Combined Alpha and Beta Blockers

Combined alpha and beta blockers block alpha-1 receptors and beta receptors together, so they lower blood pressure by vasodilation as well as by reducing cardiac output. Labetalol and carvedilol are the members. They avoid the rise in peripheral resistance seen with pure beta blockers.

Labetalol. Non-selective beta blockade plus alpha-1 blockade, in a ratio of about 3 to 1 orally and 7 to 1 intravenously. It has partial beta-2 agonist activity.

Carvedilol. Non-selective beta blockade plus alpha-1 blockade, with antioxidant and anti-proliferative effects. Lipophilic and extensively metabolised by CYP2D6 and CYP2C9.

Mechanism. Alpha-1 blockade relaxes arterioles, lowering afterload. Beta blockade slows the heart and reduces renin. Heart rate falls less than with pure beta blockers, and cardiac output is largely preserved.

Pharmacokinetics. Labetalol is metabolised by glucuronidation with a half-life of 6 to 8 hours and onset within 5 minutes intravenously. Carvedilol has a half-life of 6 to 10 hours, high first pass metabolism, and food slows absorption but reduces orthostatic effect. Carvedilol inhibits P-glycoprotein.

• Labetalol: oral and intravenous; hypertension in pregnancy, hypertensive emergencies, phaeochromocytoma-related crisis (with caution), and perioperative hypertension.
• Carvedilol: oral; heart failure with reduced ejection fraction, left ventricular dysfunction after myocardial infarction, hypertension, and portal hypertension.

• Hypertension in pregnancy: labetalol 100 to 200 mg orally twice daily, increased every 2 to 3 days to a usual maximum of 2.4 g daily in divided doses. First line in many settings, with nifedipine and methyldopa as alternatives.
• Severe hypertension (blood pressure 160/110 mmHg or more) in pregnancy: labetalol 20 mg intravenously, then 40 to 80 mg every 10 minutes to a maximum of 300 mg, or an infusion titrated from about 20 mg/hour.
• Hypertensive emergency: labetalol 20 mg intravenously over 2 minutes, then 40 to 80 mg every 10 minutes up to 300 mg, or infusion 0.5 to 2 mg/minute. Avoid in acute heart failure and in cocaine or amphetamine toxicity when bradycardia or cardiac failure is a concern.
• Heart failure with reduced ejection fraction: carvedilol 3.125 mg twice daily, doubled every 2 weeks to 25 mg twice daily (50 mg twice daily if over 85 kg), taken with food.
• Hypertension (carvedilol): 12.5 mg daily for 2 days, then 25 mg daily, to a maximum of 50 mg daily in divided doses.
• Portal hypertension: carvedilol 6.25 mg daily, increased after 3 days to 6.25 mg twice daily, maximum 12.5 mg daily. Stop if systolic pressure falls under 90 mmHg.
• Phaeochromocytoma: labetalol is not first line, and alpha blockade with phenoxybenzamine or doxazosin should come first. Paradoxical hypertension has been reported when beta blockade predominates.
• Selection: prefer a combined agent when vasodilation is wanted along with rate control, in pregnancy, and in heart failure with hypertension.

Contraindications. Asthma, heart rate under 50 beats/minute, second or third degree atrioventricular block without a pacemaker, cardiogenic shock, acute decompensated heart failure, and for carvedilol severe hepatic impairment.

Adverse effects. Postural hypotension, dizziness, fatigue, bradycardia, scalp tingling (labetalol), nausea, bronchospasm, impaired ejaculation, fluid retention and transient worsening of heart failure at carvedilol initiation, and hyperglycaemia. Labetalol rarely causes acute hepatocellular injury.

Interactions. Verapamil and diltiazem, digoxin (carvedilol raises levels by about 15%), ciclosporin (carvedilol raises levels), amiodarone, CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine) raise carvedilol, rifampicin lowers it, insulin masks hypoglycaemia, halothane adds hypotension.

Monitoring. Blood pressure supine and standing, heart rate, liver tests if symptoms of hepatitis appear, weight and signs of fluid retention in heart failure, glucose in diabetes.

Referral and escalation. Failure of intravenous labetalol to control severe hypertension needs senior review and an alternative agent. Jaundice or dark urine means stopping the drug and testing liver function.

Special groups. Pregnancy: labetalol is established and carvedilol has limited data. Neonates exposed late in pregnancy need observation for hypoglycaemia and bradycardia. Breastfeeding: labetalol is compatible. Hepatic impairment: reduce labetalol dose; avoid carvedilol in severe disease. Older adults: start low because of postural hypotension. Renal impairment: no adjustment is usually needed.