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?

Question

Accepted Answer

A. Reduction in renal perfusion and glomerular filtration rate due to inhibition of prostaglandin-mediated vasodilation. ## 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.

Answer

B. Enhanced tubular reabsorption of potassium due to aldosterone antagonism

Answer

C. Displacement of enalapril from plasma protein binding by ibuprofen

Answer

D. Inhibition of hepatic metabolism of enalapril by ibuprofen

Explanation

Mechanism of ACE Inhibitor–NSAID Interaction

Pathophysiology

Why This Interaction Matters

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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