Sacubitril in the combination sacubitril/valsartan (Entresto) acts as a prodrug for LBQ657. The mechanism of LBQ657 that benefits heart failure is:
- A Angiotensin-converting enzyme (ACE) inhibition, reducing angiotensin II and aldosterone
- B Neprilysin (neutral endopeptidase) inhibition, increasing natriuretic peptides (ANP, BNP) and reducing renin-angiotensin-aldosterone activity ✓
- C Direct renin inhibition, blocking angiotensinogen cleavage
- D Soluble guanylate cyclase stimulation, increasing intracellular cGMP
Correct answer: B. Neprilysin (neutral endopeptidase) inhibition, increasing natriuretic peptides (ANP, BNP) and reducing renin-angiotensin-aldosterone activity
Explanation
Sacubitril is cleaved by plasma esterases to the active metabolite LBQ657, a neprilysin inhibitor. Neprilysin degrades natriuretic peptides (ANP, BNP, CNP), bradykinin, and angiotensin II. Inhibiting neprilysin increases ANP/BNP, promoting natriuresis, diuresis, vasodilation, and reduced cardiac fibrosis. Because neprilysin also degrades angiotensin II, sacubitril alone would raise angiotensin II; valsartan (ARB) is combined to prevent this. Neprilysin is combined with ARB rather than ACEi because combined ACE/neprilysin inhibition risks fatal angioedema.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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