A patient with heart failure with reduced ejection fraction (HFrEF) is started on sacubitril-valsartan (Entresto). What is the mechanism of the sacubitril component?
- A Prodrug metabolized to LBQ657, a neprilysin inhibitor that reduces BNP and ANP degradation ✓
- B Direct angiotensin receptor blocker that also inhibits ACE
- C Phosphodiesterase-5 inhibitor that increases cGMP and promotes natriuresis
- D Selective aldosterone receptor antagonist that reduces myocardial fibrosis
Explanation
Sacubitril is a prodrug that undergoes esterase-mediated hydrolysis to its active metabolite LBQ657, a neprilysin (neutral endopeptidase) inhibitor. Neprilysin degrades natriuretic peptides (BNP, ANP, CNP), bradykinin, and other vasoactive peptides. Inhibition leads to elevated natriuretic peptide levels, promoting natriuresis, diuresis, and vasodilation, reducing cardiac preload and afterload. Sacubitril must be combined with valsartan (ARB) rather than an ACEi because combined neprilysin + ACE inhibition causes dangerous accumulation of bradykinin, leading to severe angioedema.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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