naproxen

**Class/Mechanism:** Propionic acid derivative NSAID (like ibuprofen, ketoprofen, flurbiprofen). Reversibly inhibits cyclooxygenase-1 and -2, decreasing conversion of arachidonic acid to prostaglandins (PGE2, PGI2) and thromboxane A2. This reduces inflammation, pain (decreased sensitization of nociceptors), and fever (decreased hypothalamic PGE2). Unlike aspirin, inhibition is reversible, so antiplatelet effect lasts only as long as drug is present.

**Pharmacokinetics:** Well absorbed orally; highly albumin-bound (>99%); hepatic metabolism (glucuronidation, demethylation), renal excretion. Half-life ~12-17 h, so dosed twice daily (ibuprofen ~2 h, needs TID-QID). OTC (Aleve) and prescription forms.

**Indications:** Osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute gout, tendinitis/bursitis, primary dysmenorrhea, mild-moderate pain, fever, migraine (acute treatment/menstrual migraine prophylaxis). Also used for pericarditis (in some cases) and as a tocolytic/PDA closure agent is an indomethacin/ibuprofen association rather than naproxen.

**Adverse effects (high-yield):** - **GI:** Gastritis, peptic ulcer, GI bleeding (loss of protective PGE2 → decreased mucus/bicarbonate and mucosal blood flow, increased acid). Mitigate with PPI or misoprostol (PGE1 analog). - **Renal:** Inhibition of vasodilatory prostaglandins at the afferent arteriole → decreased GFR, acute kidney injury (especially with ACE inhibitors/ARBs + diuretics, "triple whammy"), interstitial nephritis, papillary necrosis, fluid retention, hyperkalemia. - **Cardiovascular:** Increased risk of MI/stroke and hypertension, blunted effect of antihypertensives; naproxen is considered to have the lowest/neutral CV risk among NSAIDs (possibly due to more sustained platelet inhibition). Contraindicated in the peri-CABG setting (boxed warning). - **Hematologic:** Impaired platelet function → prolonged bleeding time (reversible). - **Hypersensitivity:** Bronchospasm in aspirin-exacerbated respiratory disease (asthma, nasal polyps, aspirin sensitivity), urticaria; cross-reactivity with other NSAIDs. - **Other:** Hepatotoxicity (rare), CNS effects, pseudoporphyria (photosensitive blistering, classically with naproxen), and avoidance in late pregnancy (premature PDA closure, oligohydramnios).

**Interactions:** Warfarin (↑ bleeding), lithium (↓ renal clearance → toxicity), methotrexate (↓ clearance), ACEi/ARB/diuretics (AKI, reduced efficacy), SSRIs/corticosteroids (↑ GI bleeding), concurrent aspirin (may interfere with aspirin's antiplatelet effect and increases GI risk).

**Boards pearls:** - Nonselective NSAIDs vs. celecoxib (selective COX-2; sulfa allergy caution, less GI toxicity, maintained CV risk, no platelet effect). - NSAIDs: Antipyretic, analgesic, anti-inflammatory; acetaminophen lacks significant anti-inflammatory effect. - Aspirin irreversibly inhibits COX; other NSAIDs are reversible. - Avoid in patients with CKD, heart failure, peptic ulcer disease, and in the third trimester of pregnancy. - Pseudoporphyria is a classic naproxen association.