Beta Adrenergic Blockers

Beta adrenergic blockers competitively antagonise beta receptors, lowering heart rate, contractility, conduction speed, and renin release. They reduce myocardial oxygen demand and mortality in heart failure with reduced ejection fraction and after myocardial infarction, and are also used for angina, arrhythmia, hypertension, portal hypertension, tremor, migraine and thyrotoxic symptoms.

Classification by selectivity. Non-selective: propranolol, nadolol, timolol, sotalol, pindolol. Beta-1 selective: atenolol, metoprolol, bisoprolol, nebivolol, esmolol, acebutolol. With added vasodilation: carvedilol and labetalol (alpha-1 blockade), nebivolol (nitric oxide).

Other properties. Intrinsic sympathomimetic activity (pindolol, acebutolol) gives less resting bradycardia. Membrane-stabilising activity (propranolol) matters in overdose. Lipophilic agents (propranolol, metoprolol) enter the brain and cause sleep disturbance and vivid dreams, hydrophilic agents (atenolol, nadolol, sotalol) are cleared by the kidney.

Mechanism. Blockade of beta-1 receptors in the sinoatrial and atrioventricular nodes slows rate and conduction, which also explains the class II antiarrhythmic effect. Blockade in the juxtaglomerular apparatus reduces renin. Beta-2 blockade causes bronchoconstriction, peripheral vasoconstriction, and impaired glycogenolysis.

Chronic effects. Chronic use upregulates receptors, so abrupt withdrawal causes rebound tachycardia, angina and myocardial infarction.

Pharmacokinetics. Propranolol and metoprolol undergo high first pass metabolism, with metoprolol and carvedilol affected by CYP2D6 variation. Atenolol, nadolol and sotalol are renally excreted, bisoprolol is cleared equally by kidney and liver.

• Propranolol: non-selective, lipophilic; hypertension, migraine, tremor, thyrotoxic symptoms, infantile haemangioma, variceal bleeding prevention.
• Atenolol: hydrophilic, once daily, renal dose adjustment.
• Metoprolol: tartrate twice daily or succinate once daily; heart failure uses succinate.
• Bisoprolol: highly beta-1 selective, once daily; heart failure and angina.
• Carvedilol: alpha and beta blockade; heart failure and portal hypertension.
• Nebivolol: beta-1 selective with nitric oxide release.
• Labetalol: hypertension in pregnancy and emergencies.
• Sotalol: beta blocker with class III action; torsades risk.
• Esmolol: ultra short acting intravenous.
• Timolol: topical for glaucoma, with systemic absorption.

• Heart failure with reduced ejection fraction: bisoprolol 1.25 mg daily, doubled every 2 to 4 weeks to 10 mg; carvedilol 3.125 mg twice daily, doubled to 25 mg twice daily (50 mg twice daily if over 85 kg); metoprolol succinate 12.5 to 25 mg daily to 200 mg. Start once euvolaemic.
• Angina: titrate to resting heart rate of 55 to 60 beats/minute.
• After myocardial infarction: benefit is clearest with reduced ejection fraction; with preserved ejection fraction benefit is uncertain.
• Atrial fibrillation rate control: bisoprolol or metoprolol; esmolol 500 micrograms/kg over 1 minute, then 50 micrograms/kg/minute, for acute settings.
• Hypertension: not first line for uncomplicated disease where alternatives are available; used for compelling indications. Monotherapy response is generally lower in people of African ancestry, who more often have low renin hypertension.
• Portal hypertension and variceal prevention: propranolol 20 to 40 mg twice daily titrated to a resting heart rate of 55 to 60 beats/minute, or carvedilol 6.25 mg daily increased to 12.5 mg.
• Other: propranolol 10 to 40 mg 3 to 4 times daily for thyrotoxic symptoms, 80 to 240 mg daily for migraine prevention, and 1 to 3 mg/kg daily for infantile haemangioma under specialist care.

Contraindications. Asthma with active bronchospasm (non-selective agents absolute), heart rate under 50 beats/minute, second or third degree atrioventricular block without a pacemaker, sick sinus syndrome, cardiogenic shock, acute decompensated heart failure, severe peripheral arterial disease, Prinzmetal angina, and untreated phaeochromocytoma.

Adverse effects. Bradycardia, fatigue, cold extremities, postural hypotension, bronchospasm, sleep disturbance, depression in some, erectile dysfunction, and masked hypoglycaemic tachycardia (sweating persists) in diabetes. Non-selective agents can worsen triglycerides and lipids.

Withdrawal. Taper over 1 to 2 weeks in patients with ischaemic heart disease.

Interactions. Verapamil and diltiazem cause severe bradycardia and block; avoid intravenous combination. Digoxin and amiodarone add bradycardia. Beta blockers raise rebound hypertension risk after clonidine withdrawal. Insulin and sulphonylureas: hypoglycaemia is masked. Fluoxetine and paroxetine inhibit CYP2D6 and raise metoprolol and carvedilol levels. NSAIDs blunt effect. Anaphylaxis is more severe and resistant to adrenaline, with glucagon as rescue.

Overdose. Bradycardia, hypotension, hypoglycaemia (especially in children), seizures and QRS widening with propranolol, and torsades with sotalol. Atropine 0.5 to 1 mg intravenously, glucagon 3 to 5 mg intravenously over 1 to 2 minutes then 1 to 5 mg/hour, high-dose insulin with glucose and potassium monitoring, calcium, and vasopressors. Refractory cases need pacing, lipid emulsion or extracorporeal support.

Monitoring. Heart rate and blood pressure, electrocardiogram for PR interval, signs of heart failure, glucose in diabetes, renal function for renally cleared agents.

Referral and escalation. Overdose, symptomatic bradycardia or block, and cardiogenic shock need urgent hospital care.

Special groups. Pregnancy: labetalol and metoprolol are used, atenolol is linked with foetal growth restriction, and neonates need observation for bradycardia and hypoglycaemia. Breastfeeding: propranolol, labetalol and metoprolol are preferred, atenolol, nadolol and sotalol accumulate in milk. Renal impairment: atenolol 50 mg daily at most with creatinine clearance 15 to 35 mL/min, and 25 mg daily under 15 mL/min. Hepatic impairment: reduce propranolol, metoprolol and carvedilol. Older adults: start low.