Beta blockers

Last updated: September 6, 2023

Summary

Beta blockers are a group of drugs that inhibit the sympathetic activation of β-adrenergic receptors. Cardioselective blockers (e.g., atenolol, bisoprolol) primarily block β₁ receptors in the heart, causing decreased heart rate, cardiac contractility, cardiac workload, and AVN conduction. Nonselective beta blockers (e.g., pindolol, propranolol) inhibit all β receptors and may cause bronchoconstriction, peripheral vasoconstriction, and metabolic imbalances (e.g., hypoglycemia and hyperglycemia, hypertriglyceridemia) in addition to cardiac effects. Cardioselective beta blockers have a lower side-effect profile and are preferred in the management of coronary heart disease, compensated heart failure, acute coronary syndrome, and certain types of arrhythmias. Propranolol, a nonselective beta blocker, is the first-line drug in the management of essential tremor, portal hypertension, migraine prophylaxis, and thyroid storm. Beta blockers are contraindicated in patients with symptomatic bradycardia, AV block, decompensated heart failure, and asthma. Initiation and cessation of beta-blocker therapy should always be gradual to avoid side effects or symptoms of withdrawal (e.g., rebound tachycardia, hypertension, acute cardiac death).

Overview

Characteristics of beta blockers
Type		Agents	Effects	Side effects	Indications
Cardioselective beta blockers (β₁ selective)	With intrinsic sympathomimetic activity (ISA)	Acebutolol Celiprolol	Selectively bind to and block β₁ receptors, which are primarily found in the heart Decrease the heart rate, contractility, and AVN conductivity Nebivolol is the only beta blocker that causes NO-mediated vasodilation: it decreases vascular resistance by stimulating β₃receptors and activating NO synthase in the vasculature ^[1]^[2]	Bradycardia Bradyarrhythmia Cardioselectivity is dose-dependent: β₂ receptor blocking activity increases with higher doses . ^[3] Generally do not cause bronchoconstriction or vasoconstriction Generally do not interfere with glycogenolysis; safe in diabetic patients	Coronary heart disease Compensated heart failure Cardiac arrhythmias (e.g., atrial fibrillation, atrial flutter, PSVT)
Cardioselective beta blockers (β₁ selective)	Without ISA	Atenolol ^[4] Metoprolol Esmolol Bisoprolol Betaxolol Bevantolol Nebivolol
Nonselective beta blockers (β₁, β₂, and β₃receptors)	With ISA	Pindolol Penbutolol Oxprenolol	Block β₁, β₂, and β₃receptors Sotalol also blocks cardiac potassium channels (antiarrhythmic effect).	Bronchoconstriction: may exacerbate asthma/COPD Vasoconstriction: avoid in patients with peripheral vascular disease Hypoglycemia and hyperglycemia Bradycardia and syncope	Alternative to cardioselective beta blockers Propranolol Essential tremor Portal hypertension Migraine prophylaxis Thyroid storm Sotalol: cardiac arrhythmias Timolol: glaucoma
	Without ISA	Propranolol Nadolol Sotalol Timolol Tertalol
	With additional α-blocking action	Labetalol Bucindolol Carvedilol ^[5]	Potent vasodilators Because of their α-blocking action: vasodilation → ↓ peripheral vascular resistance, ↓ preload, ↓ afterload, and ↑ renal blood flow Reduce portal hypertension and pressure gradient in hepatic venous Improve endothelial function and vascular remodeling	Same as side effects of nonselective beta blockers (both with and without ISA) Orthostatic hypotension	Pregnancy-induced hypertension (e.g, labetalol) Esophageal variceal bleeding (prophylactic use)

With the exception of nebivolol, all cardioselective beta blockers begin with the letters A to M (B₁ = first half of the alphabet). Except for beta blockers with alpha-blocking action (labetalol, bucindolol, carvedilol), all noncardioselective beta blockers begin with the letters N to Z (B₂ = second half of the alphabet).

References^[6]^[7]^[8]^[9]^[10]

Pharmacodynamics

Beta blockers competitively bind to and block β-adrenergic receptors, thereby inhibiting sympathetic (adrenergic and/or noradrenergic) stimulation of β receptors. See “The sympathetic vs. parasympathetic nervous system” for details regarding the effects of β-adrenergic stimulation.

Effects of β-adrenergic blockade

Overview of β-adrenergic blockade ^[3]
Types of β receptors	Main site of action	Effects of β-adrenergic blockade
β₁	Heart	Anti-ischemic effect: β₁ blockade → ↓ heart rate and ↓ cardiac contractility → ↓ blood pressure (BP) and ↓ oxygen consumption by the heart → anti-ischemic effect Antiarrhythmic effect: β₁ blockade → ↓ AVN conduction, ↑ AVN refractory time, and ↓ heart rate → anti-arrhythmic effect Anti-remodeling effect
β₁	Kidneys	β₁ blockade of the juxtaglomerular cells → ↓ renin release → ↓ angiotensin II conversion → ↓ H₂O resorption → ↓ BP
β₂	Smooth muscle	Vasculature: vasoconstriction Bronchioles: bronchoconstriction
	Ciliary body of the eye ^[11]	↓ Aqueous humor production → ↓ intraocular pressure ^[12]
	Pancreatic beta cells	↓ Insulin release → hyperglycemia and new-onset diabetes ^[3]
	Skeletal muscle	↓ Glucose uptake (↓ insulin sensitivity)
	Liver	↓ Hepatic glycogenolysis → hypoglycemia (esp. in diabetic patients)
	Lipoprotein lipase enzyme	Inhibits lipoprotein lipase → ↑ triglycerides and ↓ HDL → hyperlipidemia
β₃	Adipose tissue	↓ Lipolysis → weight gain

Beta blockers competitively inhibit adrenergic substances (e.g., adrenaline, noradrenaline) at β receptors.
A rule to remember the main effector organs for β receptors: There is 1 heart (β₁ blockers act on the heart) and 2 lungs (β₂ blockers affect bronchial smooth muscles).

Mechanism of action: inotropic drugs

Intrinsic sympathomimetic activity (ISA) ^[6]^[8]

Mechanism of action: partial agonist activity
- Beta blockers with ISA bind to and stimulate the β-adrenergic receptor (agonistic effect) while competitively inhibiting the binding of epinephrine and norepinephrine to β-adrenergic receptors (antagonistic effect).
- Produce partial sympathetic activity while inhibiting the normal and activated sympathetic activity
Effects
- Cause less bradycardia and less peripheral vasoconstriction because of their mild agonistic action
- Have a favorable effect on lipid profile (esp. pindolol and acebutolol): preferred in patients with metabolic syndrome ^[10]
- Not recommended in patients with congestive heart failure, ischemic heart disease, and tachyarrhythmias ^[13]
Agents: pindolol, acebutolol, carteolol, alprenolol ^[14]

Pharmacokinetics

Pharmacokinetics of beta blockers
	Lipophilic agents	Hydrophilic agents	Mixed
Properties	Undergo hepatic clearance Penetrate the blood-brain-barrier → central/neurological adverse effects (esp. nightmares and insomnia) Long-acting: most require a single dose per day	Undergo renal clearance Do not cross the blood-brain-barrier Short-acting: require multiple doses per day	Undergo hepatic and renal clearance
Agents	Carvedilol Labetalol Metoprolol Propranolol	Acebutolol Atenolol Celiprolol Pindolol Sotalol	Bisoprolol Nebivolol

References:^[3]

Adverse effects

See “Beta blocker poisoning” for features of overdose and their management.

Overview

Beta blockers adverse effects
Type of beta blockers	Organ system	Effects
Nonselective beta blockers and cardioselective beta blockers (β₁-receptor and β₂-receptor blockade)	Cardiac	Bradycardia Bradyarrhythmia (e.g., AV block) Ventricular tachyarrhythmia (torsades de pointes) Worsened heart failure (HF) Worsened vasospasm due to propranolol use Orthostatic hypotension (esp. in elderly patients) ^[15]^[16]
	CNS ^[17]^[18]	Fatigue/lethargy Sleep disorders, nightmares Depression, hallucinations Seizures
	Cutaneous	Psoriasis ^[19]
Nonselective beta blockers (β₂-receptor blockade)	Pulmonary	Bronchoconstriction (esp. patients with asthma and reactive airway disease) Dyspnea Bronchospasm Exacerbation of asthma and COPD
	Peripheral vasculature	Peripheral vasoconstriction Erectile dysfunction ^[20] Secondary Raynaud phenomenon ^[21] Cold extremities
	Metabolic	Hypertriglyceridemia, ↓ HDL levels with beta blockers without ISA ^[22] Hyperglycemia and new-onset diabetes Hypoglycemia: Beta blockers can mask the sympathetic effects of hypoglycemia (e.g., tachycardia, sweating), leading to dangerous silent (asymptomatic) hypoglycemia. ^[23] Weight gain

Beta blockers should be introduced gradually with slow increases in dosage and slowly tapered off when no longer needed.

A number of beta blockers (e.g., metoprolol, carvedilol) are metabolized by CYP2D6. Genetic polymorphisms of CYP2D6 (e.g., ultra-rapid metabolization, poor metabolization) can influence adverse effects and tolerated doses. ^[24]

Beta-blocker withdrawal

Caused by the sudden termination of beta blockers

Clinical features
Prevention: Taper dose over 7–10 days before discontinuing. ^[26]

We list the most important adverse effects. The selection is not exhaustive.

Indications

Cardiovascular indications

Hypertension : beta blockers lower BP by ↓ cardiac output and ↓ renin secretion ^[27]^[28]
Coronary artery disease
- Acute myocardial infarction ^[29]
  - Beta blockers should be initiated early in all patients (without contraindications) and continued long-term if tolerated. ^[30]
  - Beta blockers decrease the size of the infarct and also reduce early and delayed mortality rates in patients with acute MI.
- Angina pectoris: first-line treatment for stable angina pectoris in addition to ACE inhibitors or ARBs ^[27]^[31]
Heart failure: cardioselective beta blockers (preferred) in combination with ACE inhibitors/ARBs and spironolactone (slows progression of CHF) ^[3]^[27]
Arrhythmias: atrial flutter, atrial fibrillation, PSVT, VT, and premature ventricular contractions (beta-blockers are class II antiarrhythmic agents; e.g., metoprolol, esmolol, propranolol) ^[32]^[33]

Specific indications for propranolol

Miscellaneous

Hypertensive crises; (e.g., malignant hypertension): IV labetalol (rapid onset of action)
Glaucoma: topical beta blockers (timolol, betaxolol)
Pregnancy-induced hypertension: Labetalol is the first-line drug.

Contraindications

Contraindications to beta blockers
Symptomatic bradycardia Cardiogenic shock and hypotension Pheochromocytoma: administration of beta blockers before alpha blockers → unopposed α-adrenoceptor mediated vasoconstriction → hypertensive crisis (except nonselective beta blockers with α-antagonism, such as carvedilol and labetalol) Decompensated heart failure Combination with calcium channel blockers (diltiazem or verapamil): can precipitate AV block Sick sinus syndrome (without a pacemaker); heart block greater than first-degree	Asthma and COPD Psoriasis ^[19]^[36] Raynaud phenomenon, peripheral artery occlusive disease Pregnancy (except labetalol, which is used to treat pregnancy-induced hypertension) ^[37]^[38]

Contraindications to beta blockers

Absolute contraindications

Relative contraindications

Symptomatic bradycardia
Cardiogenic shock and hypotension
Pheochromocytoma: administration of beta blockers before alpha blockers → unopposed α-adrenoceptor mediated vasoconstriction → hypertensive crisis (except nonselective beta blockers with α-antagonism, such as carvedilol and labetalol)
Decompensated heart failure
Combination with calcium channel blockers (diltiazem or verapamil): can precipitate AV block
Sick sinus syndrome (without a pacemaker); heart block greater than first-degree

Asthma and COPD
Psoriasis ^[19]^[36]
Raynaud phenomenon, peripheral artery occlusive disease
Pregnancy (except labetalol, which is used to treat pregnancy-induced hypertension) ^[37]^[38]

We list the most important contraindications. The selection is not exhaustive.

References

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Beta blockers

Summary

Overview

Pharmacodynamics

Effects of β-adrenergic blockade

Intrinsic sympathomimetic activity (ISA) [6][8]

Pharmacokinetics

Adverse effects

Overview

Beta-blocker withdrawal

Indications

Cardiovascular indications

Specific indications for propranolol

Miscellaneous

Contraindications

References

3 free articles remaining

Intrinsic sympathomimetic activity (ISA) ^[6]^[8]