Prostaglandins, Leukotrienes & Eicosanoids

Eicosanoids are 20-carbon, oxygenated derivatives of polyunsaturated fatty acids (chiefly arachidonic acid) that act as short-range, local "autacoids" governing inflammation, vascular tone, platelet behaviour, gastric protection, parturition and renal blood flow. For NEET PG this is a high-yield, easy-scoring crossover between biochemistry and pharmacology — the COX/LOX pathways, the antagonistic TXA₂–prostacyclin pair, and aspirin's irreversible acetylation of COX recur almost every year.

Definition and classification

The word eicosanoid comes from the Greek eikosi = twenty, reflecting the 20-carbon backbone. They are not stored; they are synthesised on demand from membrane phospholipids, act locally (paracrine/autocrine) and are rapidly degraded, so they have a very short half-life (seconds to minutes).

The major families are derived from arachidonic acid (AA), an ω-6 fatty acid (20:4, with four double bonds). Two principal enzymatic routes exist:

• Cyclooxygenase (COX) pathway → prostaglandins (PGs), prostacyclin (PGI₂), thromboxanes (TXA₂/TXB₂). Collectively the "prostanoids".
• Lipoxygenase (LOX) pathway → leukotrienes (LTs), lipoxins, HETEs.
• A minor cytochrome P450 (epoxygenase) pathway → epoxyeicosatrienoic acids (EETs).

Family	Key enzyme	Major products	Headline action
Prostaglandins	COX-1 / COX-2	PGE₂, PGD₂, PGF₂α, PGI₂	Inflammation, pain, fever, gastric protection
Thromboxane	COX + thromboxane synthase	TXA₂	Platelet aggregation, vasoconstriction
Prostacyclin	COX + prostacyclin synthase	PGI₂	Vasodilation, anti-aggregation
Leukotrienes	5-LOX	LTB₄, LTC₄, LTD₄, LTE₄	Chemotaxis, bronchoconstriction
Lipoxins	12/15-LOX	LXA₄, LXB₄	Pro-resolution, anti-inflammatory

High-yield: Prostanoids contain a cyclopentane ring (made by COX); leukotrienes are linear (no ring) and are named for the conjugated triene they contain and their origin in leukocytes.

Nomenclature and the subscript number

Prostaglandins are named PG + a letter (A–I) denoting the substituents on the cyclopentane ring, then a subscript number indicating the number of double bonds in the side chains.

• Series 1 (e.g., PGE₁) derive from dihomo-γ-linolenic acid.
• Series 2 (e.g., PGE₂, TXA₂, PGI₂) derive from arachidonic acid — these are by far the most important.
• Series 3 (e.g., PGE₃, TXA₃, PGI₃) derive from eicosapentaenoic acid (EPA), the basis of the cardioprotective claim for fish-oil ω-3 fatty acids (TXA₃ is a weaker platelet aggregator than TXA₂).

The arachidonic acid cascade — stepwise

The cascade is best memorised as a flow from membrane to mediator:

Membrane phospholipid → (phospholipase A₂) → arachidonic acid → (COX or LOX) → endoperoxides/HPETE → final eicosanoids

1. A stimulus (mechanical, chemical, cytokine, complement C5a, bradykinin) activates phospholipase A₂ (PLA₂), the rate-limiting step, liberating arachidonic acid from the sn-2 position of membrane phospholipids.
2. AA is then channelled down one of two routes:
   • COX route: COX-1/COX-2 add two O₂ molecules to form the unstable cyclic endoperoxide PGG₂, then a peroxidase activity reduces it to PGH₂. PGH₂ is the common precursor of all prostanoids.
   • LOX route: 5-lipoxygenase (with the helper protein FLAP — 5-LOX activating protein) converts AA to 5-HPETE, then to the unstable epoxide LTA₄.
3. Tissue-specific synthases then convert PGH₂ → PGE₂ (PGE synthase), PGI₂ (prostacyclin synthase, in endothelium), or TXA₂ (thromboxane synthase, in platelets); and LTA₄ → LTB₄ (LTA₄ hydrolase) or LTC₄ (via conjugation with glutathione by LTC₄ synthase), then LTD₄ and LTE₄.

High-yield: PLA₂ is the rate-limiting enzyme of eicosanoid synthesis and is the target of glucocorticoids — steroids induce lipocortin/annexin-1, which inhibits PLA₂. Because steroids block the cascade upstream of both COX and LOX, they suppress prostaglandins and leukotrienes; NSAIDs block only COX.

High-yield: PGH₂ is the branch-point/common precursor for PGs, TXA₂ and PGI₂. LTA₄ is the unstable common precursor for both LTB₄ and the cysteinyl leukotrienes.

COX-1 versus COX-2

Feature	COX-1	COX-2
Expression	Constitutive (housekeeping)	Largely inducible
Main sites	Stomach, platelets, kidney, endothelium	Inflammatory cells, kidney macula densa, brain
Induced by	—	Cytokines, growth factors, endotoxin
Key products	Gastric protective PGs, TXA₂	Inflammatory PGE₂, PGI₂
Inhibition effect	GI toxicity, antiplatelet	Anti-inflammatory, analgesic

A clinically vital nuance: endothelial PGI₂ is produced largely by COX-2, whereas platelet TXA₂ is COX-1 dependent. Selective COX-2 inhibitors (coxibs) suppress the protective antiplatelet/vasodilator PGI₂ while sparing pro-thrombotic platelet TXA₂ — tipping the balance towards thrombosis, the mechanism behind the cardiovascular risk (and the withdrawal of rofecoxib).

Physiological roles of the prostanoids

The TXA₂ ↔ PGI₂ balance (must-know)

This antagonistic pair is among the most repeated facts in the subject.

Mediator	Source	Vascular effect	Platelet effect	Mechanism
Thromboxane A₂	Platelets (COX-1)	Vasoconstriction	Promotes aggregation	↓ cAMP, ↑ intracellular Ca²⁺
Prostacyclin (PGI₂)	Vascular endothelium	Vasodilation	Inhibits aggregation	↑ cAMP

High-yield: TXA₂ = vasoconstrictor + pro-aggregatory; PGI₂ = vasodilator + anti-aggregatory. They work through opposite effects on platelet cAMP. TXA₂ has the shortest half-life (~30 seconds), degrading to inactive TXB₂.

Other prostaglandin actions

• PGE₂: vasodilation, hyperalgesia (sensitises nociceptors), the principal mediator of fever (acts on the hypothalamic preoptic area via the EP3 receptor; antipyretics work by blocking its synthesis), gastric mucus/bicarbonate secretion with reduced acid, smooth-muscle relaxation of bronchi but contraction of uterus and gut. Therapeutic forms: misoprostol (PGE₁ analogue — gastroprotection, medical abortion, PPH), alprostadil (PGE₁ — keeps the ductus arteriosus patent, erectile dysfunction), dinoprostone (PGE₂ — cervical ripening, labour induction).
• PGF₂α: uterine contraction, bronchoconstriction, luteolysis. Carboprost (15-methyl PGF₂α) is used for postpartum haemorrhage (contraindicated in asthma). Latanoprost/travoprost/bimatoprost (PGF₂α analogues) lower intraocular pressure in glaucoma by increasing uveoscleral outflow.
• PGD₂: the major prostanoid of mast cells; bronchoconstriction; involved in the cutaneous flushing of niacin and in mastocytosis.
• PGE₁ and PGI₂ maintain a patent ductus arteriosus in the fetus; this is why indomethacin/ibuprofen (NSAIDs) close a PDA, while PGE₁ keeps it open in duct-dependent congenital heart disease.

High-yield (renal): Prostaglandins (PGE₂, PGI₂) maintain renal blood flow by dilating the afferent arteriole, especially in states of low effective circulating volume. NSAIDs abolish this, causing afferent vasoconstriction → acute kidney injury, sodium/water retention, hyperkalaemia, and antagonism of antihypertensives.

The lipoxygenase pathway and leukotrienes

5-LOX (assisted by FLAP) in leukocytes generates leukotrienes, central to allergy and asthma.

• LTB₄: a potent chemotactic agent for neutrophils and a stimulator of their adhesion and degranulation — the leukotriene of inflammation and chemotaxis.
• Cysteinyl leukotrienes — LTC₄, LTD₄, LTE₄: together constitute the slow-reacting substance of anaphylaxis (SRS-A). They cause intense bronchoconstriction (1000× more potent than histamine), increased vascular permeability, mucus secretion and bronchial hyper-reactivity.
• Lipoxins (LXA₄, LXB₄): "stop signals" that promote resolution of inflammation; aspirin paradoxically triggers aspirin-triggered lipoxins (ATL) via acetylated COX-2, contributing to some of its anti-inflammatory benefit.

High-yield: SRS-A = cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄), the mediators targeted by montelukast/zafirlukast (CysLT₁ receptor antagonists) and zileuton (5-LOX inhibitor) in asthma. LTB₄ = chemotaxis.

Aspirin-exacerbated respiratory disease (Samter triad)

Blocking COX shunts arachidonic acid down the LOX pathway, increasing leukotrienes. This explains aspirin-induced asthma in susceptible patients — the classic Samter (aspirin) triad: asthma + nasal polyps + aspirin/NSAID sensitivity.

Pharmacology: where biochemistry meets the clinic

NSAID mechanism and aspirin

NSAIDs (ibuprofen, naproxen, diclofenac, indomethacin) are reversible, competitive COX inhibitors. Aspirin is unique — it irreversibly acetylates a serine residue (Ser-530 in COX-1, Ser-516 in COX-2) in the COX active channel.

High-yield: Because the platelet is anucleate and cannot synthesise new COX, aspirin's effect lasts the entire platelet lifespan (~7–10 days) — the basis of low-dose aspirin (75–150 mg) for antiplatelet/cardioprotective use. Endothelial cells, being nucleated, regenerate COX, so PGI₂ recovers. This dose-dependent selectivity ("aspirin paradox") favours net antithrombotic effect at low dose.

Therefore the antiplatelet effect of aspirin is achieved at low doses (selective platelet COX-1 block), while anti-inflammatory/analgesic/antipyretic effects need higher doses.

Drug class	Target	Reversibility	Clinical note
Aspirin (low dose)	COX-1 (platelet)	Irreversible	Cardioprotection, lasts platelet lifespan
Non-selective NSAIDs	COX-1 & COX-2	Reversible	Analgesia + GI/renal toxicity
Coxibs (celecoxib)	COX-2	Reversible	Less GI bleed, ↑ CV thrombotic risk
Glucocorticoids	PLA₂ (via annexin-1)	—	Block PGs + LTs both
Montelukast	CysLT₁ receptor	—	Asthma, allergic rhinitis
Zileuton	5-LOX	—	Asthma (monitor LFTs)
Paracetamol	Central COX (CNS)	Weak/peripheral-sparing	Antipyretic + analgesic, minimal anti-inflammatory

Paracetamol is a useful exam contrast: it is a poor peripheral COX inhibitor (hence little anti-inflammatory or antiplatelet action and gastric safety) but acts centrally — explaining its antipyretic/analgesic profile.

Complications and toxicity of cascade modulation

• NSAID GI toxicity: loss of COX-1-derived protective gastric PGE₂ → reduced mucus/bicarbonate, increased acid → erosions, peptic ulcer, bleeding. Prevented by misoprostol or PPIs.
• NSAID nephrotoxicity: afferent arteriolar constriction → pre-renal AKI, analgesic nephropathy, papillary necrosis, hyperkalaemia, fluid retention, hypertension.
• Coxib cardiovascular risk: PGI₂ suppression without TXA₂ block → thrombosis, MI, stroke.
• Aspirin-specific: bleeding tendency, gastric irritation, Reye syndrome in children with viral illness (avoid aspirin in children/influenza/varicella), tinnitus and respiratory alkalosis/metabolic acidosis in salicylate overdose.
• Reproductive/ductal: NSAIDs in late pregnancy can cause premature closure of the ductus arteriosus and oligohydramnios.

High-yield: Avoid aspirin in children with viral fevers — risk of Reye syndrome (hepatic encephalopathy + fatty liver). Use paracetamol instead.

Receptors and signalling (quick map)

Eicosanoids act through specific G-protein coupled receptors, and knowing the second messenger explains the physiology:

• IP receptor (PGI₂) and EP2/EP4 (PGE₂) → Gs → ↑ cAMP → vasodilation, smooth-muscle relaxation, platelet inhibition.
• TP receptor (TXA₂) and FP receptor (PGF₂α) → Gq → ↑ IP₃/Ca²⁺ → vasoconstriction, platelet aggregation, uterine/bronchial contraction.
• EP3 (PGE₂) → Gi → ↓ cAMP → gastric acid suppression, the fever response in hypothalamus.
• CysLT₁ (LTC₄/D₄/E₄) → Gq → bronchoconstriction; blocked by montelukast.
• BLT₁ (LTB₄) → Gq → neutrophil chemotaxis.

High-yield: A simple rule — mediators that raise cAMP (PGI₂, PGE₂ via EP2/EP4) are protective/relaxant; those that raise Ca²⁺ (TXA₂, PGF₂α, cysteinyl LTs) are constrictive/aggregatory.

Key differentials / commonly confused pairs

• COX vs LOX products: prostanoids (ring) vs leukotrienes (linear, leukocyte-derived). NSAIDs block COX only; steroids block both via PLA₂.
• TXA₂ vs PGI₂: pro-thrombotic vasoconstrictor (platelet) vs anti-thrombotic vasodilator (endothelium).
• PGE₂ vs PGF₂α on the uterus: PGE₂ ripens cervix; PGF₂α (carboprost) contracts uterus for PPH.
• PGE₁ on ductus: alprostadil keeps PDA open; indomethacin closes it.
• Misoprostol (PGE₁) vs carboprost (PGF₂α): both obstetric, but misoprostol also gastroprotects.

Recently asked / exam angle

• "Rate-limiting enzyme of prostaglandin synthesis" → phospholipase A₂ (target of steroids via annexin/lipocortin).
• "Common precursor of all prostaglandins/thromboxanes" → PGH₂; precursor of cysteinyl LTs → LTA₄.
• "Aspirin acts by" → irreversible acetylation of serine in COX; effect lasts the platelet lifespan (7–10 days).
• "SRS-A is composed of" → LTC₄, LTD₄, LTE₄ (cysteinyl leukotrienes).
• "Drug keeping ductus arteriosus patent" → PGE₁ (alprostadil/dinoprostone); "drug closing PDA" → indomethacin.
• "Mechanism of fever / antipyretics" → PGE₂ in hypothalamus; NSAIDs block its synthesis.
• "Why coxibs increase CV risk" → suppress PGI₂ while sparing TXA₂.
• "Samter triad" → asthma + nasal polyps + aspirin sensitivity (leukotriene shunting).
• Drug-of-choice matches: glaucoma → latanoprost; PPH (asthmatic contraindicated) → carboprost; NSAID ulcer prophylaxis → misoprostol; leukotriene-mediated asthma → montelukast/zileuton.

Rapid revision

1. Eicosanoids = 20-carbon AA derivatives; act locally with very short half-life; made on demand, not stored.
2. PLA₂ is rate-limiting; inhibited by steroids (via annexin-1/lipocortin) blocking BOTH PGs and LTs.
3. PGH₂ = common prostanoid precursor; LTA₄ = common leukotriene precursor.
4. COX-1 = constitutive (stomach, platelets, kidney); COX-2 = inducible (inflammation).
5. TXA₂ (platelet, COX-1) = vasoconstriction + aggregation; PGI₂ (endothelium) = vasodilation + anti-aggregation.
6. Aspirin irreversibly acetylates COX serine; low dose → lifelong platelet COX-1 block (7–10 days).
7. PGE₂ mediates fever, pain sensitisation and gastric protection; antipyretics block its synthesis.
8. SRS-A = cysteinyl leukotrienes LTC₄/LTD₄/LTE₄ (bronchoconstriction); LTB₄ = neutrophil chemotaxis.
9. Montelukast blocks CysLT₁; zileuton inhibits 5-LOX — used in asthma.
10. PGE₁ (alprostadil) keeps PDA open; indomethacin closes it; misoprostol = gastroprotection + abortifacient; carboprost = PPH (avoid in asthma); latanoprost = glaucoma.
11. NSAIDs cause peptic ulcers (lost gastric PGs), AKI (afferent constriction); coxibs raise CV thrombotic risk (lost PGI₂).
12. Avoid aspirin in children with viral illness — Reye syndrome; Samter triad = asthma + polyps + aspirin sensitivity.