Beta blocker
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2008-07-10T21:14:45Z
DrGaellon
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[[Image:Propranolol-2D-skeletal.png|thumb|[[Skeletal formula]] of [[propranolol]], the first clinically successful beta blocker]]
'''Beta blockers''' (sometimes written as '''β-blocker''') are a class of [[medication|drugs]] used for various indications, but particularly for the management of [[cardiac arrhythmia]]s and cardioprotection after [[myocardial infarction]] (heart attack). Whilst once first-line treatment for [[hypertension]], their role was downgraded in June 2006 in the [[United Kingdom]] to fourth-line as they did 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 [[Diabetes mellitus type 2|type 2 diabetes]].<ref name="ref1">{{cite web | author= Sheetal Ladva | title=NICE and BHS launch updated hypertension guideline | url=http://www.nelm.nhs.uk/Record%20Viewing/viewRecord.aspx?id=567178 | date=2006-06-28 | publisher=[[National Institute for Health and Clinical Excellence]] | accessdate=2006-09-30}}</ref> However, Forest Laboratories and Mylan Inc. announced on December 18, 2007 the novel beta blocker Bystolic was approved by the FDA for treatment of hypertension.
[[Propranolol]] was the first clinically useful beta adrenergic [[receptor antagonist]]. Invented by Sir [[James W. Black]], it revolutionized the medical management of [[angina pectoris]] and is considered to be one of the most important contributions to clinical medicine and [[pharmacology]] of the 20th century.<ref name="propranolol">{{cite web | year=1997| url=http://texasheart.org/Education/THIJournal/SIRJAMES.cfm | author=Melanie Patricia Stapleton | title=Sir James Black and Propranolol | publisher=Texas Heart Institute Journal }}</ref>
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]] [[catecholamine]]s ([[epinephrine]] (adrenaline) and [[norepinephrine]] (noradrenaline) in particular), on β-[[adrenergic receptor]]s, part of the [[sympathetic nervous system]] which mediates the [[fight or flight response]].
There are three known types of beta receptor, designated β<sub>1</sub>, β<sub>2</sub> and β<sub>3</sub>. β<sub>1</sub>-Adrenergic receptors are located mainly in the heart and in the kidneys. β<sub>2</sub>-Adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β<sub>3</sub>-receptors are located in fat cells.
Examples of beta-blockers include: Sectral (acebutolol), Zebeta (bisoprolol), Brevibloc (esmolol), Inderal (propranolol), Tenormin (atenolol), Normodyne (labetalol), Coreg (carvedilol), Lopressor (metoprolol), and Bystolic (nebivolol).
===β-Receptor antagonism===
Stimulation of β<sub>1</sub> receptors by epinephrine induces a positive [[chronotropic]] and [[inotropic]] effect on the heart and increases cardiac conduction velocity and automaticity. Stimulation of β<sub>1</sub> receptors on the kidney causes renin release. Stimulation of β<sub>2</sub> 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 β<sub>3</sub> receptors induces [[lipolysis]].
Beta blockers inhibit these normal epinephrine-mediated [[sympathetic nervous system|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. 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 nervous system|sympathetic]] activity (for those β-blockers that do cross the blood-brain barrier, e.g. Propranolol).
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 [[atrium (anatomy)|atrial]] [[refractory period (cardiac)|refractory period]]s. [[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 system|renin angiotensin aldosterone system]] with a resultant decrease in blood pressure due to decreased sodium and water retention.
===Intrinsic sympathomimetic activity===
Some beta blockers (e.g. [[oxprenolol]], [[pindolol]], [[penbutolol]] and [[acebutolol]]) exhibit intrinsic sympathomimetic activity (ISA). These agents are capable of exerting low level [[receptor agonist|agonist]] activity at the β-adrenergic receptor while simultaneously acting as a receptor site [[receptor antagonist|antagonist]]. These agents, therefore, may be useful in individuals exhibiting excessive [[bradycardia]] with sustained beta blocker therapy.
Agents with ISA are not used in 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 pectoris|angina]] and [[tachyarrhythmia]].<ref name="Rossi">{{cite book | editor=Editor Rossi S | title=[[Australian Medicines Handbook]] |year=2006 |location=Adelaide |publisher=Australian Medicines Handbook}}</ref>
===α<sub>1</sub>-Receptor antagonism===
Some beta blockers (e.g. [[labetalol]] and [[carvedilol]]) exhibit mixed antagonism of both β- and α<sub>1</sub>-[[adrenergic receptor]]s, which provides additional [[arteriole|arteriolar]] vasodilating action.
===Other effects===
Beta blockers decrease nocturnal [[melatonin]] release, perhaps partly accounting for sleep disturbance caused by some agents.<ref name="pmid10335905">{{cite journal |author=Stoschitzky K, Sakotnik A, Lercher P, ''et al'' |title=Influence of beta-blockers on melatonin release |journal=Eur. J. Clin. Pharmacol. |volume=55 |issue=2 |pages=111–5 |year=1999 |pmid=10335905|doi=10.1007/s002280050604}}</ref>
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." (example- an inexperienced symphony soloist) <ref name="anxiety">{{cite web |url=http://www.medscape.com/viewarticle/416878_print |title=Social Anxiety Disorder: A Treatable Condition|accessdate=2007-10-06||first=Jonathan|last=Davidson, M.D.|coauthors=Connor M.D., Kathryn M.|publisher=Cliggott Publishing, Division of SCP Communications|work=Drug Benefit Trends 11(5)|pages=5BH-7BH|date=1999}}</ref>
Beta blockers can impair the relaxation of bronchial muscle (mediated by beta-2) and so should be avoided by asthmatics.
== 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 pectoris|Angina]]
* [[Mitral valve prolapse]]
* [[Cardiac arrhythmia]]
* [[Congestive heart failure]]
* [[Myocardial infarction]]
* [[Glaucoma]]
* [[Migraine]] [[prophylaxis]]
* Symptomatic control ([[tachycardia]], [[tremor]]) in [[anxiety]] and [[hyperthyroidism]]
* [[Essential tremor]]
* [[Phaeochromocytoma]], in conjunction with [[alpha blocker|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]]
*[[Social anxiety disorder]] and other [[anxiety disorders]]
===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.<ref name="pmid10714728">{{cite journal |author=Hjalmarson A, Goldstein S, Fagerberg B, ''et al'' |title=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 |journal=JAMA |volume=283 |issue=10 |pages=1295–302 |year=2000 |pmid=10714728|doi=10.1001/jama.283.10.1295}}</ref>
<ref name="pmid11835035">{{cite journal |author=Leizorovicz A, Lechat P, Cucherat M, Bugnard F |title=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 |journal=Am. Heart J. |volume=143 |issue=2 |pages=301–7 |year=2002 |pmid=11835035|doi=10.1067/mhj.2002.120768}}</ref>
<ref name="pmid12390947">{{cite journal |author=Packer M, Fowler MB, Roecker EB, ''et al'' |title=Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study |journal=Circulation |volume=106 |issue=17 |pages=2194–9 |year=2002 |pmid=12390947|doi=10.1161/01.CIR.0000035653.72855.BF}}</ref>
[[Bisoprolol]], [[carvedilol]] and sustained-release [[metoprolol]] are specifically indicated as adjuncts to standard [[ACE inhibitor]] and [[diuretic]] therapy in congestive heart failure.
Beta blockers are primarily known for their reductive effect on heart rate, although this is not necessarily the case. Beta blockers don't directly interact with the heart at all, but instead influence the renin/ angiotensin system at the kidneys. Beta blockers specifically cause a decrease in renin secretion, which in turn reduce the heart oxygen demand by lowering extracellular volume. 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.<ref name="pmid12173717">{{cite journal |author=Pritchett AM, Redfield MM |title=Beta-blockers: new standard therapy for heart failure |journal=Mayo Clin. Proc. |volume=77 |issue=8 |pages=839–45; quiz 845–6 |year=2002 |pmid=12173717 |doi= |url=http://www.mayoclinicproceedings.com/pdf%2F7708%2F7708crc%2Epdf |format=PDF}}</ref>
===Anxiety and performance enhancement===
Some people, particularly [[musicians]], use beta blockers to avoid [[stage fright]] and tremor during public performance and [[Audition (performing arts)|audition]]s. The physiological symptoms of the fight/flight response associated with [[Stage fright|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. Officially, beta blockers are not approved for [[anxiolytic]] use by the U.S. [[Food and Drug Administration]]. <ref name="pmid16957148">{{cite journal |author=Schneier FR |title=Clinical practice. Social anxiety disorder |journal=N. Engl. J. Med. |volume=355 |issue=10 |pages=1029–36 |year=2006 |pmid=16957148 |doi=10.1056/NEJMcp060145}}</ref>
Since they lower heart rate and reduce tremor, beta blockers have been used by some [[Olympic Games|Olympic]] [[marksman|marksmen]] to enhance performance, though beta blockers are banned by the [[International Olympic Committee]] (IOC).<ref name="ref4">{{cite web | author= World Anti-Doping Agency | title=The World Anti-Doping Code: The 2006 Prohibited List International Standard | url=http://multimedia.olympic.org/pdf/en_report_1037.pdf | date=2005-09-19 | publisher=[[World Anti-Doping Agency]] | accessdate=2006-12-13}}</ref> 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 reaction]]s (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 (medical)|fatigue]], [[dizziness]], abnormal vision, decreased concentration, [[hallucinations]], [[insomnia]], nightmares, [[clinical depression]], [[sexual dysfunction]], [[erectile dysfunction]] and/or alteration of [[glucose]] and [[lipid]] [[metabolism]]. Mixed α<sub>1</sub>/β-antagonist therapy is also commonly associated with [[orthostatic hypotension]]. [[Carvedilol]] therapy is commonly associated with [[edema]].<ref name="Rossi"/>
[[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 β<sub>2</sub>-adrenergic receptor antagonist activity (bronchospasm, peripheral vasoconstriction, alteration of glucose and lipid metabolism) are less common with β<sub>1</sub>-selective (often termed "cardioselective") agents, however receptor selectivity diminishes at higher doses. Beta blockade, especially of the beta-1 receptor at the macula densa inhibits renin release, thus decreasing the release of aldosterone. This causes hyponatremia and hyperkalemia.
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 antagonist]]s (Angiotensin Receptor Blockers) actually decrease the risk of diabetes.<ref name="pmid17240286">{{cite journal |author=Elliott WJ, Meyer PM |title=Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis |journal=Lancet |volume=369 |issue=9557 |pages=201–7 |year=2007 |pmid=17240286 |doi=10.1016/S0140-6736(07)60108-1}}</ref> 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.<ref name="pmid16809680">{{cite journal |author=Mayor S |title=NICE removes beta blockers as first line treatment for hypertension |journal=BMJ |volume=333 |issue=7557 |pages=8 |year=2006 |pmid=16809680 |doi=10.1136/bmj.333.7557.8-a |url=http://www.bmj.com/cgi/content/full/333/7557/8-a}}</ref>
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. <ref name=Toxicity,Cocaine;eMedicine>[http://www.emedicine.com/med/topic400.htm eMedicine - Toxicity, Cocaine : Article by Carlos J Roldan<!-- Bot generated title -->]</ref> The appropriate [[antihypertensive]] drugs to administer during hypertensive crisis resulting from stimulant abuse are [[vasodilators]] like [[nitroglycerin]], [[diuretics]] like [[furosemide]] and [[alpha blockers]] like [[phentolamine]]. <ref name=Toxicity,Amphetamine;eMedicine>[http://www.emedicine.com/EMERG/topic23.htm eMedicine - Toxicity, Amphetamine : Article by Neal Handly<!-- Bot generated title -->]</ref>
== Examples of beta blockers ==
[[Image:Dichloroisoprenaline.png|thumb|Dichloroisoprenaline, the first beta blocker.|200px|right]]
===Non-selective agents===
*[[Alprenolol]]
*[[Carteolol]]
*[[Levobunolol]]
*[[Mepindolol]]
*[[Metipranolol]]
*[[Nadolol]]
*[[Oxprenolol]]
*[[Penbutolol]]
*[[Pindolol]]
*[[Propranolol]]
*[[Sotalol]]
*[[Timolol]]
===β<sub>1</sub>-Selective agents===
*[[Acebutolol]]
*[[Atenolol]]
*[[Betaxolol]]
*[[Bisoprolol]]<ref name="bisoprolol">[http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a693024.html Bisoprolol] MedlinePlus</ref>
*[[Esmolol]]
*[[Metoprolol]]
*[[Nebivolol]]
===Mixed α<sub>1</sub>/β-adrenergic antagonists===
*[[Arotinolol]]
*[[Carvedilol]]
*[[Celiprolol]]
*[[Labetalol]]
===β<sub>2</sub>-Selective agents===
*[[Butaxamine]] (weak α-adrenergic agonist activity)
==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
* [[Peyronie's disease]]
==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
**Nebivolol
===Indication differences===
*Agents specifically indicated for [[cardiac arrhythmia]]
**[[Esmolol]], [[sotalol]]
*Agents specifically indicated for [[congestive heart failure]]
**[[Bisoprolol]], [[carvedilol]], [[metoprolol|sustained-release metoprolol]], [[nebivolol]]
*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 esophageal variceal bleeding, and used in conjunction with α-blocker therapy in [[phaeochromocytoma]].<ref name="Rossi"/>
==References==
*{{cite book |author=Katzung, Bertram G. |title=Basic & clinical pharmacology |edition=9th edition |publisher=Lange Medical Books/McGraw-Hill |location=New York |year=2004 |pages=130, table 9-3 |isbn=0-07-144097-6 |oclc= |doi=}}
==Footnotes==
{{reflist|2}}
==External links==
*[http://www.nytimes.com/2004/10/17/arts/music/17tind.html?ex=1270785600&en=37bef79604f97228&ei=5090&partner=rssuserland Better Playing Through Chemistry] by Blair Tindall, ''[[New York Times]]'', [[October 17]], [[2004]]. (Discussing the use of beta-blockers among professional musicians.)
*[http://www.sfgate.com/cgi-bin/article.cgi?file=/c/a/2004/10/17/MNGB599PJC1.DTL Musicians using beta blockers] by Blair Tindall. Condensed version of above article.
* {{MeshName|beta-Adrenergic+Blockers}}
{{Beta blockers}}
{{Antiglaucoma preparations and miotics}}
{{Major Drug Groups}}
{{Receptor agonists and antagonists}}
[[Category:Beta blockers|*]]
[[Category:Antihypertensive agents]]
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