Beta Blockers (Beta-Adrenergic Receptor Antagonists)

Mechanism of Action

• At rest, when sympathetic tone is low, blockade produces only modest effects.
• During exercise, stress, or disease, when sympathetic activity is high, beta blockers exert pronounced cardiac depressant effects - reducing heart rate (negative chronotropy), myocardial contractility (negative inotropy), and AV conduction (negative dromotropy).
• Goodman & Gilman's The Pharmacological Basis of Therapeutics

Classification

Generation 1 - Non-selective (block both β1 and β2)

Generation 2 - Cardioselective (β1-preferring)

Note on selectivity: Cardioselectivity is not absolute. At higher doses, β1-selective agents will also block β2 receptors.

Generation 3 - Non-selective with additional vasodilating actions

• Carvedilol - non-selective β blocker + α1 blockade; approved for hypertension and heart failure
• Labetalol - non-selective β + α1 blockade; useful in hypertensive emergencies and pregnancy
• Nebivolol - β1-selective + releases nitric oxide (vasodilation)

Key Pharmacological Properties

Intrinsic Sympathomimetic Activity (ISA)

Lipid Solubility

• Lipophilic agents (propranolol, metoprolol, carvedilol): better CNS penetration, hepatic metabolism, shorter half-life
• Hydrophilic agents (atenolol, nadolol): renal excretion, longer half-life, less CNS penetration (fewer nightmares, less fatigue)

Membrane-Stabilizing Activity

Therapeutic Uses

Cardiovascular

• Hypertension - particularly effective in high-renin states, young patients, post-MI
• Angina pectoris - reduce myocardial oxygen demand by lowering heart rate and contractility; a patient with both angina and hypertension is best treated with a cardioselective beta blocker
• Acute coronary syndromes - oral beta blockers within 24 hours of ACS without contraindications is a class I ACC/AHA recommendation; early IV use is discouraged in contemporary practice (associated with increased cardiogenic shock)
• Heart failure - once an absolute contraindication, now standard of care; metoprolol succinate (β1-selective) and carvedilol (non-selective) have demonstrated reduced mortality and morbidity in heart failure
• Arrhythmias - supraventricular and ventricular arrhythmias; rate control in atrial fibrillation
• Hypertrophic obstructive cardiomyopathy (HOCM) - reduces outflow tract gradient, relieves angina and syncope
• Aortic dissection - reduce rate of force development (dp/dt); given before nitroprusside to prevent reflex tachycardia
• Marfan syndrome - may slow aortic dilation (though losartan is increasingly used)

Non-Cardiovascular

• Glaucoma (timolol, betaxolol eye drops) - decrease aqueous humor production
• Hyperthyroidism/thyrotoxicosis - propranolol (non-selective) is preferred; also inhibits peripheral T4 → T3 conversion
• Migraine prophylaxis - propranolol, timolol, metoprolol (not for acute attacks)
• Essential tremor - propranolol
• Performance anxiety - propranolol reduces tachycardia, tremor, and sympathetic symptoms
• Alcohol withdrawal - adjunct therapy
• Pheochromocytoma - used after adequate alpha blockade to prevent unopposed alpha-mediated vasoconstriction

Adverse Effects

Cardiovascular

• Bradycardia and heart block - particularly dangerous in patients with pre-existing AV conduction defects or on other drugs affecting conduction (verapamil, antiarrhythmics)
• Hypotension
• Cold extremities / worsening peripheral vascular disease / Raynaud's phenomenon - due to unopposed alpha-mediated vasoconstriction
• Withdrawal syndrome - abrupt discontinuation causes upregulation of beta receptors, leading to rebound tachycardia, worsening angina, and risk of sudden death; must taper gradually

Pulmonary

• Bronchoconstriction - due to β2 blockade in bronchial smooth muscle; potentially life-threatening in asthma or COPD. β1-selective agents (betaxolol eye drops, cardioselective oral agents) carry lower but not zero risk.

Metabolic

• Masks signs of hypoglycemia (tachycardia) in diabetics; sweating is preserved
• Hypokalemia risk - beta blockers negate the normal catecholamine-mediated buffering of exercise-induced K+ efflux
• Dyslipidemia - may raise triglycerides and lower HDL (less with carvedilol and nebivolol)

CNS (lipophilic agents)

• Fatigue, depression, vivid dreams, nightmares, sleep disturbance

Other

• Sexual dysfunction

Contraindications

Drug Interactions

• NSAIDs (e.g., indomethacin) - blunt antihypertensive effect
• Verapamil / diltiazem - additive bradycardia and AV block; combination can be dangerous
• Enzyme inducers (phenytoin, rifampin, phenobarbital, smoking) - reduce plasma levels of hepatically metabolized agents (propranolol)
• Cimetidine / hydralazine - increase bioavailability of propranolol and metoprolol
• Aluminum salts, cholestyramine, colestipol - reduce GI absorption
• Beta blockers impair lidocaine clearance

Key Individual Drugs

Beta Blocker Overdose

• Rosen's Emergency Medicine, Tintinalli's Emergency Medicine