Sacubitril/valsartan (LCZ696) is a combination drug approved for HFrEF. The sacubitril component acts as a prodrug and exerts its benefit by inhibiting which enzyme?
- A Neprilysin (neutral endopeptidase), preventing degradation of natriuretic peptides and bradykinin ✓
- B Angiotensin-converting enzyme (ACE)
- C Aldosterone synthase (CYP11B2)
- D Renin, preventing conversion of angiotensinogen to angiotensin I
Correct answer: A. Neprilysin (neutral endopeptidase), preventing degradation of natriuretic peptides and bradykinin
Explanation
Sacubitril is a prodrug that is converted to LBQ657, which inhibits neprilysin (neutral endopeptidase 24.11). Neprilysin normally degrades natriuretic peptides (ANP, BNP), bradykinin, and other vasoactive peptides. By inhibiting neprilysin, sacubitril elevates endogenous natriuretic peptide levels, promoting natriuresis, vasodilation, and anti-fibrotic effects. The valsartan component blocks AT1 receptors and also prevents bradykinin-mediated angioedema (the main reason sacubitril cannot be combined with ACE inhibitors).
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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