A 52-year-old man with hypertension on enalapril and type 2 diabetes on metformin presents to the clinic. He is started on ibuprofen for chronic knee pain. After 2 weeks, his serum creatinine rises from 1.0 to 1.8 mg/dL and potassium increases to 5.8 mEq/L. Which is the most common mechanism of this adverse drug interaction?

Explanation

## Mechanism of ACE Inhibitor–NSAID Interaction **Key Point:** The most common mechanism of renal dysfunction in patients on ACE inhibitors (or ARBs) who receive NSAIDs is reduction in glomerular filtration rate (GFR) due to loss of prostaglandin-mediated renal vasodilation. ### Pathophysiology 1. **Baseline renal haemodynamics in ACE inhibition:** - ACE inhibitors block angiotensin II formation, reducing efferent arteriolar vasoconstriction - Renal perfusion is maintained by prostaglandin-mediated afferent arteriolar vasodilation 2. **Effect of NSAIDs:** - NSAIDs inhibit cyclooxygenase (COX), blocking prostaglandin synthesis - Loss of prostaglandin-mediated afferent vasodilation → decreased renal blood flow - Combined with reduced efferent resistance (from ACE inhibitor) → severe drop in GFR 3. **Clinical consequences:** - Acute kidney injury (rise in creatinine) - Hyperkalemia (reduced GFR → reduced potassium excretion; ACE inhibitor reduces aldosterone) **High-Yield:** This is the **"triple whammy" triad** when a third agent (diuretic) is added: ACE-I/ARB + NSAID + diuretic causes severe renal dysfunction. ### Why This Interaction Matters | Feature | Details | |---------|----------| | **Onset** | Usually 1–4 weeks after NSAID initiation | | **Reversibility** | Often reversible if NSAID stopped early | | **Risk factors** | Baseline CKD, volume depletion, elderly, diabetes | | **Prevention** | Avoid NSAIDs in patients on ACE-I/ARB; use acetaminophen or COX-2 inhibitors cautiously | **Clinical Pearl:** Hyperkalemia in this setting is multifactorial: reduced GFR + reduced aldosterone secretion (ACE inhibitor effect) + loss of prostaglandin-mediated K⁺ excretion. **Mnemonic:** **RENAL** — **R**eduction in GFR, **E**fferent vasodilation (preserved by ACE-I), **N**SAIDs block prostaglandins, **A**fferent vasodilation lost, **L**oss of renal perfusion.