General pathology · Inflammation
Arachidonic acid metabolites in inflammation, and the drugs that block them !
- Mechanism
Cell membranes release arachidonic acid, which enzymes turn into prostaglandins and leukotrienes; most anti-inflammatory drugs block this pathway.
Updated 2026-11-01
What it is
When a cell is activated, phospholipase A2 frees arachidonic acid from membrane phospholipids. Cyclooxygenases turn it into prostaglandins and thromboxane, and 5-lipoxygenase into leukotrienes; together these eicosanoids drive vasodilation, pain, fever, bronchospasm and chemotaxis. The pathway explains how glucocorticoids, aspirin, NSAIDs, COX-2 inhibitors and leukotriene blockers work, and their typical side effects.
Key facts
- PGE2: vasodilation, pain sensitisation, fever, gastric mucus and bicarbonate; keeps the ductus arteriosus open.
- PGI2 (prostacyclin, endothelium): vasodilation, blocks platelet aggregation. TXA2 (platelets): vasoconstriction, aggregation.
- PGD2 (mast cells): vasodilation, leakage, attracts eosinophils and Th2 cells.
- LTC4, LTD4 and LTE4 (once called the slow-reacting substance of anaphylaxis) cause bronchospasm and leakage.
- Lipoxins, resolvins and protectins are pro-resolving lipids that help end inflammation.
Step by step
- A stimulus raises cytoplasmic calcium and activates phospholipase A2, which releases arachidonic acid from membrane phospholipids.
- Cyclooxygenase (COX-1, constitutive; COX-2, induced by inflammation) converts it to PGG2 and then PGH2.
- Cell-specific enzymes then make PGI2 in endothelium, TXA2 in platelets, PGD2 in mast cells and PGE2 in many cells.
- 5-lipoxygenase, helped by FLAP, converts arachidonic acid to LTA4, then to LTB4 (neutrophils) or LTC4, D4, E4 (mast cells).
- Leukocytes and platelets working together make lipoxins, which slow neutrophil entry and help resolution.
- The products act on G-protein-coupled receptors near where they are made and are quickly inactivated.
Where the drugs act
| Drug | Target | Effects and key adverse effects |
|---|---|---|
| Glucocorticoids | Reduce phospholipase A2 activity (through annexin A1) and the expression of COX-2 and cytokines | Broad anti-inflammatory effect; infections, hyperglycaemia, poor wound healing |
| Aspirin | Irreversibly acetylates COX-1 and COX-2 | Anti-inflammatory and antipyretic; lasting antiplatelet effect; gastric ulcers; Reye syndrome in children |
| Other NSAIDs (ibuprofen, naproxen, indomethacin) | Reversibly inhibit COX-1 and COX-2 | Less pain and fever; peptic ulcer, kidney injury; indomethacin closes the ductus arteriosus |
| Celecoxib (COX-2 selective) | Inhibits inducible COX-2 | Fewer gastric ulcers; higher thrombotic risk |
| Zileuton | Inhibits 5-lipoxygenase | Fewer leukotrienes; used in asthma |
| Montelukast, zafirlukast | Block the CysLT1 receptor | Less bronchospasm and leakage in asthma |
| Misoprostol | PGE1 analogue | Protects the gastric mucosa against NSAID ulcers |
Clinical notes
- Aspirin-exacerbated respiratory disease: COX blockade shifts arachidonic acid toward leukotrienes, causing asthma attacks, nasal polyps and rhinitis.
- NSAIDs reduce prostaglandin-dependent kidney blood flow; risk is higher with dehydration, heart failure, cirrhosis, or with ACE inhibitors and diuretics.
- Loss of protective mucosal PGE2 explains NSAID-induced gastric ulcers, the second great cause of peptic ulcer after H. pylori.
Test yourself
Think of the answer, then tap the question to see it.
Why do selective COX-2 inhibitors increase thrombotic risk?
They lower endothelial prostacyclin (PGI2, made partly through COX-2) while platelet thromboxane A2 (made by COX-1) is unaffected, tipping the balance toward clotting.
Which leukotriene is chemotactic for neutrophils?
Leukotriene B4.
Why can aspirin trigger asthma attacks in some patients?
Blocking COX diverts arachidonic acid to the 5-lipoxygenase pathway, increasing cysteinyl leukotrienes that cause bronchospasm.
At what step of the pathway do glucocorticoids act?
Upstream: they reduce phospholipase A2 activity and the expression of COX-2 and inflammatory cytokines.
Related
- Mediators of inflammation: the table to know
- Systemic effects of inflammation: fever, acute-phase proteins, leukocytosis, sepsis
- Histamine, serotonin, bradykinin and the plasma protein cascades
- Inflammation: the cardinal signs and its five steps
Related conditions
- Peptic ulcer disease
- Asthma
- Patent ductus arteriosus
- Acute kidney injury
- Anaphylaxis
- Gout
- Rheumatoid arthritis
Elsewhere in DurgiPedia
- Prostaglandin and thromboxane synthesis
- Eicosanoids: prostaglandins, thromboxanes and leukotrienes
- Arachidonic acid
- Prostaglandin H₂ (PGH₂)
- Actions of cortisol
- Fever
In Pharmacology
- Nonsteroidal anti-inflammatory drugs (NSAIDs)
- Celecoxib
- Corticosteroids (glucocorticoids)
- Leukotriene modifiers
- Montelukast
- Misoprostol
- Ibuprofen
- Ketorolac
Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.
Sources: Pain Relievers | Analgesics | Painkillers | MedlinePlus (MedlinePlus, US National Library of Medicine, 2026); Peptic Ulcer Disease (StatPearls (NCBI Bookshelf), 2024); 17.5 Inflammation and Fever (OpenStax (Microbiology), 2016).
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Representative model, for educational purposes only.