Eicosanoid Biochemistry
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Direct answer
Twenty-carbon arachidonic acid, released from membrane phospholipid sn-2 positions by phospholipase A2, feeds three oxygenating pathways: constitutive and inducible cyclooxygenases (COX-1 and COX-2) that make prostaglandins, prostacyclin and thromboxane; 5-lipoxygenase that makes leukotrienes; and cytochrome P450 epoxygenases making epoxyeicosatrienoic acids. Eicosanoids are local, short-lived hormones (eicosa is Greek for twenty) acting on G-protein-coupled receptors at or near their site of synthesis. The examinable pharmacology falls straight out of the chemistry: aspirin irreversibly acetylates both COX isoforms; thromboxane A2 constricts and aggregates platelets while endothelial prostacyclin opposes it; and the cysteinyl leukotrienes are the slow-reacting substance of anaphylaxis, central to asthma.
What you must remember
- Precursor chemistry: arachidonic acid is 5,8,11,14-eicosatetraenoic acid (omega-6), stored in membrane phosphatidylinositol and choline phospholipids; liberated by phospholipase A2, itself activated by G-protein-coupled receptor calcium signals.
- Rate-limiting and drug target: cyclooxygenase (prostaglandin endoperoxide synthase) converts arachidonate to PGH2 through a cyclooxygenase and a peroxidase activity on the same protein; aspirin acetylates serine-530 irreversibly, non-selective NSAIDs compete reversibly.
- Platelet-endothelium balance: platelet thromboxane A2 (COX-1) promotes aggregation and vasoconstriction with a half-life of about 30 seconds; endothelial prostacyclin (PGI2, mainly COX-2) raises cyclic AMP and prevents aggregation — low-dose aspirin tips the balance by acetylating anucleate platelets for their lifetime.
- Leukotriene arm: 5-lipoxygenase with FLAP makes leukotriene A4; LTB4 is a potent neutrophil chemotaxin; LTC4, LTD4 and LTE4 compose the slow-reacting substance of anaphylaxis, bronchoconstrictors a thousand times stronger than histamine; zileuton inhibits the enzyme, montelukast blocks the CysLT1 receptor.
- COX-2 selectivity: induced at inflammatory sites by cytokines and inhibited relatively selectively by celecoxib (and formerly rofecoxib), trading gastrointestinal toxicity for thrombotic risk — the mechanistic story behind rofecoxib's withdrawal.
- Numbered shorthand: prostaglandin series 2 derives from arachidonate (two double bonds retained); series 1 from dihomo-gamma-linolenic acid; series 3 from eicosapentaenoic acid of fish oil, basis of omega-3 supplementation shifting eicosanoid balance.
- Non-steroidal side-effect logic: gastric cytoprotective prostaglandins (PGE2, COX-1) and renal vasodilator prostaglandins explain NSAID dyspepsia, ulceration and analgesic nephropathy; misoprostol is a PGE1 analogue given as gastric protection.
How to work through an aspirin-pharmacology case
A man with a coronary stent on low-dose aspirin develops arthritic knee pain and starts a conventional NSAID; his cardiologist objects. Reason from enzyme kinetics: low-dose aspirin (75-150 milligrams) exploits the portal exposure of the anucleate platelet — with no nucleus it cannot resynthesise the acetylated enzyme for its 7-10 day lifespan, so thromboxane generation stays suppressed while endothelial cells, which retain nuclei, regenerate COX and keep making prostacyclin. A reversible non-selective NSAID taken regularly competes for the same active channel and can blunt the antiplatelet effect; COX-2-selective agents spare platelets but remove prostacyclin, tilting the balance the other way, the vascular risk that ended rofecoxib.
Now the asthma mirror: a patient with aspirin-exacerbated respiratory disease worsens on NSAIDs because blocking the COX arm diverts arachidonate through 5-lipoxygenase, flooding cysteinyl leukotrienes that were already driving nasal polyposis and bronchospasm. Leukotriene receptor antagonists like montelukast are the rational add-on, a daily Indian outpatient prescription. The unifying principle: one substrate, two major enzymatic funnels, and drugs that redirect rather than delete.
Where students slip
Students call prostaglandins hormones carried in blood; they are autacoids, inactivated by 15-hydroxyprostaglandin dehydrogenase during a single pulmonary passage, which is why they act locally and are not measured as circulating hormones. The second slip is labelling COX-2 purely "the inflammatory isoform" — it is constitutive in endothelium and kidney, which is exactly why selective inhibitors raised blood pressure and thrombosis. Third, thromboxane synthase lives in platelets and prostacyclin synthase in endothelium; when a question asks why aspirin benefits coronary disease, the asymmetry of the nucleus (platelets lack one) is the answer expected.
Frequently asked questions
What releases arachidonic acid from membrane phospholipids?
Phospholipase A2, activated by receptor-driven calcium signals and inhibited indirectly by glucocorticoid-induced lipocortin.
How does low-dose aspirin achieve its antiplatelet effect?
Irreversible acetylation of platelet COX-1 abolishes thromboxane A2 synthesis for the platelet's lifetime, while nucleated endothelium regenerates prostacyclin capacity.
Which eicosanoids constitute slow-reacting substance of anaphylaxis?
LTC4, LTD4 and LTE4, the cysteinyl leukotrienes from the 5-lipoxygenase pathway; they bronchoconstrict powerfully and are targeted by montelukast and zileuton.
Why do COX-2 selective inhibitors carry cardiovascular risk?
They spare platelet thromboxane production while suppressing endothelial prostacyclin, shifting the haemostatic balance toward aggregation.
Which prostaglandin protects the gastric mucosa?
PGE2 maintains mucus and bicarbonate secretion and mucosal blood flow through COX-1; its loss explains NSAID gastropathy and is the rationale for misoprostol.