NSAIDs & the Arachidonic Acid Pathway: A Detailed Guide

Almost every NSAID exam question — mechanism, uses, the GI and renal side effects, the antiplatelet action, even the steroid comparison — traces back to a single biochemical map: the arachidonic acid pathway. Learn the pathway and you’ve learned the drugs.

The pathway in one breath

Membrane phospholipids → (phospholipase A₂) → arachidonic acid, which then splits down two roads: the COX road to prostaglandins, prostacyclin and thromboxane, and the lipoxygenase road to leukotrienes.

COX-1 vs COX-2 — the central distinction

• COX-1 (constitutive) — “housekeeping”: protects gastric mucosa, maintains renal blood flow, and makes platelet thromboxane. Blocking it explains NSAID side effects.
• COX-2 (inducible) — switched on by inflammation; makes the prostaglandins of pain, fever and inflammation. Blocking it explains NSAID benefits.

What the products actually do

• PGE₂ — vasodilation, pain sensitisation, fever, gastric mucus/bicarbonate.
• PGI₂ (prostacyclin) — vasodilator, inhibits platelet aggregation (endothelium).
• TXA₂ (thromboxane) — vasoconstrictor, promotes platelet aggregation (platelets).

NSAIDs — mechanism & effects

NSAIDs inhibit COX, reducing prostaglandins. This gives four actions: analgesic, antipyretic, anti-inflammatory, and (via TXA₂) antiplatelet.

• Non-selective (ibuprofen, diclofenac, naproxen) — block COX-1 and COX-2.
• Aspirin — irreversibly acetylates COX; low dose gives lifelong platelet inhibition (platelets can’t make new enzyme).
• COX-2 selective (coxibs, e.g. celecoxib) — gentler on the stomach, but raise cardiovascular/thrombotic risk (they spare protective PGI₂ while platelet TXA₂ continues).

Adverse effects — all predictable from the pathway

• GI — ulcers/bleeding (loss of COX-1 gastric prostaglandins).
• Renal — salt/water retention, acute kidney injury (loss of renal prostaglandins).
• Cardiovascular — raised risk, especially with coxibs.
• Aspirin specifics — Reye’s syndrome in children with viral illness; tinnitus in overdose.

The leukotriene road

Leukotrienes drive bronchoconstriction and allergic inflammation. Montelukast blocks the receptor and zileuton blocks 5-LOX — both used in asthma. Because NSAIDs block only COX, they can shunt arachidonic acid toward leukotrienes, explaining aspirin-induced asthma.

Exam tip: steroids act above the fork (phospholipase A₂), so they shut down both prostaglandins and leukotrienes; NSAIDs act at COX, so they spare leukotrienes. That single difference answers half the comparison questions on this topic.

One pathway, drawn once and understood, unlocks NSAIDs, steroids, antiplatelet therapy and the leukotriene modifiers together. It is the highest-yield diagram in autacoid pharmacology — learn to redraw it from memory.