Carvedilol

Carvedilol is a non selective beta blocker with alpha 1 blocking and antioxidant properties. It is used in chronic heart failure with reduced ejection fraction, hypertension and angina, and in portal hypertension. The alpha blockade causes orthostatic hypotension, particularly at the start.

Classification. Non selective beta 1 and beta 2 blocker with alpha 1 blocking activity.

Mechanism. Blocks beta receptors (lowering heart rate and renin) and alpha 1 receptors (vasodilation, lowering afterload). It does not increase peripheral resistance, unlike pure beta blockers.

Pharmacodynamics. Heart rate and blood pressure fall within 1 to 2 hours; effect lasts 12 hours. Improves ejection fraction and reduces mortality in heart failure with reduced ejection fraction. Good effect on glycaemic control in diabetes compared with some other beta blockers.

Pharmacokinetics. Bioavailability about 25 to 35% because of first pass metabolism; food slows absorption. Half life 6 to 10 hours. Hepatic metabolism by CYP2D6 and CYP2C9; biliary excretion.

Heart failure with reduced ejection fraction, adult.

• Start 3.125 mg twice daily for 2 weeks, with food.

• Double the dose every 2 weeks as tolerated: 6.25, 12.5, 25 mg twice daily.

• Target 25 mg twice daily; for weight over 85 kg, target and maximum 50 mg twice daily.

• Start only when euvolaemic and stable.

Hypertension, adult.

• Start 12.5 mg once daily for 2 days, then 25 mg once daily.

• Increase after 2 weeks to a maximum of 50 mg daily in one or two doses.

Angina, adult. 12.5 mg twice daily for 2 days, then 25 mg twice daily; maximum 50 mg twice daily.

Portal hypertension, prevention of variceal bleeding, adult (specialist). 6.25 mg once daily for 3 days, then 6.25 mg twice daily; maximum 12.5 mg daily. Hold for systolic pressure under 90 mmHg.

Children. Heart failure and hypertension: specialist dosing.

Contraindications. Asthma and bronchospasm; decompensated heart failure needing inotropes; second or third degree atrioventricular block; sick sinus syndrome; severe bradycardia; severe hepatic impairment; cardiogenic shock; hypersensitivity.

Warnings. First dose and titration hypotension, bradycardia and worsening heart failure (fluid retention); take with food and rise slowly. Do not stop abruptly. Masks hypoglycaemia. Intraoperative floppy iris syndrome. Caution in peripheral vascular disease, Raynaud phenomenon, and diabetes.

Adverse effects. Dizziness, fatigue, bradycardia, hypotension, oedema, weight gain, diarrhoea, hyperglycaemia, sexual dysfunction.

Interactions. Verapamil and diltiazem: bradycardia and heart block. Digoxin: raised levels and bradycardia. Rifampicin lowers levels. CYP2D6 inhibitors (fluoxetine, paroxetine) and amiodarone raise levels. Ciclosporin: raised ciclosporin. Clonidine: rebound hypertension. Insulin and sulphonylureas: masked hypoglycaemia.

Special groups.

• Pregnancy: avoid unless essential; limited data and foetal growth concerns.

• Breastfeeding: avoid; no data.

• Older adults: start at the lowest dose; falls risk.

• Kidney impairment: no adjustment.

• Liver impairment: severe: contraindicated; mild to moderate: use with caution.

Formulations. Tablets 3.125, 6.25, 12.5, 25 mg; modified release capsules 10, 20, 40, 80 mg in some markets.

Administration. Oral with food, to slow absorption and limit orthostatic hypotension. Do not crush.

Baseline. Pulse, blood pressure sitting and standing, ECG, weight, liver function, volume status.

Monitoring. Blood pressure and heart rate at each titration step; weight and oedema each day or week in heart failure; if heart failure worsens, increase the diuretic first; liver function with symptoms.

Stopping. Taper over 1 to 2 weeks.

Common prescribing errors. Starting at too high a dose in heart failure; giving it fasting; starting in decompensation; forgetting the eye surgery warning.