Selective Beta 1 Blockers

Selective beta-1 blockers preferentially antagonise cardiac beta-1 receptors, lowering heart rate, contractility and atrioventricular conduction with less effect on airway and vascular beta-2 receptors. They are core drugs in heart failure with reduced ejection fraction, angina, rate control and after myocardial infarction.

Members. Atenolol, metoprolol (tartrate and succinate), bisoprolol, nebivolol, esmolol, acebutolol and betaxolol (mainly topical).

Cardioselectivity. Selectivity is relative, not absolute. It is lost at higher doses, so beta-2 effects (bronchospasm, hypoglycaemia recovery delay) can appear. Bisoprolol is the most beta-1 selective, atenolol and metoprolol are intermediate, and nebivolol is highly selective at low doses.

Mechanism. Competitive blockade of beta-1 receptors slows sinoatrial firing and atrioventricular nodal conduction, reduces myocardial oxygen demand, and lowers renin release. Long-term use in heart failure reverses adverse remodelling and sympathetic overdrive, and improves survival.

Pharmacokinetics. Atenolol is hydrophilic, renally cleared and weakly central. Metoprolol is lipophilic, extensively metabolised by CYP2D6 with wide variation between patients. Bisoprolol is cleared about equally by kidney and liver. Nebivolol is metabolised by CYP2D6 and releases nitric oxide. Esmolol is hydrolysed by red cell esterases with a half-life of about 9 minutes.

Intrinsic sympathomimetic activity. Acebutolol has partial agonist activity and lowers resting heart rate less.

• Atenolol: once daily; renal dose adjustment; weaker outcome data in uncomplicated hypertension, so not preferred for it.
• Metoprolol: tartrate twice daily for angina and hypertension; succinate once daily for heart failure.
• Bisoprolol: once daily; heart failure, angina, hypertension and rate control.
• Nebivolol: vasodilating through nitric oxide; heart failure in older adults and hypertension; less fatigue and erectile dysfunction.
• Esmolol: intravenous, minutes to onset and offset; for acute supraventricular tachycardia, perioperative tachycardia and aortic dissection.
• Acebutolol: partial agonist; ventricular and supraventricular ectopy.
• Betaxolol: topical for glaucoma.

• Heart failure with reduced ejection fraction: bisoprolol 1.25 mg daily, doubled every 2 to 4 weeks to 10 mg; metoprolol succinate 12.5 to 25 mg daily, doubled every 2 weeks to 200 mg; nebivolol 1.25 mg daily increased to 10 mg. Start when euvolaemic and stable.
• Angina and hypertension: bisoprolol 5 to 10 mg daily (maximum 20 mg); metoprolol succinate 50 to 100 mg daily up to 400 mg; atenolol 25 to 100 mg daily; nebivolol 5 mg daily. Titrate angina to a resting heart rate of 55 to 60 beats/minute.
• Atrial fibrillation rate control: bisoprolol or metoprolol; acute control with esmolol 500 micrograms/kg over 1 minute, then 50 micrograms/kg/minute, increasing in steps of 50 micrograms/kg/minute to 200 micrograms/kg/minute.
• After myocardial infarction: long-term benefit is clearest with reduced ejection fraction. Avoid early intravenous use with heart failure, hypotension, bradycardia or shock.
• Perioperative: continue an existing beta blocker. Starting a high dose on the day of surgery raises stroke and mortality risk.
• Thyroid storm: esmolol is an option where propranolol is unsuitable.
• Selection: choose bisoprolol, metoprolol succinate or nebivolol for heart failure. Prefer a selective agent to a non-selective one in mild obstructive airway disease, diabetes and peripheral vascular disease.

Contraindications. 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 active asthma, and untreated phaeochromocytoma.

Adverse effects. Fatigue, bradycardia, cold extremities, postural hypotension, sleep disturbance and vivid dreams (lipophilic agents), erectile dysfunction, worsening of heart failure when started too fast, and masked hypoglycaemic tachycardia in diabetes.

Withdrawal. Never stop abruptly in ischaemic heart disease. Taper over 1 to 2 weeks to avoid rebound angina, arrhythmia and infarction.

Interactions. Verapamil and diltiazem add bradycardia and block. Digoxin and amiodarone add bradycardia. Fluoxetine, paroxetine and bupropion inhibit CYP2D6 and raise metoprolol and nebivolol levels. Clonidine withdrawal is more dangerous when a beta blocker is on board. Insulin and sulphonylureas: hypoglycaemia symptoms are masked.

Monitoring. Heart rate, blood pressure and signs of congestion at each titration step, electrocardiogram for PR interval, and renal function for atenolol.

Special groups. Renal impairment: atenolol 50 mg daily at most with creatinine clearance 15 to 35 mL/min and 25 mg daily under 15 mL/min; bisoprolol 10 mg daily at most under 20 mL/min. Hepatic impairment: reduce metoprolol and bisoprolol. Pregnancy: metoprolol is used, atenolol is linked with foetal growth restriction. Breastfeeding: metoprolol is preferred, atenolol accumulates in milk. Older adults: start low.