Drugs & Medication

Beta blockers (sometimes written as β-blockers) are a class of drugs used for various indications, but particularly for the management of cardiac arrhythmias and cardioprotection after myocardial infarction. Whilst once first-line treatment for hypertension, their role was downgraded in June 2006 in the United Kingdom to fourth-line as they perform less well than other drugs, particularly in the elderly, and there is increasing evidence that the most frequently used beta-blockers at usual doses carry an unacceptable risk of provoking type 2 diabetes.^[1]

Beta blockers may also be referred to as beta-adrenergic blocking agents, beta-adrenergic antagonists, or beta antagonists.

Contents 1 Pharmacology 1.1 β-Receptor antagonism 1.2 Intrinsic sympathomimetic activity 1.3 α1-Receptor antagonism 1.4 Other effects 2 Clinical use 2.1 Congestive heart failure 2.2 Anxiety and performance enhancement 3 Adverse effects 4 Examples of beta blockers 4.1 Historical 4.2 Non-selective agents 4.3 β1-Selective agents 4.4 Mixed α1/β-adrenergic antagonists 4.5 β2-Selective agents 5 Comparative information 5.1 Pharmacological differences 5.2 Indication differences 6 References 7 Footnotes 8 External links

Pharmacology

Beta blockers block the action of endogenous catecholamines, epinephrine (adrenaline) and norepinephrine (noradrenaline) in particular, on β-adrenergic receptors, part of the sympathetic nervous system which mediates the "fight or flight" response.

There are three known types of beta receptor, designated β₁, β₂ and β₃. β₁-Adrenergic receptors are located mainly in the heart, kidney, and adipose tissue. β₂-Adrenergic receptors are located mainly in the heart, lung, GI tract, liver, pancreas, and skeletal muscle. The role and location of β₃-receptors is less well-defined.

β-Receptor antagonism

Stimulation of β₁ receptors by epinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation of β2 receptors induces smooth muscle relaxation (resulting in vasodilation and bronchodilation amongst other actions), induces tremor in skeletal muscle, increases glycogenolysis in the liver and skeletal muscle.

Beta blockers inhibit these normal epinephrine-mediated sympathetic actions, but have minimal effect on resting subjects. That is, they reduce the effect of excitement/physical exertion on heart rate and force of contraction, dilation of blood vessels, opening of bronchi, reduce tremor, and breakdown of glycogen.

It is therefore somewhat unexpected that non-selective beta blockers have an antihypertensive effect, since they appear to cause vasoconstriction. The antihypertensive mechanism appears to involve: reduction in cardiac output (due to negative chronotropic and inotropic effects), reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity.

Antianginal effects result from negative chronotropic and inotropic effects, which decrease cardiac workload and oxygen demand.

The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade – resulting in depression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory periods. Sotalol, in particular, has additional antiarrhythmic properties and prolongs action potential duration through potassium channel blockade.

Intrinsic sympathomimetic activity

Some beta blockers (e.g. oxprenolol and pindolol) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low level agonist activity at the β-adrenergic receptor while simultaneously acting as a receptor site antagonist. These agents, therefore, may be useful in individuals exhibiting excessive bradycardia with sustained beta blocker therapy.

Agents with ISA are not used post-myocardial infarction as they have not been demonstrated to be beneficial. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia (Rossi, 2006).

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.

Other effects

Beta blockers decrease nocturnal melatonin release, perhaps partly accounting for sleep disturbance caused by some agents (Stoschitzky et al., 1999).

Clinical use

Large differences exist in the pharmacology of agents within the class, thus not all beta blockers are used for all indications listed below.

Indications for beta blockers include:

• Hypertension
  Angina
  Cardiac arrhythmia
  Congestive heart failure
  Myocardial infarction
  Glaucoma
  Migraine prophylaxis
  Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism
  Essential tremor
  Phaeochromocytoma, in conjunction with α-blocker

Beta blockers have also been used in the following conditions:

• Hypertrophic obstructive cardiomyopathy
  Acute dissecting aortic aneurysm
  Marfan syndrome (chronic treatment with propranolol slows progression of aortic dilation and its complications)
  Prevention of variceal bleeding in portal hypertension
  Possible mitigation of hyperhidrosis

Congestive heart failure

Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition, studies in the late 1990s showed their positive effects on morbidity and mortality in congestive heart failure (Hjalmarson, 2000; Leizorovicz, 2002; Packer, 2002). Bisoprolol, carvedilol and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure.

Anxiety and performance enhancement

Some people, particularly musicians, use beta blockers to avoid stage fright and tremor during public performance and auditions. The physiological symptoms of the fight/flight response associated with performance anxiety and panic (pounding heart, cold/clammy hands, increased respiration, sweating, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand.

Currently, no beta blocker is approved for anxiolytic use by the US FDA. Still, use of beta blockers to combat the physical symptoms of anxiety is not uncommon, particularly among performers, and there are studies which confirm their efficacy as an anxiolytics. (Schneier 2006)

Since they lower heart rate and reduce tremor, beta blockers have been used by some Olympic marksmen to enhance performance, though beta blockers are banned by the International Olympic Committee (IOC).

Adverse effects

Common adverse drug reactions (ADRs) associated with the use of beta blockers include: nausea, diarrhoea, bronchospasm, dyspnoea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart block, fatigue, dizziness, abnormal vision, decreased concentration, hallucinations, insomnia, nightmares, depression, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed α1/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with oedema. (Rossi, 2006)

Central nervous system (CNS) adverse effects (hallucinations, insomnia, nightmares, depression) are more common in agents with greater lipid solubility, which are able to cross the blood-brain barrier into the CNS. Similarly, CNS adverse effects are less common in agents with greater aqueous solubility (listed below).

Adverse effects associated with β₂-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with β₁-selective (often termed "cardioselective") agents, however receptor selectivity diminishes at higher doses.

Examples of beta blockers

Historical

• Dichloroisoprenaline
  Practolol
  Pronethaolol

Non-selective agents

• Alprenolol
  Carteolol
  Levobunolol
  Mepindolol
  Metipranolol
  Nadolol
  Oxprenolol
  Penbutolol
  Pindolol
  Propranolol
  Sotalol
  Timolol

β₁-Selective agents

• Acebutolol
  Atenolol
  Betaxolol
  Bisoprolol
  Esmolol
  Metoprolol
  Nebivolol

Mixed α₁/β-adrenergic antagonists

• Carvedilol
  Celiprolol
  Labetalol

β₂-Selective agents

• Butoxamine (weak α-adrenergic agonist activity)

Comparative information

Pharmacological differences

• Agents with intrinsic sympathomimetic action (ISA)
  • Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol
• Agents with greater aqueous solubility
  • Atenolol, celiprolol, nadolol, sotalol
• Agents with membrane stabilising activity
  • Acebutolol, betaxolol, pindolol, propranolol
• Agents with antioxidant effect
  • Carvedilol

Indication differences

• Agents specifically indicated for cardiac arrhythmia
  • Esmolol, sotalol
• Agents specifically indicated for congestive heart failure
  • Bisoprolol, carvedilol, sustained-release metoprolol
• Agents specifically indicated for glaucoma
  • Betaxolol, carteolol, levobunolol, metipranolol, timolol
• Agents specifically indicated for myocardial infarction
  • Atenolol, metoprolol, propranolol
• Agents specifically indicated for migraine prophylaxis
  • Timolol, propranolol

Propranolol is the only agent indicated for control of tremor, portal hypertension and oesophageal variceal bleeding, and used in conjunction with α-blocker therapy in phaeochromocytoma (Rossi, 2006).

References

• Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA. 2000;283(10):1295-302. PMID 10714728
• Leizorovicz A, Lechat P, Cucherat M, Bugnard F. Bisoprolol for the treatment of chronic heart failure: a meta-analysis on individual data of two placebo-controlled studies – CIBIS and CIBIS II. Cardiac Insufficiency Bisoprolol Study. Am Heart J. 2002;143(2):301-7. PMID 11835035
• Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002;106(17):2194-9. PMID 12390947
• Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
• Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, Lindner W. Influence of beta-blockers on melatonin release. Eur J Clin Pharmacol. 1999 Apr;55(2):111-5. PMID 10335905
• Schneier FR. Clinical practice. Social anxiety disorder. N Engl J Med. 2006 Sep 7;355(10):1029-36. PMID 16957148.

Footnotes

1. ^ Sheetal Ladva (28/06/2006). NICE and BHS launch updated hypertension guideline. National Institute for Health and Clinical Excellence. Retrieved on 2006-09-30.

External links

• Musicians using beta blockers
• Better Playing Through Chemistry by Blair Tindall, New York Times, October 17, 2004. (Discussing the use of beta-blockers among professional musicians.)