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Beta Blockers; Types, Indications/Uses, Side Effects, Drug Interactions

Beta blockers also written β-blockers, are a class of medications that are particularly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack (myocardial infarction) after a first heart attack (secondary prevention). They are also widely used to treat high blood pressure (hypertension), although they are no longer the first choice for initial treatment of most patients

Beta blockers inhibit the chronotropic, inotropic, and vasoconstrictor responses to the catecholamines, epinephrine, and norepinephrine. Most beta blockers have half-lives of over 6 hours. The shortest actings are pindolol (3 to 4 hours) and propranolol (3 to 5 hours). Most of the included beta blockers are metabolized in combination by the liver and kidneys, with the exception of atenolol, which is metabolized primarily by the kidneys while the liver has little to no involvement.

Classifications/Types of Beta-blockers

α₁-receptor antagonism

Some beta blockers (e.g., labetalol and carvedilol) exhibit mixed antagonism of both β- and α₁-adrenergic receptors, which provides additional arteriolar vasodilating action.

Dichloroisoprenaline, the first beta blocker

Nonselective agents

Nonselective beta-blockers display both β₁ and β₂ antagonism.

Propranolol
Bucindolol (has additional α₁-blocking activity)
Carteolol
Carvedilol (has additional α₁-blocking activity)
Labetalol (has additional α₁-blocking activity)
Nadolol
Oxprenolol (has intrinsic sympathomimetic activity)
Penbutolol (has intrinsic sympathomimetic activity)
Pindolol (has intrinsic sympathomimetic activity)
Sotalol (not considered a “typical beta blocker”)
Timolol

β₁-selective agents

β₁-selective beta blockers are also known as cardioselective beta blockers.

Acebutolol (has intrinsic sympathomimetic activity, ISA)
Atenolol
Betaxolol
Bisoprolol
Celiprolol (has intrinsic sympathomimetic activity)
Metoprolol
Nebivolol
Esmolol

β₂-selective agents

Butaxamine

Classification of overall

β, non-selective	Alprenolol Bopindolol Bupranolol Carteolol Cloranolol Mepindolol Nadolol Oxprenolol Penbutolol Pindolol/Iodopindolol Propranolol Sotalol Tertatolol Timolol
β₁-selective	Acebutolol Atenolol Betaxolol Bevantolol Bisoprolol Celiprolol Epanolol Esmolol Landiolol Metoprolol Nebivolol Practolol S-Atenolol Talinolol
β₂-selective	Butaxamine
α₁– + β-selective	Arotinolol Carvedilol Labetalol

Pharmacological differences of Beta-blockers

Agents with intrinsic sympathomimetic action (ISA)

Acebutolol, pindolol, labetalol, mepindolol, oxprenolol, celiprolol, penbutolol

Agents organized by lipid solubility (lipophilicity)

High lipophilicity: propranolol, labetalol
Intermediate lipophilicity: metoprolol, bisoprolol, carvedilol, acebutolol, timolol, pindolol
Low lipophilicity (also known as hydrophilic beta-blockers): atenolol, nadolol, and sotalol

Agents with membrane stabilizing the effect

Carvedilol, propranolol > oxprenolol > labetalol, metoprolol, timolol

Indication differences of Beta-blockers

Agents specifically labeled for cardiac arrhythmia

Esmolol, sotalol, landiolol (Japan)

Agents specifically labeled for congestive heart failure

Carvedilol, sustained-release metoprolol

Agents specifically labeled for glaucoma

Betaxolol, carteolol, levobunolol, timolol, metipranolol

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Agents specifically labeled for myocardial infarction

Atenolol, metoprolol (immediate release), propranolol (immediate release), timolol, carvedilol (after left ventricular dysfunction)

Agents specifically labeled for migraine prophylaxis

Timolol, propranolol

Propranolol is the only agent indicated for the control of tremor, portal hypertension, and esophageal variceal bleeding, and used in conjunction with α-blocker therapy in phaeochromocytoma.

Mechanism of action of Beta-blockers

Beta-blockers compete with sympathomimetic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart, inhibiting sympathetic stimulation. This results in a reduction in resting heart rate, cardiac output, systolic and diastolic blood pressure, and reflex orthostatic hypotension.

Beta blockers are classified as a non-cardioselective sympatholytic beta blocker that crosses the blood-brain barrier. It is lipid soluble and also has sodium channel blocking effects. Beta blockers are a non-selective beta blocker; that is, it blocks the action of epinephrine (adrenaline) and norepinephrine (noradrenaline) at both β₁– and β₂-adrenergic receptors. It has little intrinsic sympathomimetic activity but has strong membrane stabilizing activity (only at high blood concentrations, e.g. overdose). Beta blockers are able to cross the blood-brain barrier and exert effects in the central nervous system in addition to its peripheral activity.

In addition to blockade of adrenergic receptors, beta blockers have very weak inhibitory effects on the norepinephrine transporter and/or weakly stimulates norepinephrine release (i.e., the concentration of norepinephrine is increased in the synapse). Since beta blockers blocks β-adrenoceptors, the increase in synaptic norepinephrine only results in α-adrenoceptor activation, with the α₁-adrenoceptor being particularly important for effects observed in animal models. Therefore, it can be looked upon as a weak indirect α₁-adrenoceptor agonist in addition to the potent β-adrenoceptor antagonist. In addition to its effects on the adrenergic system, there is evidence that indicates that Beta-blockers may act as a weak antagonist of certain serotonin receptors, namely the 5-HT_1A, 5-HT_1B, and 5-HT_2Breceptors. The latter may be involved in the effectiveness of beta-blockers in the treatment of a migraine at high doses

Indication /Uses of Beta Blockers

Indications for beta blockers include

Angina pectoris(contraindicated for Prinzmetal’s angina)
Atrial fibrillation
Cardiac arrhythmia
Congestive heart failure
Essential tremor
Glaucoma (As eye drops, they decrease intraocular pressure by lowering aqueous humor secretion.
Hypertension, although they are generally not preferred as an initial treatment.
Migraine prophylaxis
Mitral valve prolapse
Myocardial infarction
Phaeochromocytoma, in conjunction with α-blocker
Postural orthostatic tachycardia syndrome
Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism
Theophylline overdose

Beta blockers have also been used for:

Acute aortic dissection
Hypertrophic obstructive cardiomyopathy
Long QT syndrome
Marfan syndrome (treatment with propranolol slows progression of aortic dilation and its complications)
Prevention of variceal bleeding in portal hypertension
Possible mitigation of hyperhidrosis
Social and other anxiety disorders
Controversially, for reduction of perioperative mortality