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Wednesday, August 20, 2025

Angiotensin receptor blockers


Introduction

Angiotensin II receptor blockers (ARBs) are a class of antihypertensive agents that act by blocking the effects of angiotensin II at its receptor. They were developed as an alternative to angiotensin-converting enzyme (ACE) inhibitors, particularly for patients who develop cough or angioedema with ACE inhibitors.

Since their introduction in the 1990s, ARBs have become one of the most widely prescribed groups of cardiovascular drugs. They are considered first-line agents for hypertension and play key roles in the management of heart failure, chronic kidney disease (CKD), and post-myocardial infarction (MI) remodeling.

Mechanism of Action

  • Angiotensin II is the main effector peptide of the renin–angiotensin–aldosterone system (RAAS).

  • It exerts its actions primarily through the AT1 receptor, which mediates:

    • Vasoconstriction (↑ blood pressure)

    • Aldosterone secretion (↑ sodium/water retention, ↑ potassium excretion)

    • Increased sympathetic nervous system activity

    • Vascular and cardiac hypertrophy and remodeling

  • ARBs selectively block the AT1 receptor, thereby:

    • Preventing vasoconstriction

    • Reducing aldosterone-mediated sodium and water retention

    • Decreasing sympathetic activation

    • Inhibiting pathologic remodeling of the heart and vessels

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

Pharmacological Effects

  • Vasodilation: Reduces systemic vascular resistance.

  • Natriuresis: Decreased sodium and water reabsorption.

  • Renal protection: Reduces intraglomerular pressure, slowing progression of diabetic nephropathy.

  • Cardiac protection: Inhibits myocardial remodeling after MI and in heart failure.

  • Vascular protection: Reduces hypertrophy and stiffness of arterial walls.

Representative Drugs and Doses

1. Losartan

  • Indications: Hypertension, diabetic nephropathy, heart failure, stroke prevention.

  • Dose: 25–100 mg orally once or twice daily.

  • Notes: Active metabolite (EXP3174) is more potent. First ARB to be approved.

2. Valsartan

  • Indications: Hypertension, heart failure, post-MI left ventricular dysfunction.

  • Dose: 80–320 mg once or twice daily.

  • Notes: Often preferred in heart failure patients (evidence from VALIANT trial).

3. Irbesartan

  • Indications: Hypertension, diabetic nephropathy in type 2 diabetes.

  • Dose: 150–300 mg once daily.

4. Candesartan

  • Indications: Hypertension, heart failure with reduced ejection fraction (HFrEF).

  • Dose: 8–32 mg once daily.

  • Notes: CHARM trial showed significant benefits in heart failure.

5. Olmesartan

  • Indications: Hypertension.

  • Dose: 20–40 mg once daily.

  • Notes: Potent antihypertensive effect.

6. Telmisartan

  • Indications: Hypertension, cardiovascular risk reduction (alternative to ACE inhibitors).

  • Dose: 20–80 mg once daily.

  • Notes: Longest half-life among ARBs (24 hours).

7. Eprosartan

  • Indications: Hypertension.

  • Dose: 400–800 mg once daily.

8. Azilsartan

  • Indications: Hypertension.

  • Dose: 40–80 mg once daily.

  • Notes: Potent, newer ARB.

Clinical Uses

1. Hypertension

  • Recommended as first-line therapy in most guidelines.

  • Effective as monotherapy or in combination with thiazide diuretics, calcium channel blockers, or beta-blockers.

  • Especially useful in patients with:

    • Diabetes

    • Chronic kidney disease

    • Left ventricular hypertrophy

2. Heart Failure (HFrEF)

  • ARBs reduce hospitalization and mortality (especially candesartan, valsartan, losartan).

  • Indicated in patients intolerant of ACE inhibitors.

  • Can be used in combination with beta-blockers, diuretics, and mineralocorticoid receptor antagonists.

3. Diabetic Nephropathy / CKD with Proteinuria

  • Reduce intraglomerular hypertension and proteinuria.

  • Delay progression of renal disease in type 2 diabetes (irbesartan, losartan).

  • Often combined with strict blood pressure and glycemic control.

4. Post-Myocardial Infarction

  • Improve survival and reduce remodeling.

  • Alternative to ACE inhibitors in patients intolerant to them (valsartan has strongest evidence).

5. Stroke Prevention

  • Losartan demonstrated stroke prevention in the LIFE trial in hypertensive patients with left ventricular hypertrophy.

Contraindications

  • Pregnancy (Category D; teratogenic, fetotoxic).

  • Bilateral renal artery stenosis or severe unilateral stenosis in a solitary kidney (risk of acute renal failure).

  • Severe hepatic impairment (dose adjustments may be required).

  • Hypersensitivity to the drug.

Adverse Effects

  • Generally well tolerated; side effects are usually mild.

Common:

  • Dizziness, headache, fatigue.

  • Hypotension (especially in volume-depleted patients).

  • Hyperkalemia (due to reduced aldosterone).

Serious (rare):

  • Angioedema (much less common than with ACE inhibitors).

  • Renal impairment, especially in patients with bilateral renal artery stenosis.

Precautions

  • Monitor serum potassium and renal function regularly.

  • Caution when combining with potassium supplements or potassium-sparing diuretics.

  • Use carefully in elderly patients and those with renal impairment.

  • Not recommended during lactation.

Drug Interactions

  • Potassium-sparing diuretics, potassium supplements, salt substitutes: Risk of hyperkalemia.

  • NSAIDs: May reduce antihypertensive effect, increase risk of renal dysfunction.

  • Lithium: Increased risk of lithium toxicity (reduced renal clearance).

  • Aliskiren: Combination contraindicated in diabetic patients (increased renal risk).

  • Other antihypertensives: Additive hypotensive effects.

Clinical Evidence

  • LIFE trial (Losartan): Demonstrated stroke risk reduction compared to atenolol.

  • VALIANT trial (Valsartan): Shown to be as effective as captopril post-MI.

  • CHARM trial (Candesartan): Improved survival and reduced hospitalizations in HFrEF.

  • IDNT and IRMA-2 trials (Irbesartan): Delayed progression of diabetic nephropathy.

  • ROADMAP trial (Olmesartan): Delayed onset of microalbuminuria in diabetics.

Comparison with ACE Inhibitors

  • Both classes act on RAAS but at different sites.

  • ACE inhibitors: Block angiotensin II formation, increase bradykinin (leading to cough, angioedema).

  • ARBs: Block angiotensin II receptors directly, do not increase bradykinin.

  • Clinical evidence: ACE inhibitors historically had stronger outcome data, but ARBs are considered equally effective in most indications, and often better tolerated.

Future Perspectives

  • Expanded role in combination therapies (e.g., ARNI: sacubitril/valsartan).

  • Exploration in resistant hypertension, CKD progression, and metabolic syndrome.

  • Ongoing studies investigating ARBs in preventing atrial fibrillation and other cardiovascular outcomes.

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.

  • Eprosartan: 400–800 mg/day PO.

  • Azilsartan: 40–80 mg/day PO.



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