NSAIDs: Mechanisms and Risks

## Mechanism of Action

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes, blocking the conversion of arachidonic acid to prostaglandins and thromboxanes. Prostaglandins mediate pain sensitization, inflammation, fever, gastric mucosal protection, and renal blood flow regulation. Thromboxane A2 (produced via COX-1 in platelets) promotes platelet aggregation.

## COX-1 vs COX-2

**COX-1** is constitutively expressed in most tissues and produces prostaglandins essential for gastric mucosal protection, renal perfusion, and platelet function.

**COX-2** is induced at sites of inflammation and is the primary source of prostaglandins that mediate pain, fever, and inflammatory swelling. It is also constitutively expressed in the kidney and vascular endothelium.

Traditional NSAIDs (ibuprofen, naproxen, diclofenac) inhibit both COX-1 and COX-2. Selective COX-2 inhibitors (celecoxib) spare COX-1, reducing GI toxicity but raising cardiovascular concerns.

## Common NSAIDs

| Drug | COX Selectivity | Half-Life | Notes |
|------|----------------|-----------|-------|
| Aspirin | Irreversible COX-1 > COX-2 | 15-20 min (active) | Antiplatelet at low dose |
| Ibuprofen | Non-selective | 2-4 h | OTC, short duration |
| Naproxen | Non-selective, slight COX-1 | 12-17 h | Twice daily, lowest CV risk among NSAIDs |
| Diclofenac | Non-selective, slight COX-2 | 1-2 h | Potent, topical available |
| Celecoxib | COX-2 selective | 11 h | Lower GI risk, similar CV risk at moderate doses |
| Ketorolac | Non-selective | 5-6 h | IV/IM, max 5 days, potent analgesic |

## Gastrointestinal Risks

NSAIDs cause GI damage through two mechanisms: direct topical injury to gastric mucosa and systemic COX-1 inhibition reducing protective prostaglandin synthesis. Risks include dyspepsia, gastric/duodenal ulcers, and upper GI bleeding. Risk factors include age >65, history of ulcer disease, concurrent anticoagulants or corticosteroids, and H. pylori infection.

Gastroprotection with a PPI is recommended for high-risk patients requiring chronic NSAIDs.

## Cardiovascular Risks

All NSAIDs (except aspirin and possibly naproxen) increase the risk of myocardial infarction and stroke. COX-2 inhibition reduces vascular prostacyclin (PGI2, an endogenous vasodilator and antiplatelet agent) without affecting thromboxane A2, tipping the balance toward thrombosis. This led to the withdrawal of rofecoxib (Vioxx) in 2004.

Current guidelines recommend the lowest effective dose for the shortest duration. Naproxen has the most favorable cardiovascular profile among traditional NSAIDs.

## Renal Effects

Prostaglandins maintain renal blood flow, particularly when circulating volume is reduced. NSAIDs can cause sodium retention, hypertension, acute kidney injury, and interstitial nephritis. Avoid in patients with CKD, heart failure, or hypovolemia. The risk is compounded by concurrent ACE inhibitors/ARBs and diuretics (the "triple whammy").

## Key Takeaways

- NSAIDs are effective but carry real GI, CV, and renal risks -- not just "painkillers."
- Naproxen is generally preferred for patients with cardiovascular risk.
- Co-prescribe a PPI for patients at high GI risk who require chronic NSAID therapy.
- Avoid the combination of NSAIDs + ACE inhibitor/ARB + diuretic in renal-impaired patients.