Angiotensin Receptor Blockers

Angiotensin receptor blockers selectively antagonise the AT1 receptor, blocking vasoconstriction, aldosterone release and sodium retention caused by angiotensin II. They offer the benefits of ACE inhibition without bradykinin accumulation, so cough is uncommon and angioedema is rare.

Members. Losartan, valsartan, candesartan, irbesartan, telmisartan, olmesartan, azilsartan and eprosartan.

Mechanism. The AT1 receptor mediates vasoconstriction, aldosterone secretion, sodium retention, cell growth and fibrosis. Blockade lowers blood pressure, reduces proteinuria and slows remodelling. Angiotensin II rises, which stimulates unblocked AT2 receptors that may add vasodilation.

Pharmacokinetics. Losartan is converted to an active metabolite (EXP3174) by CYP2C9 and CYP3A4, and also has a uricosuric effect. Candesartan cilexetil is a prodrug. Telmisartan has the longest half-life (about 24 hours) and partial PPAR-gamma activity. Olmesartan medoxomil is a prodrug. Most are excreted in bile and faeces, and candesartan, telmisartan and irbesartan are less dependent on renal clearance.

Pregnancy risk. The same foetal toxicity as ACE inhibitors.

• Losartan: shortest acting; uricosuric; diabetic nephropathy, left ventricular hypertrophy and Marfan syndrome use.
• Valsartan: hypertension, heart failure and after myocardial infarction.
• Candesartan: heart failure, hypertension and migraine prevention.
• Irbesartan: type 2 diabetic nephropathy.
• Telmisartan: once daily with long action; cardiovascular risk reduction in ACE inhibitor intolerance.
• Olmesartan: potent; sprue-like enteropathy is described.
• Azilsartan: high potency; limited use.

• Hypertension: losartan 50 mg daily (25 mg if volume depleted or with hepatic impairment) to 100 mg; valsartan 80 mg daily to 320 mg; candesartan 8 mg daily to 32 mg; irbesartan 150 mg daily to 300 mg; telmisartan 40 mg daily to 80 mg; olmesartan 20 mg daily to 40 mg.
• Heart failure with reduced ejection fraction (ACE inhibitor intolerance): candesartan 4 to 8 mg daily increased to 32 mg; valsartan 40 mg twice daily increased to 160 mg twice daily; losartan 25 to 50 mg daily increased to 150 mg.
• After myocardial infarction with left ventricular dysfunction: valsartan 20 mg twice daily, titrated to 160 mg twice daily.
• Diabetic kidney disease with albuminuria: losartan 50 to 100 mg daily or irbesartan 300 mg daily.
• Migraine prevention: candesartan 16 mg daily.
• Marfan syndrome: losartan titrated to the maximum tolerated dose, under specialist care.
• Selection: use in place of an ACE inhibitor for cough. After ACE inhibitor angioedema, use only with specialist input. Never combine with an ACE inhibitor or aliskiren.

Contraindications. Pregnancy, bilateral renal artery stenosis, hyperkalaemia, and severe hepatic impairment or biliary obstruction (several agents). Use with caution after ACE inhibitor-related angioedema, as cross-reactivity is rare but reported.

Adverse effects. Dizziness, hypotension, hyperkalaemia, acute kidney injury, fatigue, rare angioedema, and sprue-like enteropathy with olmesartan (weight loss and chronic diarrhoea).

Interactions. NSAIDs and potassium-raising drugs as with ACE inhibitors, lithium, fluconazole (lowers losartan activation through CYP2C9 inhibition), telmisartan raises digoxin, rifampicin lowers losartan, and combination with an ACE inhibitor or aliskiren raises hyperkalaemia, kidney injury and hypotension without added benefit.

Monitoring. Blood pressure, potassium and creatinine before starting, 1 to 2 weeks after each dose change, then yearly. Accept a creatinine rise up to 30%.

Sick day rule. Withhold during dehydrating illness.

Special groups. Pregnancy: stop before conception. Breastfeeding: limited data, so prefer enalapril or captopril. Hepatic impairment: start losartan at 25 mg daily and limit candesartan and valsartan doses. Renal impairment: adjust and monitor potassium closely. Black patients: lower monotherapy blood pressure response, but better than ACE inhibitors for angioedema risk. Older adults: start low.