Carvedilol for Portal Hypertension

Carvedilol is a nonselective beta-blocker with alpha-1 blocking activity. The alpha-1 action reduces intrahepatic vascular resistance, giving a larger fall in portal pressure than propranolol. It is used to prevent first variceal bleeding and rebleeding in cirrhosis, and it is now a preferred beta-blocker where it is available and blood pressure allows.

Classification. Nonselective beta-blocker with alpha-1 blockade.

Mechanism. Blocks beta-1 and beta-2 receptors, reducing cardiac output and causing splanchnic vasoconstriction. Alpha-1 blockade lowers intrahepatic resistance by relaxing hepatic stellate cells and sinusoidal tone, and reduces portal pressure further.

Pharmacodynamics. Reduces hepatic venous pressure gradient by about 20% to 25%, more than propranolol, with a higher response rate. It also lowers systemic blood pressure more than propranolol.

Pharmacokinetics. Oral bioavailability about 25% to 35% because of first-pass metabolism, and higher in cirrhosis. Peak at 1 to 2 hours. Half-life 6 to 10 hours. Protein binding above 98%.

Metabolism. Hepatic via CYP2D6 and CYP2C9; active metabolites; excreted mainly in bile and faeces.

Adult oral doses unless stated.

Prevention of first variceal bleeding (medium or large varices) and rebleeding.

• Start 3.125 mg twice daily.

• Increase after 3 days to 6.25 mg twice daily.

• Usual maintenance 6.25 mg twice daily, or 12.5 mg once daily.

• Maximum 12.5 mg daily in most patients (6.25 mg twice daily); up to 25 mg daily if blood pressure allows and there is no ascites.

• Aim for systolic blood pressure of at least 90 mmHg and a heart rate above 55 beats/min.

Prevention of rebleeding. Combine with endoscopic band ligation until varices are eradicated.

Acute variceal bleeding. Withhold until the acute episode is controlled and vasoactive drugs are stopped.

Decompensated cirrhosis with ascites. Use the lowest dose (3.125 mg twice daily) with strict monitoring; stop if systolic pressure falls under 90 mmHg, mean arterial pressure under 65 mmHg, kidney injury or sodium under 130 mmol/L.

Kidney and liver adjustment.

• Kidney impairment: no fixed adjustment; stop if acute kidney injury or hepatorenal syndrome develops.

• Liver impairment: Child-Pugh A and B: use the usual doses; Child-Pugh C: avoid or use with extreme caution.

Contraindications.

• Asthma; severe chronic obstructive pulmonary disease.

• Second or third degree heart block, sick sinus syndrome, severe bradycardia.

• Decompensated heart failure, cardiogenic shock.

• Systolic blood pressure under 90 mmHg; hepatorenal syndrome; acute kidney injury.

• Severe hepatic impairment (Child-Pugh C) in many labels.

• Hypersensitivity.

Common adverse effects. Dizziness, fatigue, hypotension, bradycardia, headache and oedema.

Serious adverse effects.

• Hypotension and acute kidney injury in decompensated cirrhosis with refractory ascites.

• Bronchospasm and heart block.

• Masking of hypoglycaemia symptoms.

• Abrupt withdrawal: rebound tachycardia and hypertension.

• Orthostatic hypotension and syncope after the first dose.

Major interactions.

• Verapamil and diltiazem: bradycardia and heart block; avoid.

• Insulin and oral antidiabetics: masked hypoglycaemia; enhanced glucose lowering.

• Other antihypertensives, diuretics and nitrates: additive hypotension.

• NSAIDs: reduced effect and kidney injury; avoid.

• CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine): raise carvedilol levels.

• Rifampicin: reduces levels.

• Digoxin: raised levels and added bradycardia.

• Ciclosporin: raised ciclosporin levels.

Special groups.

• Pregnancy: avoid; foetal growth restriction and neonatal bradycardia and hypoglycaemia.

• Breastfeeding: avoid or monitor the infant; levels in milk are low.

• Children: specialist use only.

• Older adults: start low; higher risk of hypotension.

• Kidney impairment: no adjustment, but monitor.

• Liver impairment: caution in Child-Pugh B; avoid in Child-Pugh C.

• Regional: availability and cost vary in East Africa; propranolol remains an option where carvedilol is not stocked.

Formulations. Tablets 3.125 mg, 6.25 mg, 12.5 mg and 25 mg; modified-release capsules in some markets.

Administration.

• Take with food to slow absorption and reduce orthostatic hypotension.

• Take the first dose and each increase when able to sit or lie down.

• Do not stop abruptly.

Baseline. Heart rate, blood pressure (sitting and standing), kidney function, sodium, endoscopy findings and presence of ascites.

Monitoring.

• Blood pressure and heart rate at each dose change and every visit.

• Sodium and creatinine every 1 to 3 months, particularly with ascites.

• Dizziness, fatigue and syncope.

• Endoscopy for varices at 3 to 6 months.

Therapeutic drug monitoring. Not applicable.

Stopping. Taper over 1 to 2 weeks. Stop at once for systolic pressure under 90 mmHg, acute kidney injury, hepatorenal syndrome, severe bradycardia or sepsis with shock.

Referral and escalation. Refer urgently for variceal bleeding. Refer for banding, transjugular intrahepatic portosystemic shunt assessment and liver transplant assessment.