Prostaglandins, Leukotrienes & Eicosanoids

Eicosanoids are 20-carbon oxygenated derivatives of arachidonic acid that act as locally-produced, short-lived autacoids ("local hormones") modulating inflammation, vascular tone, platelet function, gastric protection, uterine activity and bronchial calibre. This is a favourite NEET PG topic because the pathway logic directly explains the pharmacology of NSAIDs, montelukast, misoprostol and the classic aspirin-exacerbated respiratory disease question.

Overview & nomenclature

"Eicosanoid" derives from the Greek eikosi (twenty) — they all have a 20-carbon backbone. The major families are:

• Prostaglandins (PG) and prostacyclin (PGI₂) — products of cyclo-oxygenase (COX).
• Thromboxanes (TX) — also COX products, chiefly from platelets.
• Leukotrienes (LT) — products of 5-lipoxygenase (5-LOX).
• Lipoxins and resolvins — pro-resolution mediators of lipoxygenase pathways.

The numerical subscript (e.g. PGE₂, PGF₂α, TXA₂, LTB₄) indicates the number of double bonds in the side chains, which depends on the precursor fatty acid (arachidonic acid → "2-series" prostanoids and "4-series" leukotrienes).

High-yield: Eicosanoids are NOT stored pre-formed. They are synthesised de novo on demand from membrane phospholipids and act locally (paracrine/autocrine) before rapid enzymatic inactivation, largely in the lung.

The arachidonic acid cascade — the master diagram

The entire topic hangs on one branching pathway. Memorise the fork.

Membrane phospholipid → (phospholipase A₂) → Arachidonic acid → splits into two arms:

1. COX arm (cyclo-oxygenase): Arachidonic acid → PGG₂ → PGH₂ → tissue-specific synthases → PGE₂, PGF₂α, PGD₂, PGI₂ (prostacyclin), TXA₂.
2. LOX arm (5-lipoxygenase): Arachidonic acid → (with FLAP, 5-LOX-activating protein) → 5-HPETE → LTA₄ → either LTB₄ (via LTA₄ hydrolase) or the cysteinyl-leukotrienes LTC₄ → LTD₄ → LTE₄ (via LTC₄ synthase + glutathione).

High-yield: Phospholipase A₂ (PLA₂) is the rate-limiting and committed step of the whole cascade. It is inhibited by glucocorticoids (via lipocortin/annexin-1 induction). Because steroids block at PLA₂, they suppress BOTH prostaglandins and leukotrienes — unlike NSAIDs, which block only the COX arm.

Key enzyme/inhibitor map:

Step	Enzyme	Inhibited by
Phospholipid → arachidonic acid	Phospholipase A₂	Glucocorticoids (lipocortin-1/annexin-1)
Arachidonic acid → PGH₂	COX-1 / COX-2	NSAIDs, aspirin (irreversible), coxibs (COX-2 selective)
Arachidonic acid → 5-HPETE/LTA₄	5-lipoxygenase (+ FLAP)	Zileuton (5-LOX inhibitor)
LTD₄/LTC₄ at CysLT₁ receptor	(receptor)	Montelukast, zafirlukast, pranlukast

COX-1 vs COX-2

Both isoenzymes convert arachidonic acid to PGH₂, but their distribution and roles differ — this underlies NSAID side-effect and selectivity questions.

Feature	COX-1	COX-2
Expression	Constitutive	Mainly inducible (cytokines, mitogens); constitutive in kidney, brain, endothelium
Main physiological role	Gastric mucosal protection, platelet TXA₂, renal homeostasis	Inflammation, pain, fever, also renal & endothelial PGI₂
Key product	TXA₂ (platelets), gastric PGE₂/PGI₂	PGE₂, PGI₂ at inflamed sites
Inhibition effect	GI ulceration, antiplatelet effect	Anti-inflammatory; ↑thrombotic risk via PGI₂ suppression
Selective inhibitor	—	Celecoxib, etoricoxib, parecoxib

High-yield: Selective COX-2 inhibitors (coxibs) spare gastric COX-1 (less ulcer risk) but suppress endothelial PGI₂ without affecting platelet TXA₂, tilting the balance toward thrombosis → increased cardiovascular/thrombotic events (rofecoxib was withdrawn for this reason).

High-yield: Aspirin irreversibly acetylates COX (serine residue). In platelets, which lack a nucleus and cannot synthesise new enzyme, this antiplatelet effect lasts the platelet's lifespan (~7–10 days). Hence low-dose aspirin's prolonged antithrombotic action.

Individual eicosanoids — actions to remember

Prostacyclin (PGI₂) vs Thromboxane A₂ (TXA₂)

These two are physiological opposites and the most examined pair.

Parameter	PGI₂ (prostacyclin)	TXA₂ (thromboxane)
Source	Vascular endothelium	Platelets
Synthase	Prostacyclin synthase	Thromboxane synthase
Platelets	Inhibits aggregation	Promotes aggregation
Vessels	Vasodilator	Vasoconstrictor
Net role	Anti-thrombotic	Pro-thrombotic

High-yield: The PGI₂ : TXA₂ balance governs haemostasis. Low-dose aspirin preferentially knocks out platelet TXA₂ (because platelets cannot regenerate COX) while endothelium recovers PGI₂ — net antithrombotic. This "aspirin dilemma" is classic.

PGE₂

• Vasodilatation, hyperalgesia (sensitises nociceptors), fever (acts on hypothalamic OVLT → set-point rise; explains antipyretic action of NSAIDs).
• Maintains patency of the ductus arteriosus in the fetus.
• Cytoprotection of gastric mucosa (↓acid, ↑mucus/bicarbonate).
• Uterine contraction (cervical ripening).

PGF₂α

• Potent uterine contraction (oxytocic) and bronchoconstriction.
• Luteolysis. Therapeutic analogues used in glaucoma (latanoprost ↑uveoscleral outflow).

PGD₂

• Major prostaglandin in mast cells; bronchoconstriction; involved in the flushing of niacin (via DP receptor) — niacin flush is blocked by aspirin/laropiprant.

Leukotrienes

• LTB₄ — potent chemotactic agent for neutrophils and a major mediator of inflammation/neutrophil recruitment.
• Cysteinyl-LTs (LTC₄, LTD₄, LTE₄) — formerly "slow-reacting substance of anaphylaxis (SRS-A)". Cause bronchoconstriction, increased vascular permeability, mucus secretion — central to asthma. Far more potent bronchoconstrictors than histamine.

High-yield: SRS-A = mixture of LTC₄, LTD₄, LTE₄. These are 1000× more potent than histamine as bronchoconstrictors.

Prostaglandin receptors — quick map

Prostanoids act on G-protein-coupled receptors named after their ligand:

• DP (PGD₂), EP₁–EP₄ (PGE₂), FP (PGF₂α), IP (PGI₂), TP (TXA₂).
• CysLT₁ and CysLT₂ for cysteinyl-leukotrienes; BLT for LTB₄.

EP receptors are the most diverse: EP₁ → smooth-muscle contraction; EP₂/EP₄ → relaxation/vasodilatation; EP₃ → gastric acid ↓ and fever. TP receptor activation (by TXA₂) → platelet aggregation + vasoconstriction.

Clinical pharmacology — drugs you must know

Misoprostol (PGE₁ analogue)

• Gastric: Prevents NSAID-induced peptic ulcers (replaces protective PGs). DOC for prophylaxis in high-risk NSAID users.
• Obstetric: Cervical ripening, medical abortion (with mifepristone), and management of postpartum haemorrhage (PPH) — heat-stable, oral/sublingual/rectal, useful where oxytocin cold-chain is unavailable.
• Adverse: diarrhoea, abdominal cramps; contraindicated in pregnancy when continuation desired (abortifacient, teratogenic — Möbius sequence).

Dinoprostone (PGE₂)

• Intravaginal gel/insert for cervical ripening and labour induction.

Carboprost (15-methyl PGF₂α)

• Refractory PPH due to uterine atony (when oxytocin and ergometrine fail).
• Contraindicated in asthma (bronchoconstriction via FP/TP).

Alprostadil (PGE₁)

• Maintains patency of the ductus arteriosus in duct-dependent congenital heart disease (e.g. transposition, pulmonary atresia) until surgery — given as IV infusion to neonates.
• Intracavernosal/intraurethral for erectile dysfunction.

High-yield: To keep the ductus OPEN → give PGE₁ (alprostadil). To CLOSE a patent ductus arteriosus → give a COX inhibitor (indometacin or ibuprofen) in the neonate. This open/close pair is asked almost every year.

Epoprostenol / treprostinil / iloprost (PGI₂ analogues)

• Pulmonary arterial hypertension (PAH): potent pulmonary vasodilators. Epoprostenol is given by continuous IV infusion (very short t½, ~3–5 min). Iloprost is inhaled; treprostinil SC/IV/inhaled; selexipag is an oral IP-receptor agonist.

Note: The job blurb mentions alprostadil for PAH; in standard pharmacology the PGI₂ analogues (epoprostenol/iloprost/treprostinil) are the prostanoid class used for PAH, while alprostadil (PGE₁) is used for ductus-dependent CHD and erectile dysfunction. Know both so you can pick the best single answer.

Latanoprost / bimatoprost / travoprost (PGF₂α analogues)

• Open-angle glaucoma — lower intraocular pressure by increasing uveoscleral outflow. ADR: iris hyperpigmentation, eyelash growth (hypertrichosis), periorbital fat atrophy.

Leukotriene-modifying drugs

• Montelukast, zafirlukast, pranlukast — CysLT₁ receptor antagonists. Used in chronic asthma prophylaxis (not acute attack), exercise-induced bronchospasm, allergic rhinitis, and especially aspirin-exacerbated respiratory disease. Montelukast is oral, once-daily, well-suited for children.
• Zileuton — 5-LOX inhibitor; blocks synthesis of all leukotrienes. Requires LFT monitoring (hepatotoxic).

High-yield: Montelukast carries a black-box warning for neuropsychiatric effects (mood changes, agitation, suicidal ideation, sleep disturbances).

Stepwise place in asthma: SABA for acute relief → inhaled corticosteroid (controller) → add LABA or LTRA (montelukast) → escalate. Leukotriene antagonists are controllers/add-ons, never rescue.

Aspirin-exacerbated respiratory disease (AERD) — the signature question

AERD (Samter's triad / aspirin-induced asthma) = asthma + nasal polyps + aspirin (NSAID) sensitivity.

Mechanism (the shunt): Aspirin/NSAIDs inhibit COX → arachidonic acid is diverted ("shunted") down the 5-LOX pathway → ↑cysteinyl-leukotrienes (LTC₄/D₄/E₄) → severe bronchoconstriction, rhinorrhoea, nasal congestion within minutes to hours of NSAID intake.

High-yield: In AERD, COX inhibition shunts arachidonic acid to the lipoxygenase arm → excess cysteinyl-leukotrienes → bronchospasm. Treatment/prevention uses leukotriene modifiers (montelukast, zileuton) and aspirin avoidance; aspirin desensitisation in selected patients.

Mnemonic — "ASA triad": Asthma, Sinus polyps (nasal polyps), Aspirin sensitivity.

NSAID pharmacodynamics summarised

NSAIDs inhibit COX, reducing PGE₂/PGI₂ → antipyretic (block PGE₂-mediated hypothalamic set-point rise), analgesic (block PG-mediated peripheral nociceptor sensitisation), anti-inflammatory (block vasodilator/permeability PGs), antiplatelet (block TXA₂).

Predictable mechanism-based adverse effects from PG suppression:

• GI: loss of gastric cytoprotective PGE₂ → erosions, ulcers, bleeding.
• Renal: loss of vasodilator PGs → ↓renal perfusion, sodium/water retention, hyperkalaemia, acute kidney injury (especially in volume-depleted, elderly, CKD).
• Cardiovascular: coxibs ↑thrombotic risk.
• Pregnancy: late NSAID use → premature ductus arteriosus closure and oligohydramnios.

Complications & cautions table

Drug class	Major complication
Non-selective NSAIDs	Peptic ulcer/GI bleed, AKI, bronchospasm in AERD
COX-2 selective (coxibs)	Thrombotic CV events (MI, stroke)
PGF₂α analogues (carboprost)	Bronchoconstriction (avoid in asthma)
PGE analogues (misoprostol/dinoprostone)	Uterine hyperstimulation, diarrhoea, teratogenic
Montelukast	Neuropsychiatric effects; (historically) Churg-Strauss unmasking on steroid taper
Zileuton	Hepatotoxicity
Latanoprost	Iris hyperpigmentation, lash growth

Key differentials / "which agent" discriminators

• Keep ductus open vs close it: PGE₁ (alprostadil) opens; indometacin/ibuprofen close.
• Steroid vs NSAID block point: Steroid = PLA₂ (blocks PG + LT); NSAID = COX (blocks PG/TX only, leaves LT). This is why steroids help AERD but NSAIDs worsen it.
• Montelukast vs zileuton: Montelukast blocks the CysLT₁ receptor; zileuton blocks 5-LOX synthesis (and so also reduces LTB₄).
• PGI₂ vs TXA₂: endothelial antithrombotic vasodilator vs platelet prothrombotic vasoconstrictor.
• PAH prostanoid (epoprostenol/iloprost) vs ED/ductus prostanoid (alprostadil).

Recently asked / exam angle

• "Arachidonic acid is shunted to which pathway in aspirin-induced asthma?" → 5-lipoxygenase / cysteinyl-leukotriene pathway.
• "Drug to maintain ductus arteriosus patency in a cyanotic neonate" → Alprostadil (PGE₁).
• "Rate-limiting enzyme of eicosanoid synthesis" → Phospholipase A₂.
• "Enzyme inhibited by glucocorticoids that explains their dual PG + LT suppression" → PLA₂ (via lipocortin/annexin-1).
• "Which prostanoid opposes thromboxane A₂?" → Prostacyclin (PGI₂).
• "DOC for prevention of NSAID-induced peptic ulcer" → Misoprostol (or PPI).
• "Mechanism of low-dose aspirin's prolonged antiplatelet effect" → irreversible COX acetylation in anucleate platelets.
• "Leukotriene receptor antagonist used in asthma/allergic rhinitis" → Montelukast (CysLT₁ blocker).
• "Black-box warning of montelukast" → neuropsychiatric events.
• "Constituents of SRS-A" → LTC₄, LTD₄, LTE₄.
• "Coxibs increase cardiovascular risk because they suppress" → endothelial PGI₂ while sparing platelet TXA₂.
• "Glaucoma drug causing iris hyperpigmentation" → latanoprost (PGF₂α analogue).

Rapid revision

1. PLA₂ = rate-limiting step; inhibited by steroids (lipocortin) → blocks both PGs and LTs.
2. NSAIDs block COX only → suppress PGs/TXA₂, spare leukotrienes.
3. COX-1 = housekeeping (gastric, platelet, renal); COX-2 = inducible inflammation.
4. Aspirin = irreversible COX acetylation; platelet effect lasts 7–10 days.
5. PGI₂ (endothelium) = antiplatelet vasodilator; TXA₂ (platelet) = proaggregatory vasoconstrictor — opposites.
6. PGE₁ (alprostadil) keeps ductus OPEN; indometacin/ibuprofen CLOSE the PDA.
7. Misoprostol = NSAID-ulcer prophylaxis + cervical ripening/PPH; carboprost = atonic PPH but avoid in asthma.
8. Epoprostenol/iloprost/treprostinil (PGI₂ analogues) = pulmonary arterial hypertension.
9. Montelukast = CysLT₁ antagonist (controller, not rescue); zileuton = 5-LOX inhibitor (hepatotoxic).
10. AERD/Samter's triad = asthma + nasal polyps + aspirin sensitivity; NSAIDs shunt arachidonic acid to leukotrienes → bronchospasm.
11. SRS-A = LTC₄ + LTD₄ + LTE₄; LTB₄ = neutrophil chemotaxis.
12. Latanoprost (PGF₂α) lowers IOP in glaucoma; ADR = iris pigmentation + lash growth.