Mechanism of Action of Entresto (Sacubitril/Valsartan)

Introduction

Entresto is a combination drug containing sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker (ARB). It’s primarily used for the treatment of heart failure with reduced ejection fraction (HFrEF). The combination enhances natriuretic peptide levels while blocking deleterious effects of angiotensin II, working synergistically to reduce mortality and hospitalizations in heart failure.

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Step-by-Step Mechanism of Action

1. Neprilysin inhibition by sacubitril
   Sacubitril (a prodrug) is converted to its active form, LBQ657, which inhibits neprilysin—an enzyme that degrades natriuretic peptides (ANP, BNP), bradykinin, and adrenomedullin.
2. Increased natriuretic peptide levels
   With neprilysin inhibited, ANP/BNP accumulate, promoting natriuresis, diuresis, systemic vasodilation, and reduced sympathetic tone.
3. Valsartan blocks AT₁ receptors
   Valsartan competitively inhibits angiotensin II at the AT₁ receptor, reducing vasoconstriction, aldosterone release, and vasopressin secretion, and decreasing cardiac remodeling.
4. Synergistic effect in heart failure
   By enhancing vasodilatory and natriuretic effects while blocking RAAS activation, Entresto improves hemodynamics, reduces preload and afterload, and mitigates progression of heart failure.
5. Balanced pharmacodynamics
   The ARB component limits the risk of angioedema associated with increased bradykinin from neprilysin inhibition, making it safer than neprilysin inhibitors alone.

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Pharmacokinetic Parameters

Parameter	Entresto / Components
Bioavailability	~60% (sacubitril), ~23% (valsartan)
Time to peak plasma	0.5–1 hour (LBQ657), 1–2 hours (valsartan)
Protein Binding	LBQ657 ~97%, valsartan ~95%
Metabolism	Sacubitril → LBQ657 via esterases; valsartan unaffected
Half-life	LBQ657 ~11 hours, valsartan ~14 hours
Elimination	LBQ657 renal; valsartan biliary/renal

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Clinical Uses

• Management of HFrEF to reduce cardiovascular death and hospitalization
• Recommended in place of ACE inhibitor or ARB in appropriate patients
• Not indicated for hypertension alone

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Adverse Effects

• Hypotension (most common)
• Hyperkalemia
• Cough and dizziness
• Renal impairment
• Potential angioedema (rare)
• Contraindicated with ACE inhibitors (due to angioedema risk)

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Comparative Analysis

Therapy	Mechanism Interaction	Advantage over ACE inhibitor alone
Entresto	Dual neprilysin and AT₁ blockade	Greater mortality reduction
ACE inhibitor + sacubitril	Inhibits ACE and neprilysin	Higher risk of angioedema
Valsartan alone	AT₁ blockade only	Less benefit than combination

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MCQs (15 Questions)

1. Entresto is a combination of:
a) ACE inhibitor + beta-blocker
b) Neprilysin inhibitor + ARB
c) Statin + ARB
d) ARB + diuretic
Answer: b) Neprilysin inhibitor + ARB

2. Sacubitril inhibits:
a) ACE
b) Neprilysin
c) Renin
d) Aldosterone synthase
Answer: b) Neprilysin

3. Increased natriuretic peptides cause all EXCEPT:
a) Natriuresis
b) Sympathetic activation
c) Vasodilation
d) Diuresis
Answer: b) Sympathetic activation

4. Valsartan blocks:
a) AT₂ receptor
b) AT₁ receptor
c) ACE
d) Bradykinin
Answer: b) AT₁ receptor

5. Combination therapy is preferred because:
a) Reduces bradykinin levels
b) Increases cardiac remodeling
c) Provides synergistic neurohormonal blockade
d) Causes more hypertension
Answer: c) Provides synergistic neurohormonal blockade

6. Major side effect of Entresto is:
a) Hypokalemia
b) Hypotension
c) Weight gain
d) Cough
Answer: b) Hypotension

7. Angioedema risk is reduced compared to:
a) ARB alone
b) ACE inhibitor alone
c) Beta-blocker + ARB
d) Statin
Answer: b) ACE inhibitor alone

8. Entresto is indicated for:
a) Hypertension only
b) HFrEF
c) Stroke prevention
d) Dyslipidemia
Answer: b) HFrEF

9. Neprilysin degrades all EXCEPT:
a) ANP
b) BNP
c) Bradykinin
d) Epinephrine
Answer: d) Epinephrine

10. Half-life of sacubitril’s active form LBQ657 is approx:
a) 2 hours
b) 11 hours
c) 24 hours
d) 1 hour
Answer: b) 11 hours

11. Protein binding of valsartan is around:
a) 50%
b) 80%
c) 95%
d) <10%
Answer: c) 95%

12. Sacubitril is converted to LBQ657 by:
a) CYP enzymes
b) Esterases
c) Dehydrogenases
d) Kinases
Answer: b) Esterases

13. Entresto therapy requires stopping ACE inhibitor 36 hours prior to avoid:
a) Hyperkalemia
b) Angioedema
c) Hypotension
d) Cough
Answer: b) Angioedema

14. Which lab may increase on Entresto?
a) Sodium
b) Potassium
c) Calcium
d) LDL
Answer: b) Potassium

15. Patients with renal artery stenosis should:
a) Use Entresto freely
b) Avoid Entresto
c) Double the dose
d) Add ACE inhibitor
Answer: b) Avoid Entresto

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FAQs

1. Can Entresto be started directly in ACE inhibitor-naïve patients?
Yes, but ACE inhibitors must be discontinued at least 36 hours before starting.

2. Is Entresto safe during pregnancy?
No—it’s contraindicated due to ARB component.

3. What monitoring is required?
Blood pressure, renal function, and potassium levels.

4. Can Entresto cause cough?
Less likely than ACE inhibitors due to ARB component.

5. Is dose adjustment needed in renal impairment?
Moderate impairment usually not contraindicated, but severe may require cautious use.

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References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition
• KD Tripathi. Essentials of Medical Pharmacology, 8th Edition
• PARADIGM‑HF trial analysis of sacubitril/valsartan efficacy
• StatPearls: Sacubitril/Valsartan in heart failure
• PubMed: Pharmacokinetics of LBQ657
• Mechanistic insights into natriuretic peptide modulation