Nonselective Beta Blockers

Nonselective beta blockers antagonise beta-1 and beta-2 receptors alike. Beta-1 blockade slows the heart and lowers renin. Beta-2 blockade constricts airways and peripheral vessels, reduces tremor and lowers portal inflow. They are used for hypertension, angina, migraine prevention, tremor, thyrotoxic symptoms, portal hypertension, inherited arrhythmia and topical glaucoma therapy.

Members. Propranolol, nadolol, timolol, sotalol, pindolol, carteolol and levobunolol.

Properties that differ. Propranolol is highly lipophilic, enters the brain and has membrane-stabilising (sodium channel) activity. Nadolol is hydrophilic, renally cleared and has a half-life of 20 to 24 hours. Sotalol also blocks potassium channels (class III action). Pindolol has intrinsic sympathomimetic activity. Timolol, carteolol and levobunolol are used mainly as eye drops.

Mechanism. Beta-2 blockade in skeletal muscle reduces physiological tremor. In the splanchnic bed it leaves alpha-mediated vasoconstriction unopposed, lowering portal inflow. In the liver and muscle it blunts glycogenolysis, so recovery from hypoglycaemia is slower.

Pharmacokinetics. Propranolol has about 25% bioavailability from high first pass metabolism, with a half-life of 3 to 6 hours and CYP2D6 and CYP1A2 metabolism. Smoking induces its clearance. Nadolol is not metabolised. Sotalol is eliminated unchanged by the kidney.

• Propranolol: hypertension, angina, migraine, essential tremor, thyrotoxicosis, portal hypertension, infantile haemangioma, performance anxiety.
• Nadolol: long acting; angina, hypertension, portal hypertension, and a preferred agent in catecholaminergic polymorphic ventricular tachycardia and congenital long QT syndrome.
• Timolol: eye drops for glaucoma; oral use for migraine prevention and after infarction is limited.
• Sotalol: ventricular and atrial arrhythmia; started in hospital with QT monitoring.
• Pindolol: hypertension; less bradycardia at rest.
• Carteolol, levobunolol: glaucoma.

• Hypertension: propranolol 80 mg twice daily, increased to 160 to 320 mg daily; nadolol 40 mg daily up to 320 mg. Not first line for uncomplicated hypertension.
• Angina: propranolol 40 mg 2 to 3 times daily, titrated to a resting heart rate of 55 to 60 beats/minute.
• Migraine prevention: propranolol 80 to 240 mg daily in divided doses. Review benefit at 3 months.
• Tremor: propranolol 40 mg twice or 3 times daily.
• Thyrotoxic symptoms: propranolol 10 to 40 mg 3 to 4 times daily until the thyroid state is controlled.
• Portal hypertension: propranolol 20 to 40 mg twice daily, titrated to a resting heart rate of 55 to 60 beats/minute with systolic pressure at least 90 mmHg. Stop in refractory ascites with hypotension, hyponatraemia or kidney injury.
• Infantile haemangioma: propranolol 1 mg/kg daily in 2 divided doses, increased to 2 to 3 mg/kg daily, started with monitoring of heart rate, blood pressure and glucose under specialist care.
• Inherited arrhythmia: nadolol 1 to 2 mg/kg daily in catecholaminergic polymorphic ventricular tachycardia, under specialist care.
• Sotalol: 80 mg twice daily, increased to 160 mg twice daily in atrial fibrillation. Stop if QTc exceeds 500 milliseconds or rises by more than 60 milliseconds.
• Glaucoma: timolol 0.25% to 0.5% drops twice daily.

Contraindications. Asthma and any history of bronchospasm, obstructive airway disease with reversibility, heart rate under 50 beats/minute, second or third degree atrioventricular block, cardiogenic shock, acute heart failure, severe peripheral arterial disease, Prinzmetal angina and untreated phaeochromocytoma. Topical timolol shares the airway risk.

Adverse effects. Fatigue, bradycardia, cold hands and feet, Raynaud phenomenon, bronchospasm, sleep disturbance, nightmares, depression in some, erectile dysfunction, hypoglycaemia in children and fasting patients, raised triglycerides and lower HDL cholesterol. Sotalol: torsades de pointes, higher risk in women, hypokalaemia, hypomagnesaemia and renal impairment.

Overdose. Bradycardia, hypotension, hypoglycaemia (especially children), seizures and QRS widening with propranolol. Treat with atropine 0.5 to 1 mg intravenously, sodium bicarbonate 1 to 2 mmol/kg for QRS widening, glucagon 3 to 5 mg intravenously then 1 to 5 mg/hour, high-dose insulin with glucose and potassium monitoring, calcium and vasopressors.

Interactions. Verapamil and diltiazem (severe bradycardia and block), digoxin, amiodarone, clonidine rebound, insulin and sulphonylureas (masked hypoglycaemia), adrenaline in anaphylaxis (resistance and unopposed alpha effect), cimetidine (raises propranolol), smoking and rifampicin (lower propranolol), lidocaine and sotalol with other QT-prolonging drugs.

Monitoring. Heart rate, blood pressure, glucose in diabetes and children, electrocardiogram with sotalol and at dose change, potassium and magnesium, and renal function with nadolol and sotalol.

Referral and escalation. Overdose, symptomatic bradycardia or block, and sotalol-related QT prolongation need urgent hospital assessment.

Special groups. Pregnancy: propranolol is used, but neonates need observation for bradycardia and hypoglycaemia. Breastfeeding: propranolol is preferred, nadolol and sotalol accumulate in milk. Renal impairment: extend the dosing interval of nadolol and reduce sotalol as creatinine clearance falls. Older adults: start low. Mixed airway disease: avoid.