Sacubitril/valsartan (LCZ696) reduces mortality in heart failure with reduced ejection fraction. What is the mechanism of sacubitril's active metabolite?
- A LBQ657 (active metabolite) inhibits neprilysin, preventing degradation of BNP, ANP, and bradykinin, augmenting their vasodilatory and natriuretic effects ✓
- B Sacubitril is a prodrug that is converted to a direct ANP receptor agonist
- C LBQ657 inhibits ACE, preventing angiotensin II formation while also blocking neprilysin
- D Sacubitril directly activates guanylyl cyclase in vascular smooth muscle
Explanation
Sacubitril is a prodrug hydrolyzed to LBQ657, which inhibits neprilysin (neutral endopeptidase 24.11), an enzyme that degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, and angiotensin II. By inhibiting neprilysin, LBQ657 increases circulating ANP and BNP, promoting natriuresis, vasodilation, and reduced cardiac fibrosis. The valsartan (ARB) component is essential because neprilysin inhibition alone would increase angiotensin II levels (also a neprilysin substrate); combining with ARB prevents compensatory vasoconstriction. Earlier attempts using omapatrilat (ACE + neprilysin inhibitor) caused angioedema due to bradykinin excess.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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