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 do not perform as well as other drugs, particularly in the elderly,
and there is increasing evidence that the most frequently used beta-blockers especially in combination with thiazide-type
diuretics carry an unacceptable risk of provoking type 2 diabetes.[1]
Sir James W. Black invented propranolol, the first beta adrenergic receptor
antagonist that revolutionized the medical management of angina pectoris, considered to be one of the most important contributions to clinical medicine and
pharmacology of the 20th century.[2]
Beta blockers may also be referred to as beta-adrenergic blocking agents, beta-adrenergic antagonists, or
beta antagonists.
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 and in the kidneys. β2-Adrenergic receptors are
located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle.
β3-receptors are located in fat cells.
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 β1 receptors on the kidney causes renin release. Stimulation of β2 receptors induces
smooth muscle relaxation (resulting in vasodilation
and bronchodilation amongst other actions), induces tremor in skeletal muscle, and increases glycogenolysis in the
liver and skeletal muscle. Stimulation of β3
receptors induces lipolysis.
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 and opening of bronchi, and also reduce tremor and breakdown of
glycogen.
It is therefore expected 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.
Blockade of the sympathetic nervous system on renin release leads to reduced aldosterone via the renin angiotensin aldosterone
system with a resultant decrease in blood pressure due to decreased sodium [and H20] retention.
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.[3]
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.[4] Beta blockers protect against social anxiety: "Improvement of physical symptoms has been
demonstrated with beta-blockers such as propranolol; however, these effects are limited to the social anxiety experienced in
performance situations." [5]
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:
Beta blockers have also been used in the following conditions:
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.[6]
[7] [8] Bisoprolol, carvedilol and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE
inhibitor and diuretic therapy in congestive heart failure.
The beta blockers are a benefit due to the reduction of the heart rate which will lower the myocardial energy expenditure.
This is turns prolongs the diastolic filling and lengthens the coronary perfusion as a result.[9] Beta blockers have also been a benefit to improving the ejection
fraction of the heart despite an initial reduction in it.
Trials have shown that Beta blockers reduce the absolute risk of death by 4.5% over a 13 month period. As well as reducing the
risk of mortality, the number of hospital visits and hospitalizations were also reduced in the trials.[9]
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 U.S. Food and Drug Administration. 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 anxiolytics.[10]
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).[11] Although they have no recognisable benefit to most sports, it is
acknowledged that they are beneficial to sports such as archery and shooting.
Adverse effects
Adverse drug reactions (ADRs) associated with the use of beta blockers include:
nausea, diarrhea, bronchospasm, dyspnea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, heart failure, heart
block, fatigue, dizziness, abnormal vision,
decreased concentration, hallucinations, insomnia, nightmares, clinical 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 edema.[3]
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.
A 2007 study revealed that diuretics and beta-blockers used for hypertension increase a patient's risk of developing
diabetes whilst ACE inhibitors and
Angiotensin II receptor antagonists (Angiotensin Receptor Blockers)
actually decrease the risk of diabetes.[12] Clinical guidelines in Great Britain, but not in the United States, call for avoiding
diuretics and beta-blockers as first-line treatment of hypertension due to the risk of diabetes.[13]
Beta blockers must not be used in the treatment of cocaine, amphetamine, or other alpha adrenergic stimulant overdose. The blockade of only beta receptors increases hypertension, reduces coronary blood flow, left ventricular
function, and cardiac output and tissue perfusion by means of leaving the alpha
adrenergic system stimulation unopposed. [14] The appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant abuse are
diuretics like furosemide and alpha blockers like phentolamine. [15]
Examples of beta blockers
Dichloroisoprenaline, the first beta blocker.
Non-selective agents
β1-Selective agents
Mixed α1/β-adrenergic antagonists
β2-Selective agents
Side Effects / Health Consequences
- Low Blood Pressure
- Slow Heart Rate
- Impaired Circulation
- Loss of Sleep
- Heart Failure
- Asthma
- Depression
- Sexual Dysfunction
- Nausea
- Headaches
- Dizziness
- Muscle Cramps
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
Indication differences
Propranolol is the only agent indicated for control of tremor, portal hypertension and esophageal variceal bleeding, and used in conjunction with α-blocker therapy
in phaeochromocytoma.[3]
References
- Katzung, Bertram G. (2004). Basic & clinical pharmacology, 9th
edition, New York: Lange Medical Books/McGraw-Hill, 130, table 9-3. ISBN 0-07-144097-6.
Footnotes
- ^ Sheetal Ladva (28/06/2006). NICE and BHS launch
updated hypertension guideline. National Institute
for Health and Clinical Excellence. Retrieved on 2006-09-30.
- ^ Melanie Patricia Stapleton (1997). Sir James Black and
Propranolol. Texas Heart Institute Journal.
- ^ a b c (2006) in Editor Rossi S: Australian Medicines
Handbook. Adelaide: Australian Medicines Handbook.
- ^ Stoschitzky K,
Sakotnik A, Lercher P, et al (1999). "Influence of beta-blockers on melatonin release". Eur. J. Clin. Pharmacol.
55 (2): 111–5. PMID 10335905.
- ^ Davidson, M.D., Jonathan; Connor M.D., Kathryn M. (1999).
Social Anxiety Disorder: A
Treatable Condition. Drug Benefit Trends 11(5) 5BH-7BH. Cliggott Publishing, Division of SCP Communications. Retrieved
on 2007-10-06.
- ^ Hjalmarson A,
Goldstein S, Fagerberg B, et al (2000). "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 283 (10): 1295–302. PMID 10714728.
- ^ Leizorovicz A,
Lechat P, Cucherat M, Bugnard F (2002). "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.
143 (2): 301–7. PMID 11835035.
- ^ Packer M, Fowler
MB, Roecker EB, et al (2002). "Effect of carvedilol on the morbidity of patients with severe chronic heart failure:
results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study". Circulation 106 (17):
2194–9. PMID 12390947.
- ^ a b Pritchett AM, Redfield MM (2002).
"Beta-blockers:
new standard therapy for heart failure" (PDF). Mayo Clin. Proc. 77 (8): 839–45; quiz 845–6. PMID
12173717.
- ^ Schneier FR (2006).
"Clinical practice. Social anxiety disorder". N. Engl. J. Med. 355 (10): 1029–36. DOI:10.1056/NEJMcp060145. PMID 16957148.
- ^ World Anti-Doping Agency (19/09/2005). The World Anti-Doping Code: The 2006
Prohibited List International Standard. World Anti-Doping Agency. Retrieved
on 2006-12-13.
- ^ Elliott WJ, Meyer
PM (2007). "Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis". Lancet 369
(9557): 201–7. DOI:10.1016/S0140-6736(07)60108-1. PMID 17240286.
- ^ Mayor S (2006).
"NICE removes beta blockers as
first line treatment for hypertension". BMJ 333 (7557): 8. DOI:10.1136/bmj.333.7557.8-a. PMID 16809680.
- ^ http://www.emedicine.com/med/topic400.htm
- ^
http://www.emedicine.com/EMERG/topic23.htm
- ^ Bisoprolol
MedlinePlus
External links
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