Entresto
Entresto
Generic Name
Entresto
Mechanism
- Sacubitril: pro‑drug converted to the active neprilysin inhibitor LBQ657, increasing levels of natriuretic peptides, bradykinin, and adrenomedullin → vasodilation, natriuresis, diuresis, and inhibition of myocardial fibrosis.
- Valsartan: blocks angiotensin II type 1 (AT₁) receptors → reduces vasoconstriction, aldosterone release, sympathetic activation, and myocardial remodeling.
- The combination synergistically improves neurohormonal balance and hemodynamics in HFrEF.
Pharmacokinetics
| Parameter | Key Points |
| Absorption | Oral bioavailability ~30 % (sacubitril) and 6 % ( valsartan). Peak plasma ~1‑2 h after dosing. |
| Distribution | Protein binding: sacubitril ~10 %; valsartan ~90 %. |
| Metabolism | Sacubitril → LBQ657 by esterases; valsartan metabolized by CYP2C9/3A4. |
| Elimination | 70 % excreted renally (LBQ657), 30 % biliary. Clearance is linear; no accumulation after steady‑state dosing. |
| Half‑life | LBQ657 ~11 h; valsartan ~6 h (extended due to active metabolites). |
| Dose Adjustments | Renal: no adjustment, but monitor BUN/Cr; hepatic: no adjustment in mild‑moderate impairment. |
Indications
- Chronic heart failure with reduced ejection fraction (HFrEF) in patients ≥18 yrs, NYHA class II‑IV, left ventricular ejection fraction (LVEF) ≤35 %, and elevated NT‑proBNP.
- Use in heart failure patients who are intolerant of ACE inhibitors or ARBs or who have progressed on standard therapy.
> *Note*: Not indicated for heart failure with preserved ejection fraction (HFpEF) or isolated systolic hypertension.
Contraindications
| Category | Details |
| Contraindicated |
• History of angioedema related to ACE‑I or prior sacubitril/valsartan exposure. • Severe renal impairment (eGFR < 30 mL/min/1.73 m²). |
| Warnings |
• Hypotension, especially post‑load reduction. • Hyperkalaemia; monitor K⁺ and thyroid function. • Renal dysfunction: monitor BUN/Cr and electrolytes. • Pregnancy: Category X – teratogenic. |
| Precautions |
• Use with caution in patients with diabetes‑related nephropathy. • Avoid concurrent use of ACE inhibitors or ARBs beyond 7‑day washout; increase angioedema risk. |
Dosing
- Initial dose: 24 mg sacubitril / 26 mg valsartan BID (or 48 mg/52 mg if tolerated).
- Titration: after 1 week, increase to 97 mg / 103 mg BID if tolerated; may increase further to 194 mg / 205 mg BID per protocol.
- Administration: Oral tablets; may be taken with or without food.
- Timing: Maintain consistent dosing schedule; avoid overnight gaps >24 h.
- Switching: When transitioning from ACE‑I or ARB, allow a 36‑hour washout to mitigate angioedema risk.
Adverse Effects
| Adverse Effect | Incidence | Comments |
| Hypotension | 10–15 % | May require dose adjustment or diuretic adjustment. |
| Hyperkalaemia | 5–10 % | Baseline K⁺ >5.0 mmol/L is a relative contraindication. |
| Renal impairment | 3–6 % | Monitor eGFR; drug not indicated below 30 mL/min. |
| Cough | 3–4 % | Typically mild; distinguish from ACE‑I cough. |
| Dizziness; syncope | 3–5 % | Often related to blood pressure changes. |
| Angioedema (rare) | <0.01 % | Must discontinue immediately if occurs. |
| Elevated liver enzymes | <1 % | Monitor with chronic therapy. |
Monitoring
- Baseline: BUN/Cr, serum K⁺, BP, HR, LVEF, NT‑proBNP.
- Follow‑up (1–4 weeks after dose change): repeat renal panel, K⁺, vital signs.
- Ongoing: monitor weight, signs of fluid overload, and patient adherence.
- Annual: LVEF assessment in patients with progressive heart failure.
Clinical Pearls
- Washout Matters: Always allow ≥36 h between discontinuation of an ACE‑I/ARB and initiation of Entresto to avoid angioedema.
- Start Low, Go Slow: Begin at 24/26 mg BID unless evidence of intolerance; titrate twice weekly only if BP and renal function remain stable.
- Hyperkalaemia Watch: In patients on potassium‑sparing diuretics, statins, or ACE‑Is, keep K⁺ <5.2 mmol/L before adding Entresto.
- Pregnancy Precaution: Use barrier contraception; pregnancy‑test patients prior to therapy. Abortifacient effects documented.
- Patient Counseling: Emphasize consistent dosing, avoid alcohol (hypotension risk), and communicate signs of angioedema.
- Drug Interactions: Avoid concomitant use of other neprilysin inhibitors (e.g., inactivated; no other products). Beware of NSAID-induced renal dysfunction.
- Economic Note: The generic sacubitril/valsartan offers substantial cost savings while maintaining evidence-based efficacy.
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• Key Terms:
• Neprilysin inhibitor
• Angiotensin II receptor blocker
• Heart failure with reduced ejection fraction (HFrEF)
• NT‑proBNP
• Renal function
• Hyperkalaemia
These points distill Entresto’s pharmacology into a concise, searchable card suitable for medical students and healthcare professionals.