Abbreviations: NSAID = nonsteroidal anti-inflammatory drug · COX = cyclooxygenase · PGE2 = prostaglandin E2 · PGI2 = prostacyclin · TXA2 = thromboxane A2 · LOX = lipoxygenase · PLA2 = phospholipase A2 · AERD = aspirin-exacerbated respiratory disease · PPI = proton pump inhibitor
Arachidonic Acid Cascade
PGE2 — pain, fever, gastric protection, renal perfusion
PGI2 — vasodilation, inhibits platelets (endothelium)
TXA2 — vasoconstriction, promotes platelets (platelets only)
LOX pathway
Not blocked by NSAIDs
Leukotrienes — bronchoconstriction, allergic inflammation
AERD: COX block → LOX shunting → bronchoconstriction
Glucocorticoids block PLA2 via annexin A1 — suppressing both COX and LOX branches. NSAIDs block COX only.
COX-1 vs COX-2
- Gastric mucosa — cytoprotection
- Platelets — TXA2 synthesis
- Kidney — perfusion under stress
- Inhibition → GI toxicity, platelet effects
- Inflamed tissue — PGE2, fever
- Endothelium — PGI2 (anti-platelet)
- Selective block → ↓PGI2, TXA2 intact
- Prothrombotic state → CV risk
Aspirin — Dose-Dependent Pharmacology
| Dose Range |
Effect |
Mechanism |
| 75–325 mg/day |
Antiplatelet |
Irreversible COX-1 acetylation in platelets; endothelium regenerates COX-2 between doses |
| 300–1,000 mg/dose |
Analgesia, antipyresis |
COX inhibition in peripheral nociceptors and hypothalamus |
| 3,000–6,000 mg/day |
Anti-inflammatory |
Sustained systemic COX inhibition; rarely used (GI toxicity) |
| Toxic |
Tinnitus, hyperventilation, acidosis |
Respiratory alkalosis → metabolic acidosis; mitochondrial uncoupling |
Key Aspirin Rule
Platelets are anucleate — cannot make new COX. One aspirin permanently silences TXA2 in that platelet for its 8–10 day lifespan. Daily dosing is required to suppress the renewing platelet pool.
High-Priority Drug Interactions
Ibuprofen + Aspirin
Ibuprofen blocks aspirin access to platelet COX-1 — take aspirin first, wait 30 min
NSAIDs + ACE/ARB + Diuretic
Triple whammy — additive reduction of GFR → acute kidney injury
NSAIDs + Lithium
Reduced renal lithium clearance → lithium toxicity; monitor levels
NSAIDs + Anticoagulants
Additive GI bleeding risk; use PPI if combination unavoidable
NSAIDs + SSRIs
Additive platelet dysfunction → GI bleed risk; use PPI
CYP2C9 inhibitors
Fluconazole, amiodarone → raise NSAID levels → toxicity
Key Agent Differences
- Long half-life → sustained COX-1 inhibition
- Partial antiplatelet effect → lowest CV risk
- Does not block aspirin antiplatelet effect
- Less gastric mucosal injury than nonselective NSAIDs
- GI benefit lost if patient also takes aspirin
- CYP2D6 inhibitor — raises metoprolol, codeine levels
- Only NSAID for IV/IM use
- Opioid-sparing in acute pain
- Significant GI/renal risk limits duration
- Most potent nonselective COX inhibitor
- IV formulation closes patent ductus arteriosus in neonates
- High CNS side effects limit long-term use