Recallab › Question bank › Pharmacology › #50125
Neprilysin inhibition
Sacubitril is combined with valsartan for heart failure with reduced ejection fraction. What is the pharmacological effect of the sacubitril component?
- A. It inhibits angiotensin-converting enzyme
- B. It blocks the angiotensin II type 1 receptor
- correctC. It inhibits neprilysin, so natriuretic peptides are not broken down
- D. It blocks the mineralocorticoid receptor in the distal nephron
Explanation
Key fact
Sacubitril inhibits neprilysin, the enzyme that degrades natriuretic peptides, so their vasodilator and natriuretic effects are prolonged.
It inhibits neprilysin, so natriuretic peptides are not broken down. Valsartan supplies the receptor blockade; sacubitril supplies the peptide.
Why
A failing ventricle secretes atrial and B-type natriuretic peptides as a compensating response.
They cause vasodilatation, natriuresis and suppression of the renin-angiotensin-aldosterone axis.
Neprilysin, a neutral endopeptidase, degrades them within minutes.
Sacubitril's active metabolite inhibits neprilysin and prolongs their action.
Neprilysin also degrades angiotensin II, which is why an angiotensin receptor blocker must be given with it.
Boost the peptide the failing heart is already making, and block the one it is not helped by
Why not the others
- A. It inhibits angiotensin-converting enzyme — is the ACE inhibitor class. Combining an ACE inhibitor with sacubitril is in fact contraindicated, because both raise bradykinin and the two together risk angioedema.
- B. It blocks the angiotensin II type 1 receptor — is what the valsartan half does. The question asks about the sacubitril component.
- D. It blocks the mineralocorticoid receptor in the distal nephron — is spironolactone or eplerenone, a separate pillar of treatment.
Remember
Boost the good peptide, block the bad one. Natriuretic peptides up, angiotensin blocked - that is the whole design.
Go deeper
BNP itself is a neprilysin substrate, so it rises on treatment. Monitor NT-proBNP instead, which is not cleaved by neprilysin.
The 36-hour washout after stopping an ACE inhibitor exists for exactly the bradykinin reason, and is not needed when switching from an angiotensin receptor blocker.
Watch for hypotension and hyperkalaemia, and avoid it in previous angioedema.
Tripathi KD. Essentials of Medical Pharmacology, 9th ed. (Jaypee, 2024); Katzung's Basic & Clinical Pharmacology, 16th ed. (McGraw Hill, 2024).