Corrected Statement for USMLE
The original sentence is correct: Glucocorticoids inhibit phospholipase A₂, reducing both prostaglandins and leukotrienes, whereas NSAIDs inhibit cyclooxygenase and reduce prostaglandin production only.
Mechanism of Glucocorticoid Anti-Inflammatory Action
Glucocorticoids act upstream in the arachidonic acid cascade by inhibiting phospholipase A₂ (PLA₂), thereby preventing the release of arachidonic acid from membrane phospholipids. 1, 2 This mechanism explains their superior anti-inflammatory efficacy compared to NSAIDs, as they block the formation of both:
- Prostaglandins (via the cyclooxygenase pathway) 1, 3
- Leukotrienes (via the lipoxygenase pathway) 1, 3
Molecular Mechanisms of Glucocorticoid Action
Glucocorticoids work through multiple complementary pathways:
- Induction of lipocortin synthesis: Glucocorticoids induce a family of phospholipase inhibitory proteins (lipocortins) that inhibit PLA₂, phospholipase C, and phosphatidylinositol phospholipase C 1
- Direct enzyme suppression: In inflammatory contexts, glucocorticoids inhibit the expression of both PLA₂ and cyclooxygenase-2 (COX-2) at transcriptional and translational levels 2, 4, 5
- Constitutive COX-1 is unaffected: Under normal physiological conditions, COX-1-mediated prostaglandin synthesis is not affected by glucocorticoids 2
Mechanism of NSAID Anti-Inflammatory Action
NSAIDs act downstream by inhibiting cyclooxygenase enzymes (COX-1 and/or COX-2), thereby blocking only prostaglandin synthesis. 6 They have no effect on leukotriene production because they do not inhibit the lipoxygenase pathway. 3
Types of NSAIDs Based on COX Selectivity
- Non-selective NSAIDs: Reversibly inhibit both COX-1 and COX-2 (e.g., ibuprofen, naproxen, indomethacin) 6, 7
- Selective COX-2 inhibitors (coxibs): Preferentially inhibit COX-2 over COX-1 due to higher affinity for COX-2 6, 7
- Aspirin: Irreversibly blocks both COX-1 and COX-2 enzymes 6, 8
Clinical Implications of These Mechanistic Differences
The broader mechanism of glucocorticoids explains why they are more potent anti-inflammatory agents than NSAIDs, but this comes at the cost of more systemic side effects. 3
Key Clinical Considerations
- Glucocorticoids should be used at the lowest effective dose due to their effects on lipids, glucose tolerance, blood pressure, and bone density, particularly with long-term high-dose therapy 6
- NSAIDs carry significant gastrointestinal and cardiovascular risks: All NSAIDs increase risk of GI bleeding and ulceration, with non-selective NSAIDs causing approximately 100,000 hospitalizations annually in the United States 6
- COX-2 selective inhibitors reduce GI complications by approximately 50% compared to traditional NSAIDs, but increase cardiovascular thrombotic risk 6, 7, 8
Common Pitfall to Avoid
Do not assume that glucocorticoids directly inhibit cyclooxygenase like NSAIDs do—this is incorrect. Glucocorticoids reduce prostaglandin synthesis indirectly by preventing arachidonic acid release through PLA₂ inhibition and by suppressing COX-2 expression in inflammatory states, not by directly blocking COX enzyme activity. 2, 5