Which antiplatelet drug irreversibly inhibits platelet aggregation by covalently acetylating cyclooxygenase-1 (COX-1)?

Explanation

## Mechanism of Aspirin **Key Point:** Aspirin is the only antiplatelet agent that irreversibly acetylates COX-1, permanently blocking thromboxane A₂ (TXA₂) synthesis in platelets. ### Why Aspirin is Unique Aspirin's antiplatelet effect is **irreversible** because: 1. Platelets lack a nucleus and cannot synthesize new COX-1 enzyme 2. The acetyl group covalently binds to a serine residue in the COX-1 active site 3. Effect persists for the platelet lifespan (7–10 days) 4. Platelet function recovers only after new platelets are produced ### Comparison with Other Antiplatelet Agents | Drug | Mechanism | Reversibility | Onset | Offset | | --- | --- | --- | --- | --- | | **Aspirin** | COX-1 inhibition | **Irreversible** | 30 min | 7–10 days | | **Clopidogrel** | P2Y₁₂ ADP receptor antagonist | Reversible | 3–7 days | 5–7 days | | **Ticagrelor** | P2Y₁₂ ADP receptor antagonist | Reversible | 2–4 hours | 3–5 days | | **Dipyridamole** | Phosphodiesterase inhibitor | Reversible | 1–2 hours | 12–24 hours | **High-Yield:** The irreversible nature of aspirin's action makes it the drug of choice for long-term cardiovascular protection and explains why patients must discontinue it 5–7 days before elective surgery. **Clinical Pearl:** Aspirin's irreversible COX-1 inhibition also blocks prostacyclin synthesis in endothelial cells, but endothelial cells can regenerate COX-1, so the net antiplatelet effect dominates clinically. [cite:KD Tripathi 8e Ch 19]