Sacubitril/valsartan (sacubitril being an ARNI — angiotensin receptor-neprilysin inhibitor) reduces mortality in HFrEF. Neprilysin inhibition amplifies the effect of:

• A Bradykinin causing ACE inhibitor-like beneficial vasodilation and renal effects
• B Aldosterone degradation, reducing sodium retention
• C BNP and ANP, enhancing natriuresis, vasodilation, and anti-fibrotic/anti-hypertrophic effects ✓
• D Renin degradation, lowering angiotensin II formation

Explanation

Neprilysin is an endopeptidase that degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, and angiotensin II. Inhibiting neprilysin raises levels of BNP and ANP, which promote natriuresis, vasodilation, reduce fibrosis, and inhibit RAAS and sympathetic activity. Sacubitril is paired with valsartan (ARB) to prevent the simultaneous rise in angiotensin II from neprilysin inhibition. It is NOT combined with an ACEi (risk of angioedema from elevated bradykinin). Aldosterone and renin are not neprilysin substrates.

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

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Written and medically reviewed by the StethoPrep medical team.