Enalapril is an ACE Inhibitor
Enalapril is an angiotensin-converting enzyme (ACE) inhibitor, not an angiotensin receptor-neprilysin inhibitor (ARNI). 1
Mechanism of Action
- Enalapril inhibits ACE, the enzyme that converts angiotensin I to angiotensin II, thereby reducing vasoconstriction and aldosterone secretion. 1
- After oral administration, enalapril is hydrolyzed to its active metabolite enalaprilat, which is the actual ACE inhibitor. 1
- ACE is identical to kininase, an enzyme that degrades bradykinin; therefore, ACE inhibitors like enalapril increase bradykinin levels, which may contribute to both therapeutic effects and adverse effects like angioedema. 1
Clinical Distinction from ARNIs
- ARNIs are a completely different drug class that combine an angiotensin receptor blocker (ARB) with a neprilysin inhibitor. 2
- The prototypical ARNI is sacubitril/valsartan (Entresto), which blocks the AT1 receptor while simultaneously inhibiting neprilysin to increase beneficial natriuretic peptides. 2
- Enalapril was used as the comparator drug in the landmark PARADIGM-HF trial, where sacubitril/valsartan demonstrated 20% reduction in cardiovascular death or heart failure hospitalization compared to enalapril. 2
Critical Safety Distinction
- ARNIs and ACE inhibitors must never be given together because both increase bradykinin levels through different mechanisms, creating an unacceptably high risk of life-threatening angioedema. 2
- When switching from enalapril (or any ACE inhibitor) to an ARNI, a mandatory 36-hour washout period is required to allow bradykinin levels to normalize. 2
- The failed drug omapatrilat, which combined ACE inhibition with neprilysin inhibition in a single molecule, was terminated due to a 3-fold increased angioedema risk compared to enalapril alone. 2
Clinical Use
- Enalapril remains a cornerstone therapy for hypertension and heart failure with reduced ejection fraction (HFrEF), typically dosed 10-40 mg daily. 1, 3
- In current heart failure guidelines, ARNIs are now preferred over ACE inhibitors like enalapril for patients with symptomatic HFrEF who can tolerate the medication, but enalapril remains an appropriate alternative when ARNIs are not feasible. 2