhibition | COX-2 Inhibition | GI Risk | | --- | --- | --- | --- | | Non-selective (Ibuprofen, Naproxen) | ✓✓✓ | ✓✓ | **High** | | Selective COX-2 (Celecoxib) | ✗ | ✓✓✓ | **Lower** | **High-Yield:** COX-1 is constitutively expressed in gastric mucosa and is responsible for baseline prostaglandin production. This is why **non-selective NSAIDs have higher GI toxicity** than selective COX-2 inhibitors. **Clinical Pearl:** Gastroprotection strategies include: - **PPI** (omeprazole, pantoprazole) — reduces acid - **Misoprostol** — exogenous prostaglandin analog; restores protective PGE₂ effect - **H₂-receptor antagonists** — less effective than PPIs for NSAID-induced ulcers **Mnemonic:** **NSAID GI toxicity = COX-1 ↓ → PG ↓ → Mucus & HCO₃⁻ ↓ → Ulcer**