Sacubitril/valsartan (Entresto) is used in heart failure with reduced ejection fraction. Sacubitril's mechanism involves inhibition of which enzyme, and what is the resulting pharmacological consequence?

• A Inhibition of ACE, reducing angiotensin II and increasing bradykinin
• B Inhibition of neprilysin, reducing degradation of natriuretic peptides and bradykinin ✓
• C Inhibition of aldosterone synthase, reducing sodium and water retention
• D Inhibition of endothelin-converting enzyme, reducing endothelin-1 levels

Explanation

Sacubitril is a prodrug converted to LBQ657, which inhibits neprilysin (neutral endopeptidase, NEP). Neprilysin degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, and adrenomedullin. Inhibition increases these vasoprotective/natriuretic peptides, reducing preload, afterload, and fibrosis. Valsartan (ARB) is combined to block the RAAS simultaneously and prevent the angiotensin II elevation that would otherwise result from neprilysin inhibition. Sacubitril+valsartan (ARNI) must not be combined with ACEi due to risk of angioedema from excessive bradykinin accumulation.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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