Sacubitril-valsartan (LCZ696) is used in HFrEF. Sacubitril's active metabolite LBQ657 improves haemodynamics by:

• A Inhibiting angiotensin-converting enzyme, reducing angiotensin II and aldosterone
• B Activating angiotensin type 2 receptors, causing vasodilation
• C Inhibiting aldosterone synthesis in the adrenal cortex
• D Blocking neprilysin (neutral endopeptidase), increasing natriuretic peptides and reducing preload and afterload ✓

Explanation

Sacubitril is a prodrug; its active metabolite LBQ657 inhibits neprilysin (neutral endopeptidase 24.11), which normally degrades natriuretic peptides (ANP, BNP), bradykinin, and other vasoactive peptides. Neprilysin inhibition raises circulating ANP and BNP levels, promoting natriuresis, diuresis, and vasodilation, reducing preload and afterload. Valsartan (ARB) component blocks AT1 to prevent RAAS-driven vasoconstriction. ACEI inhibition and AT2 activation are different mechanisms. Aldosterone synthesis inhibition is the mechanism of aminoglutethimide or metyrapone.

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

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Written and medically reviewed by the StethoPrep medical team.