Non-cardioselective beta blockers

I. Introduction

Non-cardioselective beta blockers are β-adrenergic receptor antagonists that inhibit both β1 and β2 adrenergic receptors. These agents reduce the effects of endogenous catecholamines (epinephrine and norepinephrine) across cardiac, pulmonary, vascular, metabolic, and ocular systems. Unlike cardioselective (β1-selective) beta blockers that primarily act on the heart, non-cardioselective agents affect both β1 (heart, kidney) and β2 (bronchi, vasculature, liver, skeletal muscle) receptors, resulting in a broader range of physiological effects and a wider side-effect profile.

These agents are used in various cardiovascular, neurological, ophthalmic, and endocrine conditions. However, they must be used cautiously in patients with asthma, COPD, or peripheral vascular disease due to potential β2-mediated bronchoconstriction and vasospasm.

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II. Mechanism of Action

Non-cardioselective beta blockers competitively antagonize both β1 and β2 adrenergic receptors, leading to:

β1 Blockade:

• ↓ Heart rate (negative chronotropy)

• ↓ Myocardial contractility (negative inotropy)

• ↓ Cardiac output and blood pressure

• ↓ Renin release from the juxtaglomerular apparatus in the kidney

β2 Blockade:

• Bronchoconstriction (due to unopposed cholinergic activity)

• Vasoconstriction in peripheral and skeletal muscle vasculature

• ↓ Glycogenolysis and gluconeogenesis (may mask hypoglycemia)

• Inhibition of uterine relaxation

• ↓ Intraocular pressure (in ocular preparations)

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III. Common Non-Cardioselective Beta Blockers

Generic Name	Brand Names	Additional Properties
Propranolol	Inderal®, Avlocardyl®	Lipophilic, CNS penetration
Nadolol	Corgard®	Long-acting
Timolol	Blocadren®, Timoptic®	Oral and ophthalmic formulations
Sotalol	Betapace®	Also a class III antiarrhythmic
Pindolol	Visken®	Intrinsic sympathomimetic activity
Carteolol	Cartrol®, Ocupress®	Ophthalmic use
Levobunolol	Betagan®	Ophthalmic
Metipranolol	OptiPranolol®	Ophthalmic
Penbutolol	Levatol®	Mild intrinsic activity

IV. Pharmacokinetics Overview

Agent	Lipophilicity	Half-life	Hepatic/Renal Elimination	Notes
Propranolol	High	3–6 hrs	Hepatic	CNS effects prominent
Nadolol	Low	14–24 hrs	Renal	Long-acting, once daily
Timolol	Moderate	4–5 hrs	Hepatic	Used in glaucoma (eye drops)
Sotalol	Low	12 hrs	Renal	Prolongs QT interval
Pindolol	Moderate	3–4 hrs	Hepatic	Has partial agonist activity

V. Therapeutic Indications

Non-cardioselective beta blockers are used in a variety of clinical settings:

1. Cardiovascular Disorders

• Hypertension (especially propranolol, nadolol)

• Angina pectoris (chronic stable angina)

• Supraventricular and ventricular arrhythmias (sotalol, propranolol)

• Myocardial infarction (secondary prevention)

• Hypertrophic obstructive cardiomyopathy

• Portal hypertension and variceal bleeding prophylaxis (propranolol, nadolol)

2. Neurological Conditions

• Migraine prophylaxis (propranolol)

• Essential tremor (propranolol)

• Performance anxiety (propranolol)

3. Endocrine and Metabolic Disorders

• Thyrotoxicosis/Thyroid storm (propranolol: also inhibits peripheral conversion of T4 to T3)

• Pheochromocytoma (only after alpha-blockade)

4. Ophthalmic Use (Glaucoma)

• Timolol, carteolol, levobunolol, metipranolol (as eye drops)

• ↓ Intraocular pressure by reducing aqueous humor production

5. Other Indications

• Tetralogy of Fallot (infantile cyanotic spells)

• Portal hypertension in cirrhosis (non-selective β-blockers reduce splanchnic blood flow)

• Prevention of sudden death in long QT syndrome (propranolol, nadolol)

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VI. Adverse Effects

Due to blockade of both β1 and β2 receptors, non-cardioselective beta blockers exhibit a broader side-effect profile than cardioselective agents.

A. Cardiovascular

• Bradycardia

• Hypotension

• Heart block

• Worsening of heart failure in decompensated cases

B. Respiratory

• Bronchospasm (β2 blockade) – contraindicated in asthma and COPD

C. Metabolic

• Masks hypoglycemia symptoms (tachycardia, tremor)

• Inhibits glycogenolysis and gluconeogenesis

• May worsen insulin resistance or dyslipidemia

D. Central Nervous System

• Fatigue

• Depression

• Vivid dreams or nightmares (especially with lipophilic agents like propranolol)

E. Other

• Cold extremities (vasoconstriction)

• Erectile dysfunction

• Worsening of peripheral vascular disease

• Raynaud's phenomenon

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VII. Contraindications

Absolute contraindications include:

• Asthma or bronchospastic disease

• Severe bradycardia

• Second or third-degree heart block

• Overt heart failure (decompensated)

• Cardiogenic shock

Relative cautions:

• Diabetes mellitus (especially insulin-treated)

• Peripheral vascular disease

• Depression (for lipophilic agents)

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VIII. Drug Interactions

Interacting Drug/Class	Effect / Concern
Calcium channel blockers (non-DHP)	Additive bradycardia, AV block
Antidiabetic agents	May mask hypoglycemia symptoms
Clonidine	Rebound hypertension on withdrawal
NSAIDs	May reduce antihypertensive efficacy
Antiarrhythmics (amiodarone, digoxin)	Additive AV blockade effects
CYP enzyme modulators	Affects propranolol metabolism

IX. Clinical Comparison with Cardioselective Beta Blockers

Feature	Non-Cardioselective BBs	Cardioselective BBs (e.g., atenolol, metoprolol)
β1 Selectivity	No	Yes (dose-dependent)
Use in Asthma/COPD	Contraindicated	Safer (with caution)
Metabolic impact	Higher (mask hypoglycemia, lipid effects)	Lower
CNS penetration	Higher in lipophilic agents	Variable
Additional uses	Migraines, essential tremor, hyperthyroidism (propranolol)	CHF, angina

X. Special Populations

1. Pregnancy

• Propranolol and nadolol: Category C; can be used if benefit outweighs risk

• May cause fetal growth restriction or neonatal bradycardia

2. Pediatrics

• Propranolol used in infantile hemangiomas

• Dose titration based on weight

3. Renal Impairment

• Nadolol and sotalol: excreted renally → dose adjustment required

4. Hepatic Impairment

• Propranolol: hepatic metabolism → monitor for accumulation

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XI. Summary of Selected Non-Cardioselective Beta Blockers

Agent	Indications	Unique Features
Propranolol	HTN, angina, migraine, tremor, thyrotoxicosis	Lipophilic, CNS-active, non-selective
Nadolol	HTN, angina, arrhythmias, long QT	Long-acting, renal excretion
Timolol	HTN, migraine, glaucoma	Oral and ophthalmic use
Sotalol	Arrhythmias (Class III effect)	QT prolongation, needs ECG monitoring
Pindolol	HTN (mild cases)	Partial β agonist (ISA)
Carteolol	Glaucoma	Ophthalmic β-blocker

XII. Clinical Guidelines and Use in Practice

• Hypertension: Beta blockers are not first-line for uncomplicated cases but are useful in specific indications (e.g., post-MI, angina, arrhythmias).

• Heart Failure: Only cardioselective beta blockers (e.g., bisoprolol, metoprolol succinate, carvedilol) are used routinely.

• Migraine/Anxiety/Thyrotoxicosis: Propranolol remains the beta blocker of choice.

• Glaucoma: Timolol, carteolol, levobunolol are standard options for intraocular pressure control.