Acetaminophen produces analgesia and antipyresis but overdose is dangerous because hepatic CYP2E1 converts it to the toxic metabolite NAPQI, which is normally detoxified by glutathione. In overdose glutathione is depleted and centrilobular hepatic necrosis ensues, so the antidote N-acetylcysteine replenishes glutathione stores and is most effective when given early. Aspirin irreversibly inhibits COX-1 and COX-2, blocking thromboxane A2 in platelets (antithrombotic) and reducing prostaglandin synthesis (analgesic, antipyretic, anti-inflammatory). Aspirin overdose creates a characteristic mixed acid-base disturbance: early respiratory alkalosis from direct medullary stimulation followed by anion-gap metabolic acidosis from uncoupled oxidative phosphorylation. Aspirin should be avoided in children with viral illness because of Reye syndrome, an acute hepatic encephalopathy with mitochondrial dysfunction.
NSAIDs share COX inhibition but have distinct safety profiles. Nonselective NSAIDs cause GI bleeding because COX-1 inhibition depletes protective gastric prostaglandins (PGE2, PGI2) that maintain mucus, bicarbonate, and mucosal blood flow. Renal prostaglandin inhibition reduces afferent arteriolar dilation, lowering GFR and predisposing to acute interstitial nephritis and papillary necrosis in volume-depleted, elderly, or CKD patients. Celecoxib selectively inhibits COX-2, sparing antiplatelet activity but raising cardiovascular and thrombotic risk.
Gout therapy uses NSAIDs (indomethacin, naproxen) as first-line for acute flares, with colchicine as an alternative within the first 24 hours; colchicine binds tubulin to impair microtubule polymerization and neutrophil chemotaxis, with diarrhea as its main toxicity and myelosuppression with chronic use. Allopurinol and febuxostat inhibit xanthine oxidase to lower uric acid synthesis, with a critical drug interaction warning for azathioprine (also metabolized by xanthine oxidase). Febuxostat is a non-purine alternative used in allopurinol intolerance but carries a higher cardiovascular death warning. Probenecid is a uricosuric that blocks proximal tubular reabsorption of uric acid but is ineffective when GFR is reduced and can precipitate urate stones. Rasburicase, a recombinant urate oxidase that converts uric acid to soluble allantoin, is reserved for tumor lysis syndrome and is contraindicated in G6PD deficiency.