Sacubitril/valsartan (LCZ696) is superior to enalapril in HFrEF because the neprilysin inhibition component:
- A Blocks conversion of angiotensin I to angiotensin II, additively inhibiting the RAAS
- B Directly inhibits aldosterone synthase in the adrenal gland, reducing aldosterone-mediated myocardial fibrosis
- C Inhibits degradation of natriuretic peptides (BNP, ANP, CNP) and bradykinin, enhancing vasodilation, natriuresis, and anti-fibrotic effects while valsartan prevents AII receptor activation ✓
- D Prevents bradykinin degradation only, providing the additional cough-free ACE inhibitor effect
Explanation
Neprilysin (neutral endopeptidase 24.11) degrades several vasoactive peptides including ANP, BNP, CNP, bradykinin, and substance P. Sacubitril (a prodrug → sacubitrilat) inhibits neprilysin, allowing these beneficial peptides to accumulate: natriuretic peptides promote natriuresis, vasodilation, and anti-fibrotic/anti-hypertrophic effects. The valsartan component (ARB) prevents AII-mediated vasoconstriction and aldosterone release. Neprilysin cannot be given alone without ARB because it also degrades angiotensin II — sole neprilysin inhibition would lead to AII accumulation causing hypertension. PARADIGM-HF trial showed 20% relative risk reduction in cardiovascular death vs. enalapril.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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