Angiotensin receptor blockers and neprilysin inhibitors

Introduction

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Among pharmacological strategies, renin-angiotensin-aldosterone system (RAAS) inhibitors play a central role in the management of hypertension, heart failure, and chronic kidney disease.

Two important categories within this therapeutic spectrum are:

• Angiotensin II receptor blockers (ARBs): Block the angiotensin II type 1 (AT1) receptor, reducing vasoconstriction, aldosterone release, and hypertensive effects.

• Angiotensin receptor–neprilysin inhibitors (ARNIs): Combine an ARB with a neprilysin inhibitor, augmenting natriuretic peptide activity and providing superior outcomes in chronic heart failure.

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Mechanism of Action

Angiotensin II Receptor Blockers (ARBs)

• Selectively block AT1 receptors, preventing angiotensin II from exerting its pressor effects.

• This leads to:

  • Vasodilation (reduced peripheral resistance)

  • Decreased aldosterone secretion (less sodium and water retention)

  • Reduced sympathetic activation

  • Anti-proliferative and anti-remodeling effects in the heart and vasculature

• Unlike ACE inhibitors, ARBs do not inhibit bradykinin breakdown, so they have a lower incidence of cough and angioedema.

Neprilysin Inhibitors

• Neprilysin is a neutral endopeptidase that degrades vasoactive peptides such as natriuretic peptides (ANP, BNP), bradykinin, and adrenomedullin.

• Inhibition of neprilysin increases levels of these peptides, leading to:

  • Vasodilation

  • Natriuresis and diuresis

  • Reduced sympathetic tone

  • Inhibition of cardiac fibrosis and hypertrophy

ARNI (Angiotensin Receptor–Neprilysin Inhibitor)

• Sacubitril/valsartan is the first-in-class ARNI.

• Sacubitril (prodrug converted to LBQ657) inhibits neprilysin.

• Valsartan blocks AT1 receptors, preventing the RAAS from counteracting the effects of increased natriuretic peptides.

• This combination produces synergistic benefits: improved hemodynamics, reduced hospitalizations, and decreased mortality in chronic heart failure with reduced ejection fraction (HFrEF).

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Representative Drugs

Angiotensin II Receptor Blockers (ARBs)

1. Losartan

• First ARB approved.

• Indications: Hypertension, diabetic nephropathy, heart failure (off-label).

• Dose: 25–100 mg daily in 1–2 divided doses.

2. Valsartan

• Indications: Hypertension, heart failure, post-myocardial infarction.

• Dose: 80–320 mg daily in 1–2 divided doses.

3. Irbesartan

• Indications: Hypertension, diabetic nephropathy.

• Dose: 150–300 mg once daily.

4. Candesartan

• Indications: Hypertension, heart failure.

• Dose: 8–32 mg once daily.

5. Olmesartan

• Indication: Hypertension.

• Dose: 20–40 mg once daily.

6. Telmisartan

• Indications: Hypertension, cardiovascular risk reduction.

• Dose: 20–80 mg once daily.

7. Eprosartan

• Indication: Hypertension.

• Dose: 400–800 mg once daily.

8. Azilsartan

• Indication: Hypertension.

• Dose: 40–80 mg once daily.

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Angiotensin Receptor–Neprilysin Inhibitors (ARNIs)

1. Sacubitril/Valsartan (Entresto®)

• Indications:

  • Chronic symptomatic heart failure with reduced ejection fraction (NYHA class II–IV).

  • Recently studied for heart failure with preserved EF (HFpEF) with modest benefits.

• Doses:

  • Starting: 49/51 mg orally twice daily.

  • Low-dose initiation (24/26 mg BID) in renal/hepatic impairment or low BP.

  • Target: 97/103 mg orally twice daily.

• Switching from ACE inhibitors: Must allow a 36-hour washout period to avoid risk of angioedema.

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Clinical Uses

ARBs

• Hypertension: First-line therapy in many guidelines, especially in patients intolerant of ACE inhibitors.

• Heart failure: Reduce hospitalizations, improve symptoms, alternative to ACE inhibitors.

• Diabetic nephropathy and proteinuric CKD: Slow progression of renal disease.

• Post-MI: Improve survival and reduce remodeling (valsartan, losartan).

• Stroke prevention: Losartan in LIFE trial demonstrated benefit in hypertensive patients with left ventricular hypertrophy.

ARNIs

• Heart failure with reduced ejection fraction (HFrEF):

  • PARADIGM-HF trial demonstrated superior mortality and morbidity reduction compared to enalapril.

• Heart failure with preserved EF (HFpEF):

  • PARAGON-HF trial showed modest reduction in hospitalizations, with some subgroup benefit.

• Evolving role in hypertension and cardiovascular protection beyond HF.

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Contraindications

• ARBs:

  • Hypersensitivity.

  • Pregnancy (Category D in 2nd/3rd trimester, teratogenic risk).

  • Bilateral renal artery stenosis (risk of acute renal failure).

  • Severe hepatic impairment (drug-specific adjustments).

• ARNIs:

  • Same as ARBs, plus:

  • Concomitant use with ACE inhibitors (risk of angioedema).

  • History of angioedema with ACE inhibitors or ARBs.

  • Use with aliskiren in diabetic patients.

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Adverse Effects

ARBs

• Hypotension, dizziness.

• Hyperkalemia (due to aldosterone suppression).

• Worsening renal function in susceptible patients.

• Rare: angioedema (less frequent than ACE inhibitors).

ARNIs

• Hypotension (more common than with ACE inhibitors).

• Hyperkalemia.

• Worsening renal function.

• Cough (less than ACE inhibitors, more than ARBs).

• Angioedema (rare, higher risk in Black patients).

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Precautions

• Monitor blood pressure, renal function, and serum potassium regularly.

• Avoid potassium supplements and potassium-sparing diuretics unless essential.

• Use caution in patients with volume depletion or hyponatremia.

• Elderly patients may be more prone to hypotension.

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Drug Interactions

• Potassium-sparing diuretics / Potassium supplements: Increased risk of hyperkalemia.

• NSAIDs: Reduce antihypertensive and renal-protective effects; increase risk of renal impairment.

• Lithium: Reduced clearance, risk of lithium toxicity.

• ACE inhibitors / aliskiren: Contraindicated with ARNIs due to angioedema risk.

• PDE5 inhibitors (sildenafil): Additive hypotension.

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Clinical Evidence

• LIFE trial (Losartan): Reduced risk of stroke compared with atenolol in hypertensive patients with LVH.

• VALUE trial (Valsartan): Effective in lowering BP and reducing morbidity in high-risk hypertensives.

• CHARM trial (Candesartan): Improved outcomes in chronic heart failure patients.

• PARADIGM-HF trial (Sacubitril/Valsartan): 20% reduction in cardiovascular death and HF hospitalization compared with enalapril.

• PARAGON-HF trial: Did not reach primary endpoint in HFpEF, but subgroup benefits noted.

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Future Perspectives

• Development of next-generation ARNIs with longer half-life and improved tolerability.

• Potential use in resistant hypertension, CKD progression, and prevention of atrial fibrillation.

• Ongoing studies exploring ARNI use in pediatric heart failure.

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Summary of Key Agents and Doses

• Losartan: 25–100 mg/day PO.

• Valsartan: 80–320 mg/day PO.

• Irbesartan: 150–300 mg/day PO.

• Candesartan: 8–32 mg/day PO.

• Olmesartan: 20–40 mg/day PO.

• Telmisartan: 20–80 mg/day PO.

• Sacubitril/Valsartan: Start 49/51 mg BID, target 97/103 mg BID.