The mechanism by which COX-2 selective inhibitors (e.g., celecoxib) increase cardiovascular risk compared to non-selective NSAIDs is best explained by:
- A Direct inhibition of cardiac COX-2, reducing prostaglandin E2-mediated cardioprotection during ischemia
- B Upregulation of COX-1 in platelets, increasing thromboxane A2 production as a compensatory mechanism
- C Selective suppression of COX-2-derived endothelial prostacyclin (PGI2 — antithrombotic and vasodilatory) while sparing platelet COX-1-derived thromboxane A2 (prothrombotic), creating a prothrombotic imbalance ✓
- D Inhibition of renal COX-2-derived prostaglandins, causing sodium retention and hypertension as the sole cardiovascular mechanism
Explanation
Vascular endothelium uses predominantly COX-2 for prostacyclin (PGI2) synthesis — a potent vasodilator and platelet aggregation inhibitor. Platelets express only COX-1 for thromboxane A2 (TXA2) synthesis — a vasoconstrictor and platelet activator. COX-2 selective inhibitors reduce vascular PGI2 without affecting platelet TXA2 production, shifting the physiological TXA2/PGI2 balance toward thrombosis and vasoconstriction. This was demonstrated in the APPROVE trial (rofecoxib withdrawal). Renal effects cause secondary hypertension but the prothrombotic PGI2/TXA2 imbalance is the primary mechanism of atherothrombotic events.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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