Sacubitril and valsartan | Pharmacology Mentor

Generic Name

Sacubitril/valsartan

Sacubitril is a prodrug of LBQ657, a potent, non‑peptide neprilysin inhibitor. By blocking neprilysin, it blocks the degradation of natriuretic peptides (NPs), bradykinin, adrenomedullin, and adenosine, leading to:
vasodilation
natriuresis & diuresis
diuretic‑independent, renal‑protective effects
inhibition of cardiac remodeling.
Valsartan competitively antagonizes the angiotensin II type‑1 (AT1) receptor, preventing vasoconstriction, aldosterone release, sympathetic activation, and fibrotic changes.
The combined effect synergistically lowers blood pressure, reduces preload/afterload, and improves survival in HFrEF patients.

Absorption: Oral bioavailability ~40% (after 4‑hour delayed release). Tmax 3–5 h.
Distribution: Large volume of distribution; plasma protein binding ~80% (sacubitril ~87%, valsartan ~70%).
Metabolism: Sacubitril → LBQ657 via esterases; LBQ657 mainly metabolized by CYP3A4/3A5; valsartan glucuronidated by UGT1A9; minimal CYP450 involvement.
Elimination: Renal excretion (~60%) of LBQ657; valsartan excreted renal (≈45%) & hepatic (≈55%).
Half‑life: LBQ657 ~10 h, valsartan ~9 h; supports BID dosing.
Food: No clinically meaningful effect.
Drug‑Drug Interactions:
↑ potassium‑sparing agents ↑ hyperkalemia risk.
Concomitant ACE inhibitors/ARBs contraindicated.
CYP3A4 inhibitors/inducers minimally affect efficacy.

HFrEF: NYHA class II–IV with LVEF ≤ 35 % on guideline‑directed therapy.
Primary endpoints: ↓ all‑cause mortality, ↓ HF hospitalizations.
Off‑label: Unapproved for hypertension; limited evidence as sole antihypertensive in HFrEF.

Contraindications
History of angioedema related to previous ACEi/ARB or ARNI therapy.
Severe renal impairment (CrCl < 30 mL/min) or hemodynamic instability (*see warnings*).
Pregnancy; potential fetal harm.
Biphasic or complete atrioventricular block without pacemaker.
Warnings & Precautions
Hypotension – especially post‑initiation or dose escalation.
Hyperkalemia – monitor serum K⁺; avoid concomitant K⁺‑sparing diuretics or supplements.
Renal Function Decline – may worsen serum creatinine up to 30 % initially; expect steady‑state after 3–4 weeks.
Reversible angioedema – prompt discontinuation if swelling develops.
Drug‑elevated risk of angioedema with concomitant NSAIDs, corticosteroids, or IL‑1/IL‑6 inhibitors.

Initiation (stable HFrEF on ACEi/ARB):
Start: 24/26 mg BID (sacubitril/valsartan).
Titration: In 2‑week intervals → 49/51 mg BID → 97/103 mg BID (target).
Maximum: 97/103 mg BID, but 49/51 mg BID may be adequate in elderly or renal impairment.
Patient‑Specific Adjustments
Renal impairment (CrCl 30–50 mL/min): start 24/26 mg BID, titrate cautiously.
Severe impairment (CrCl 15–30 mL/min) or dialysis: not recommended.
Switching from ACEi/ARB → 36 h washout before starting ARNI.
Administration: With meals, take one dose in the morning, the second dose 12 h later. Avoid skipping >1 dose.

Parameter	Target / Interval	Notes
Blood pressure	90–140 / 60–90 mm Hg	Check baseline, weeks 2, 4, then monthly.
Serum creatinine & eGFR	≤ increase 30 %	Baseline; weeks 1‑2; then quarterly.
Serum potassium	3.5–5.5 mmol/L	Baseline; add 2–3 weeks; then quarterly.
LVEF	≥ 30 %	Imaging at baseline, 6–12 months.
NYHA class	Improvement/steady	Every clinic visit.
Adverse reaction screening	During titration	Angioedema, dizziness, syncope.

ARNI vs. ACEi/ARB – *Entresto* reduces mortality by ~25 % over ACEi alone in HFrEF; use as first‑line when tolerated.
Switching Protocol – Always observe a 36‑hour washout after stopping ACEi or 12‑hour after ARB to prevent angioedema.
Initiate Low – In frail, elderly, or mild renal impairment, start at 24/26 mg BID and titrate every 2 weeks; avoid exceeding 49/51 mg BID if CrCl  30 % after 4 weeks, reassess dose or discontinue.
Pregnancy Caution – Category X; availed only in patients agreeing on effective contraception.
Drug Interaction “Tip” – CYP3A4 inhibitors (ketoconazole, clarithromycin) increase LBQ657 exposure by ~30 %; monitor for hypotension.
Cost‑Effectiveness Insight – Though expensive, ARNI may reduce readmission costs by ~30 % in long‑term HF management.

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• References

1. McMurray JJ, et al. *N Engl J Med* 2014;371:593‑603.

2. ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2022.

3. FDA Drug Label: Entresto (Sacubitril/valsartan).

4. Mayo Clinic: Arni (Sacubitril‑Valsartan).

*(All data current as of 2026-01-02).*