Mode of action of arni
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angiotensin neprilysin inhibitor
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ARNI sacubitril valsartan mechanism of action prescribing information
ARNI = Angiotensin receptor-neprilysin inhibitor, usually referring to the combination sacubitril + valsartan.
Mechanism of action
It works by two complementary mechanisms:
-
Sacubitril inhibits neprilysin
- Sacubitril is a prodrug, converted to the active metabolite sacubitrilat (LBQ657).
- Neprilysin normally breaks down natriuretic peptides such as ANP, BNP, and CNP.
- Its inhibition increases these peptides, leading to:
- Vasodilation
- Increased sodium and water excretion (natriuresis and diuresis)
- Reduced aldosterone activity
- Reduced cardiac preload and afterload
- Less myocardial hypertrophy and fibrosis
-
Valsartan blocks angiotensin-II AT1 receptors
- It prevents angiotensin II mediated vasoconstriction, sodium retention, aldosterone release, sympathetic activation, and adverse cardiac remodeling.
- This is necessary because neprilysin also metabolizes angiotensin II. Neprilysin inhibition alone could therefore increase angiotensin II activity.
Net effect: ARNI enhances the beneficial natriuretic peptide system while blocking the harmful renin-angiotensin-aldosterone system. This reduces congestion and cardiac remodeling and improves outcomes in heart failure with reduced ejection fraction. FDA prescribing information
Simple flow
Sacubitril → inhibits neprilysin → ↑ ANP/BNP → vasodilation + natriuresis + anti-fibrotic effects
Valsartan → AT1 receptor blockade → ↓ vasoconstriction + ↓ aldosterone + ↓ remodeling
Valsartan → AT1 receptor blockade → ↓ vasoconstriction + ↓ aldosterone + ↓ remodeling
Important clinical point
Do not combine an ARNI with an ACE inhibitor. A 36-hour washout is required when switching from an ACE inhibitor to sacubitril/valsartan because combined bradykinin-related effects increase the risk of angioedema.
Source: Lippincott Illustrated Reviews: Pharmacology, Figure 10.6; Fuster and Hurst's The Heart, Sacubitril/Valsartan section.
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