Phospholipase A2 (PLA2) liberates arachidonic acid from membrane phospholipids on inflammatory or hormonal cue. AA flows through two main enzymatic branches: cyclooxygenase (COX-1 constitutive + COX-2 inducible) → prostaglandin H2 → tissue-specific prostaglandins (PGE2 pain/fever, PGI2 vasodilator, TXA2 platelet aggregation) — NSAID + coxib target. Lipoxygenase (5-LOX) → leukotriene A4 → LTB4 (chemotaxis), LTC4/D4/E4 (cysteinyl leukotrienes — asthma + allergic rhinitis) — montelukast / zileuton target. Glucocorticoids inhibit PLA2 (via lipocortin/annexin-1 induction), blocking the entire cascade upstream.
Organ Systems
cardiovascular
immune-hematologic
reproductive
Pathway Steps
arachidonic-acid → prostaglandin-h2 — via COX-1 / COX-2 — NSAID + COXIB TARGET. Cyclooxygenase (constitutive COX-1, inducible COX-2) makes the prostanoid precursor PGH2 and is the NSAID target. Aspirin irreversibly acetylates COX (permanently in anucleate platelets); COX-2-selective coxibs spare gastric COX-1 but raise CV risk by shifting the TXA2/prostacyclin balance.
prostaglandin-h2 → prostaglandin-e2 — via PGE synthase (mPGES-1 inducible). PGE2 (via inducible mPGES-1) drives inflammation, pain, hypothalamic fever, and gastric mucosal protection — the last being why COX inhibition causes ulcers. It also keeps the fetal ductus arteriosus open, the basis of indomethacin closure.
prostaglandin-h2 → thromboxane-a2 — via thromboxane synthase (platelet-restricted). Platelet thromboxane synthase makes TXA2, a potent vasoconstrictor and platelet aggregator. Low-dose aspirin’s antiplatelet action is irreversible knockout of platelet TXA2 (platelets cannot resynthesize COX), while endothelium recovers.
prostaglandin-h2 → prostacyclin — via prostacyclin synthase (endothelial). Endothelial prostacyclin (PGI2) opposes thromboxane — vasodilating and inhibiting platelet aggregation. The TXA2:PGI2 balance governs hemostasis and vascular tone (and underlies coxib CV risk); PGI2 analogs treat pulmonary hypertension.
arachidonic-acid → leukotriene-a4 — via 5-lipoxygenase (5-LOX) + FLAP — ZILEUTON TARGET. 5-lipoxygenase (with FLAP) diverts arachidonate to leukotrienes rather than prostanoids and is the zileuton target. COX blockade can shunt substrate toward this LOX branch — a proposed mechanism of aspirin-exacerbated respiratory disease.
leukotriene-a4 → leukotriene-b4 — via LTA4 hydrolase (neutrophil chemotaxis). LTB4 is a powerful neutrophil chemoattractant and activator, central to neutrophilic inflammation (IBD, psoriasis) — distinct from the cysteinyl leukotrienes’ bronchoconstrictor role.
leukotriene-a4 → cysteinyl-leukotrienes — via LTC4 synthase → LTC4 → LTD4 → LTE4 — MONTELUKAST blocks CysLT1 receptor. LTC4/D4/E4 (the “slow-reacting substance of anaphylaxis”) drive bronchoconstriction, mucus, and vascular leak in asthma/allergy; montelukast and zafirlukast block the CysLT1 receptor.
diclofenac (inhibitor) — COX-1 + COX-2. NSAID; potent; CV-event signal at high doses (similar to selective COX-2)
indomethacin (inhibitor) — COX-1 + COX-2. NSAID; potent anti-inflammatory; gout + PDA closure in neonates; CNS side effects
meloxicam (inhibitor) — COX-2 preferential. NSAID; preferential COX-2 at low dose; OA
etoricoxib (inhibitor) — COX-2 selective. coxib; outside US; gout + OA + RA
arachidonic acid (substrate) — 20:4ω6 PUFA released by PLA2; COX/LOX/CYP substrate
epa (inhibitor) — AA-derived eicosanoid output (2-series PG, 4-series LT). EPA competes with arachidonic acid at COX/LOX; shifts output toward less-inflammatory 3-series prostaglandins + 5-series leukotrienes, and is a substrate for E-series resolvin biosynthesis.
dha (inhibitor) — membrane AA pool; AA-derived eicosanoid output. DHA incorporates into phospholipids, displacing AA from membrane pools and lowering COX/LOX substrate supply; precursor of D-series resolvins and protectins.
fish oil (inhibitor) — AA-derived eicosanoid output (via EPA + DHA membrane incorporation). Combined EPA+DHA marine source; suppresses AA-derived 2-series PG and 4-series LT via the EPA/DHA mechanisms above.