Anti-Inflammatory Drugs · Module 1 of 4

NSAIDs — Mechanisms, Pharmacokinetics, and COX Selectivity

Arachidonic acid cascade, COX isoform biology, and aspirin pharmacology

NSAIDs block COX but not lipoxygenase — when COX is inhibited, more arachidonic acid shifts into the LOX pathway, increasing leukotriene synthesis; this leukotriene shunting is the mechanism of AERD, in which any COX-1-inhibiting NSAID triggers severe bronchoconstriction in susceptible patients (~10–20% of asthmatics, 30% of those with nasal polyps); glucocorticoids act upstream via PLA2 inhibition (annexin A1), blocking both COX and LOX branches simultaneously — explaining their broader anti-inflammatory potency.
The cardiovascular risk of selective COX-2 inhibitors follows directly from their mechanism — vascular endothelium constitutively uses COX-2 to produce PGI2 (antiplatelet, vasodilatory); COX-2 selective agents suppress endothelial PGI2 while leaving platelet TXA2 (pro-aggregatory, vasoconstrictive) fully intact, creating a prothrombotic imbalance; naproxen has the most favorable cardiovascular profile among nonselective NSAIDs due to sustained COX-1 inhibition providing a partial antiplatelet effect from its long half-life.
Aspirin uniquely irreversibly acetylates COX-1 at a serine residue — all other NSAIDs are reversible; in anucleate platelets this means permanent TXA2 suppression for the platelet’s 8–10 day lifespan, while endothelial cells (nucleated) regenerate COX-2/PGI2 between daily doses; this asymmetry is the pharmacological basis of low-dose aspirin’s selective antiplatelet effect and explains why only ~75–325 mg/day is needed for cardiovascular protection.
Ibuprofen can block aspirin’s antiplatelet effect — ibuprofen occupies the COX-1 active site reversibly and can prevent aspirin from accessing the serine residue for irreversible acetylation; patients on aspirin for cardiovascular protection must take aspirin at least 30 minutes before ibuprofen, or substitute naproxen (which does not interfere); enteric-coated aspirin should not be used as the loading dose in ACS because delayed absorption misses the critical early window.
All NSAIDs are CYP2C9 substrates and highly protein-bound — fluconazole and amiodarone (CYP2C9 inhibitors) raise NSAID plasma concentrations and increase toxicity risk; enteric coating delays absorption without reducing gastric toxicity (GI injury is a systemic prostaglandin-suppression effect, not a local contact effect); half-life governs dosing interval: ibuprofen/diclofenac/ketorolac are short-acting; naproxen/meloxicam/piroxicam allow once or twice daily dosing but have slower offset when adverse effects occur.

Abbreviations: COX = cyclooxygenase · PGE2 = prostaglandin E2 · PGI2 = prostacyclin · TXA2 = thromboxane A2 · LOX = lipoxygenase · PLA2 = phospholipase A2 · AA = arachidonic acid · AERD = aspirin-exacerbated respiratory disease · CYP2C9 = cytochrome P450 2C9 · PPI = proton pump inhibitor · SSRI = selective serotonin reuptake inhibitor · ARB = angiotensin receptor blocker · eGFR = estimated glomerular filtration rate · ACS = acute coronary syndrome

Arachidonic Acid Cascade — Branch Points and Drug Targets

Membrane Phospholipids

PLA2 releases arachidonic acid on cell activation; glucocorticoids → annexin A1 → PLA2 inhibition (upstream block of ALL eicosanoids)

→

COX Pathway ← NSAIDs block here

AA → PGH2 → PGE2 (pain, fever, inflammation, gastric protection), PGI2 (endothelial antiplatelet), TXA2 (platelet aggregation)

↓ shunts

LOX Pathway ← NSAIDs do NOT block

AA → leukotrienes → bronchoconstriction and allergic inflammation; when COX blocked, more AA diverts here (AERD mechanism)

COX-1 vs. COX-2 — Expression, Function, and Selectivity Consequences

Constitutive — Homeostatic Prostaglandins

COX-1

Expressed in most tissues including gastric mucosa, platelets, kidney
Gastric mucosa: PGE2/PGI2 drive mucus, bicarbonate, blood flow, and acid inhibition
Platelets: TXA2 → platelet aggregation and vasoconstriction
Kidney: maintains GFR and perfusion under physiological stress
Inhibition = GI toxicity, platelet dysfunction, renal risk — the class-wide NSAID adverse effect profile

Inducible — Inflammatory + Endothelial COX-2

COX-2

Induced by cytokines and inflammatory stimuli → PGE2 mediates pain, fever, inflammation
Constitutive in vascular endothelium → PGI2 (antiplatelet, vasodilatory)
Selective COX-2 inhibitors: less gastric mucosal injury (spares COX-1 gastric protection)
Selective COX-2 inhibitors: suppress endothelial PGI2 while platelets’ TXA2 intact → prothrombotic imbalance → CV risk
GI benefit of COX-2 selectivity attenuated when patient also takes low-dose aspirin

Key NSAID Agents — Selectivity, Properties, and Clinical Notes

Agent	Selectivity	Half-life	Key Clinical Points
Ibuprofen	Nonselective	2 h	Blocks aspirin’s access to platelet COX-1 — take aspirin ≥30 min first; or switch to naproxen. OTC availability; rapid offset
Naproxen	Nonselective	12–15 h	Preferred NSAID in patients with cardiovascular risk — sustained COX-1 inhibition provides partial antiplatelet effect; twice-daily dosing
Indomethacin	Nonselective (potent)	4–5 h	First-line for acute gout and pseudogout; IV to close PDA in neonates; high CNS adverse effects (headache, dizziness) limit chronic use
Ketorolac	Nonselective (potent)	5–6 h	Only parenteral NSAID (IM/IV); opioid-comparable analgesia; limited to 5 days maximum (renal/GI toxicity)
Diclofenac	COX-2 preferential	2 h	Hepatotoxicity signal: transaminase elevations more common than other NSAIDs — monitor LFTs in prolonged use; CV risk similar to COX-2 selective agents at high doses
Celecoxib	COX-2 selective	11 h	Less GI mucosal injury; preferred in AERD (no COX-1 inhibition at therapeutic doses — no leukotriene shunting); moderate CYP2D6 inhibitor (metoprolol, codeine). GI advantage lost if patient also takes aspirin
Aspirin (low dose)	Irreversible COX-1	15–20 min (aspirin) → 8–10 day platelet effect	Irreversible platelet COX-1 acetylation; endothelium regenerates COX-2/PGI2 between doses; use plain (not enteric-coated) for ACS loading; requires daily dosing

Aspirin Dose-Response and High-Yield Drug Interactions

Aspirin dose-response: 75–325 mg/day → irreversible platelet COX-1 acetylation → permanent TXA2 suppression for platelet lifespan; endothelium recovers PGI2 between doses (selective antiplatelet). 300–1,000 mg/dose → analgesia and antipyresis. 3,000–6,000 mg/day → anti-inflammatory. Toxic doses → tinnitus, hyperventilation, respiratory alkalosis then metabolic acidosis. At high anti-inflammatory doses, conjugation pathways saturate and elimination shifts to renal excretion of unchanged salicylate — small dose increases produce disproportionate concentration rises. Alkalinizing the urine traps ionized salicylate in the tubular lumen and dramatically accelerates elimination (used in salicylate toxicity management).

High-yield drug interactions: NSAIDs + ACE inhibitor/ARB + diuretic (“triple whammy”) → markedly elevated AKI risk — avoid; monitor creatinine in 1–2 weeks if unavoidable. NSAIDs + lithium → reduced renal lithium clearance → toxicity; check levels within 5–7 days. NSAIDs + high-dose methotrexate (>15 mg/week) → impaired methotrexate excretion; avoid within 24 hours of infusion. NSAIDs + SSRIs → additive GI bleeding risk (SSRIs deplete platelet serotonin; NSAIDs suppress TXA2) → co-prescribe PPI. NSAIDs + warfarin/DOACs → multiplicative GI bleed risk → avoid or use PPI. CYP2C9 inhibitors (fluconazole, amiodarone) → raise NSAID concentrations.

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