COX-2

COX-2 (prostaglandin-endoperoxide synthase 2) is one of two major cyclooxygenase isoforms that catalyze the rate-limiting step in prostaglandin synthesis from arachidonic acid. While COX-1 is constitutively expressed in most tissues (gastric mucosa, platelets, kidney) and maintains homeostatic functions such as gastric cytoprotection and platelet thromboxane A2 production, COX-2 is primarily induced by inflammatory stimuli (cytokines, growth factors, endotoxins) in macrophages, synoviocytes, and endothelial cells, producing prostaglandins (especially PGE2) that mediate inflammation, pain, and fever. COX-2 also plays roles in renal blood flow autoregulation and is constitutively expressed in some tissues like the kidney and brain. Clinically, COX-2 selective inhibitors (coxibs: celecoxib, rofecoxib [withdrawn]) were developed to provide anti-inflammatory/analgesic effects similar to nonselective NSAIDs while sparing COX-1-mediated gastric protection, reducing GI ulceration/bleeding risk. However, because COX-2 inhibition reduces prostacyclin (PGI2, antithrombotic) without affecting COX-1-derived thromboxane A2 (prothrombotic) in platelets, coxibs shift the hemostatic balance toward thrombosis, increasing risk of myocardial infarction and stroke—this led to rofecoxib's market withdrawal. COX-2 inhibitors still carry renal toxicity risk similar to nonselective NSAIDs (afferent arteriole vasoconstriction, decreased GFR, sodium/water retention, hyperkalemia) because COX-2 contributes to renal prostaglandin synthesis. Aspirin, in contrast, irreversibly inhibits both COX-1 and COX-2 but at low doses preferentially inhibits platelet COX-1, providing cardioprotective antiplatelet effects. Understanding COX-1 vs COX-2 selectivity is essential for predicting NSAID side effect profiles, especially regarding GI bleeding risk vs cardiovascular risk, which is frequently tested on USMLE Step 1 and Step 2.