A 65-year-old patient with heart failure with reduced ejection fraction (HFrEF) is started on sacubitril/valsartan. The sacubitril component acts as a prodrug converted to sacubitrilat, which inhibits which enzyme to produce its haemodynamic benefits?

• A Angiotensin-converting enzyme (ACE)
• B Neprilysin (neutral endopeptidase) ✓
• C Angiotensin II type-1 receptor (AT1)
• D Aldosterone synthase (CYP11B2)

Explanation

Sacubitrilat (the active form of sacubitril) inhibits neprilysin, a neutral endopeptidase that degrades natriuretic peptides (BNP, ANP), bradykinin and adrenomedullin. Neprilysin inhibition raises endogenous BNP levels, promoting natriuresis, vasodilation and remodelling reversal. Because neprilysin inhibition also raises bradykinin (raising angioedema risk), sacubitril must always be combined with valsartan (AT1 blocker) rather than an ACE inhibitor. ACE inhibition and AT1 blockade are the roles of enalapril and valsartan respectively.

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

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