Propranolol for Portal Hypertension

Propranolol is a nonselective beta-blocker used to lower portal pressure and reduce variceal bleeding in cirrhosis. It is used for primary prevention of first variceal bleeding in patients with medium or large varices, and with endoscopic band ligation for secondary prevention after bleeding. Carvedilol is a preferred alternative.

Classification. Nonselective beta-adrenergic blocker.

Mechanism. Blocks beta-1 receptors, reducing cardiac output, and beta-2 receptors, causing unopposed alpha-mediated splanchnic vasoconstriction. Both lower splanchnic blood flow and portal pressure.

Pharmacodynamics. Reduces hepatic venous pressure gradient by about 10% to 20%. A fall to below 12 mmHg, or by at least 20% from baseline, protects against bleeding. Heart rate falls within 1 to 2 hours.

Pharmacokinetics. Oral bioavailability about 25% because of high first-pass metabolism, rising in cirrhosis. Peak at 1 to 4 hours. Half-life 3 to 6 hours. Protein binding about 90%.

Metabolism. Hepatic via CYP2D6 and CYP1A2; active metabolite 4-hydroxypropranolol. Excreted in urine.

Adult oral doses unless stated.

Prevention of first variceal bleeding (medium or large varices, or varices with red signs).

• Start 20 to 40 mg twice daily.

• Increase every 2 to 3 days to reach a resting heart rate of 55 to 60 beats/min, systolic blood pressure of at least 90 mmHg, and no symptoms.

• Usual maintenance 40 to 160 mg daily in divided doses; for long-acting formulations, 80 to 160 mg once daily.

• Maximum 160 mg daily in patients without ascites and 80 mg daily in patients with ascites.

Prevention of rebleeding (with endoscopic band ligation). Same titration; continue indefinitely with banding sessions every 2 to 4 weeks until varices are eradicated.

Acute variceal bleeding. Beta-blockers are withheld in acute bleeding until stable (vasoconstrictor, endoscopic therapy and antibiotics are used first), then started once vasoactive drugs are stopped, usually day 3 to 5.

Kidney and liver adjustment.

• Kidney impairment: reduce the dose in severe impairment; stop if acute kidney injury or hepatorenal syndrome develops.

• Liver impairment: use the lowest effective dose; stop if refractory ascites with systolic pressure under 90 mmHg, sodium under 130 mmol/L or kidney injury.

Contraindications.

• Asthma and severe chronic obstructive pulmonary disease.

• Second or third degree heart block, sick sinus syndrome, bradycardia under 50 beats/min.

• Cardiogenic shock, severe heart failure (decompensated), untreated phaeochromocytoma.

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

• Refractory ascites with spontaneous bacterial peritonitis (caution; stop in severe cases).

• Hypersensitivity.

Common adverse effects. Fatigue, bradycardia, dizziness, cold extremities, sleep disturbance and erectile dysfunction.

Serious adverse effects.

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

• Bronchospasm.

• Heart block and heart failure.

• Masking of hypoglycaemia symptoms in diabetes.

• Abrupt withdrawal: rebound tachycardia, hypertension and angina.

Major interactions.

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

• Insulin and oral antidiabetic drugs: masked hypoglycaemia.

• Other antihypertensives and diuretics: additive hypotension.

• NSAIDs: reduced effect and kidney injury in cirrhosis; avoid.

• Adrenaline: severe hypertension and bradycardia.

• CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine): increase propranolol levels.

• Rifampicin: reduces levels.

Special groups.

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

• Breastfeeding: low levels; monitor the infant for bradycardia.

• Children: specialist use only.

• Older adults: start low; risk of bradycardia and hypotension.

• Kidney impairment: reduce the dose in severe impairment.

• Liver impairment: titrate carefully; stop for refractory ascites with systolic pressure under 90 mmHg, sodium under 130 mmol/L or kidney injury.

• Regional: low cost and widely available, which is why it remains the main option for portal hypertension in East Africa.

Formulations. Tablets 10 mg, 40 mg, 80 mg; long-acting capsules 80 mg and 160 mg; oral solution 5 mg in 5 mL.

Administration.

• Take consistently with or without food.

• Swallow long-acting capsules whole.

• Do not stop abruptly.

Baseline. Heart rate, blood pressure, ECG if indicated, kidney function, sodium, endoscopy findings and presence of ascites.

Monitoring.

• Resting heart rate and blood pressure at each titration step and every visit; target heart rate 55 to 60 beats/min.

• Sodium and creatinine, especially with ascites.

• Symptoms of fatigue, dizziness or breathlessness.

• Endoscopy at 3 to 6 months for varices.

Therapeutic drug monitoring. Not applicable.

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

Referral and escalation. Refer urgently for variceal bleeding (haematemesis or melaena). Refer for banding, transjugular intrahepatic portosystemic shunt assessment in refractory bleeding, and liver transplant assessment.