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Beta blocker

Beta blockers (β-blockers, beta-adrenergic blocking agents, beta antagonists, beta-adrenergic antagonists, beta-adrenoreceptor antagonists, or beta adrenergic receptor antagonists) are a class of drugs that are par- ticularly used for the management of cardiac arrhyth- mias, protecting the heart from a second heart attack (myocardial infarction) after a first heart attack (sec- ondary prevention), [1] and hypertension. [2]

Beta blockers block the action of endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) -in particular on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response. [3][4] Some block all activation of β-adrenergic receptors and others are selective.

Three types of beta receptors are known, designated β 1 , β 2 and β 3 receptors. [5] β 1 -adrenergic receptors are located mainly in the heart and in the kidneys. [4] β 2 - adrenergic receptors are located mainly in the lungs, gas- trointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. [4] β 3 -adrenergic receptors are lo- cated in fat cells. [6]

Beta receptors are found on cells of the heart muscles, smooth muscles, airways, arteries, kidneys, and other tis- sues that are part of the sympathetic nervous system and lead to stress responses, especially when they are stim- ulated by epinephrine (adrenaline). Beta blockers inter- fere with the binding to the receptor of epinephrine and other stress hormones, and weaken the effects of stress hormones.

In 1962, Sir James W. Black [7] found the first clinically significant beta blockerspropranolol and pronethalol; it revolutionized the medical management of angina pec- toris [8] and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century. [9]

In comparison with other antihypertensive drugs, beta- blockers are less than optimal for the treatment of pri- mary hypertension, with a raised risk of stroke. [10]

1 Medical uses

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:

1

Angina pectoris [11][12]

Glaucoma

Phaeochromocytoma, in conjunction with α-blocker

Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism

Theophylline overdose

Beta blockers have also been used for:

Acute aortic dissection

Hypertrophic obstructive cardiomyopathy

Marfan syndrome (treatment with propranolol slows progression of aortic dilation and its complications)

Prevention of variceal bleeding in portal hyperten- sion

Possible mitigation of hyperhidrosis

Social and other anxiety disorders

Controversially, for reduction of perioperative mor- tality

2

2 ADVERSE EFFECTS

Since they promote lower heart rates and reduce tremors,

beta blockers have been used in professional sports where Although beta blockers were once contraindicated high accuracy is required, including archery, shooting,

in congestive heart failure, as they have the po- tential to worsen the condition, studies in the late 1990s showed their efficacy at reducing morbidity and mortality. [14][15][16] Bisoprolol, carvedilol and sustained- release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in conges- tive heart failure.

Beta blockers are known primarily for their reductive ef- fect on heart rate, although this is not the only mechanism of action of importance in congestive heart failure. Beta blockers, in addition to their sympatholytic B1 activity in the heart, influence the renin–angiotensin system at the kidneys. Beta blockers cause a decrease in renin secre- tion, which in turn reduces the heart oxygen demand by lowering extracellular volume and increasing the oxygen- carrying capacity of blood. Beta blockers’ sympatholytic activities reduce heart rate, thereby increasing the ejec- tion fraction of the heart despite an initial reduction in ejection fraction.

Trials have shown beta blockers reduce the absolute risk of death by 4.5% over a 13-month period. In addition to reducing the risk of mortality, the number of hospital vis- its and hospitalizations were also reduced in the trials. [17]

1.1 Congestive heart failure

golf [21] and snooker. [21] Beta blockers are banned by the International Olympic Committee. [22] A recent, high- profile transgression took place in the 2008 Summer Olympics, where 50 metre pistol silver medallist and 10 metre air pistol bronze medallist Kim Jong-su tested pos- itive for propranolol and was stripped of his medals.

For similar reasons, beta blockers have also been used by stutterers and surgeons. [23]

1.3 Surgery

The use of beta blockers around the time of cardiac surgery decreases the risk of heart dysrhythmias. [24] Starting them around the time of other types of surgery; however, worsens outcomes. [24]

2 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, alopecia (hair loss), abnor- mal vision, hallucinations, insomnia, nightmares, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism. Mixed α 1 /β-antagonist therapy is also commonly associated with orthostatic hy- potension. Carvedilol therapy is commonly associated with edema. [25] Due to the high penetration across the blood–brain barrier, lipophilic beta blockers, such as propranolol and metoprolol, are more likely than other, less lipophilic, beta blockers to cause sleep disturbances, such as insomnia and vivid dreams and nightmares. [26]

Adverse effects associated with β 2 -adrenergic receptor antagonist activity (bronchospasm, peripheral vasocon- striction, alteration of glucose and lipid metabolism) are less common with β 1 -selective (often termed “cardiose- lective”) 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.

Hypoglycemia can occur with beta blockade because β2-adrenoceptors normally stimulate hepatic glycogen breakdown (glycogenolysis) and pancreatic release of glucagon, which work together to increase plasma glu- cose. Therefore, blocking β2-adrenoceptors lowers plasma glucose. β1-blockers have fewer metabolic side effects in diabetic patients; however, the tachycardia that serves as a warning sign for insulin-induced hypoglycemia may be masked. Therefore, beta blockers are to be used cautiously in diabetics. [27]

1.2 Anxiety

Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration. [18] How- ever, many controlled trials in the past 25 years indicate beta blockers are effective in anxiety disorders, though the mechanism of action is not known. [19] The physiolog- ical symptoms of the fight-or-flight response (pounding heart, cold/clammy hands, increased respiration, sweat- ing, etc.) are significantly reduced, thus enabling anxious individuals to concentrate on the task at hand.

Musicians, public speakers, actors, and professional dancers have been known to use beta blockers to avoid performance anxiety, stage fright and tremor during both auditions and public performances. The application to stage fright was first recognized in The Lancet in 1976, and by 1987, a survey conducted by the International Conference of Symphony Orchestra Musicians, repre- senting the 51 largest orchestras in the United States, revealed 27% of its musicians had used beta blockers and 70% obtained them from friends, not physicians. [20] Beta blockers are inexpensive, said to be relatively safe and, on one hand, seem to improve musicians’ perfor- mances on a technical level, while some, like Barry Green, the author of “The Inner Game of Music,” and Don Greene, a former Olympic diving coach who teaches Juilliard students to overcome their stage fright naturally, say the performances may be perceived as “soulless and inauthentic.” [20]

3

A 2007 study revealed diuretics and beta blockers used

for hypertension increase a patient’s risk of developing diabetes, while ACE inhibitors and angiotensin II recep- tor antagonists (angiotensin receptor blockers) actually decrease the risk of diabetes. [28] Clinical guidelines in Great Britain, but not in the United States, call for avoid- ing diuretics and beta blockers as first-line treatment of hypertension due to the risk of diabetes. [29]

Beta blockers must not be used in the treatment of cocaine, amphetamine, or other alpha-adrenergic stimulant overdose. The blockade of only beta re- ceptors 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. [30] The ap- propriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant abuse are vasodilators such as nitroglycerin, diuretics such as furosemide and alpha blockers such as phentolamine. [31]

2.1 Contraindications

Beta blockers are contraindicated in patients with asthma

as stated in the British National Formulary 2011. They should also be avoided in patients with a history of co- caine use or in cocaine-induced tachycardia.

Beta blockers should not be used as a first-line treatment

in the acute setting for cocaine-induced acute coronary

syndrome (CIACS). No recent studies have been iden- tified that show the benefit of beta blockers in reducing

coronary vasospasm, or coronary vascular resistance, in patients with CIACS. In the multiple case studies identi- fied, the use of beta blockers in CIACS resulted in detri- mental outcomes, and the discontinuation of beta block- ers used in the acute setting led to improvement in clin- ical course. The guidelines by the American College of Cardiology/American Heart Association also support this idea, and recommend against the use of beta blockers

in cocaine-induced ST-segment elevation myocardial in-

farction (MI) because of the risk of coronary vasospasm.

Though, in general, beta blockers improve mortality in patients who have suffered MI, it is unclear whether pa-

tients with CIACS will benefit from this mortality reduc- tion because there are no studies assessing use of beta blockers in the long term, and because cocaine users may

be prone to continue to abuse the substance, thus compli-

cating the effect of drug therapy. [32]

2.2 Toxicity

Glucagon, used in the treatment of overdose, [33][34] in- creases the strength of heart contractions, increases in- tracellular cAMP, and decreases renal vascular resis- tance. It is therefore useful in patients with beta-blocker cardiotoxicity. [35][36] Cardiac pacing is usually reserved for patients unresponsive to pharmacological therapy.

Patients experiencing bronchospasm due to the β 2 receptor-blocking effects of non-selective beta block- ers may be treated with anticholinergic drugs, such as ipratropium, which are safer than beta agonists in pa- tients with cardiovascular disease. Other antidotes for beta-blocker poisoning are salbutamol and isoprenaline.

3 β-Receptor antagonism

Stimulation of β 1 receptors by epinephrine and norepinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity. [37] Stimulation of β 1 receptors on the kidney causes renin release. [38] Stimulation of β 2 receptors induces smooth muscle relaxation, [39] induces tremor in skeletal muscle, [40] and increases glycogenolysis in the liver and skeletal mus- cle. [41] Stimulation of β 3 receptors induces lipolysis. [42]

Beta blockers inhibit these normal epinephrine and norepinephrine-mediated sympathetic actions, [3] but have minimal effect on resting subjects. That is, they re- duce excitement/physical exertion on heart rate and force of contraction, [43] and also tremor [44] and breakdown of glycogen, but increase dilation of blood vessels [45] and constriction of bronchi. [46]

Therefore, nonselective beta blockers are expected to have antihypertensive effects. [47] The primary antihy- pertensive mechanism of beta blockers is unclear, but may involve reduction in cardiac output (due to nega- tive chronotropic and inotropic effects). [48] It may also be due to reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activ- ity (for those beta 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. Negative chronotropic properties of beta blockers allow the lifesaving property of heart rate control. Beta blockers are readily titrated to optimal rate control in many pathologic states.

The antiarrhythmic effects of beta blockers arise from sympathetic nervous system blockade—resulting in de- pression of sinus node function and atrioventricular node conduction, and prolonged atrial refractory peri- ods. 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 water re- tention.

4

7 EXAMPLES

4 Intrinsic sympathomimetic activ- ity

Also referred to as intrinsic sympathomimetic effect, this term is used particularly with beta blockers that can show both agonism and antagonism at a given beta receptor, de- pending on the concentration of the agent (beta blocker) and the concentration of the antagonized agent (usually an endogenous compound, such as norepinephrine). See partial agonist for a more general description.

Some beta blockers (e.g. oxprenolol, pindolol, penbutolol and acebutolol) exhibit intrinsic sympathomimetic ac- tivity (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 ther- apy.

Agents with ISA are not used after myocardial infarc- tions, 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. [25]

5 α 1 -Receptor antagonism

Some beta blockers (e.g., labetalol and carvedilol) exhibit mixed antagonism of both β- and α 1 -adrenergic recep- tors, which provides additional arteriolar vasodilating ac- tion.

6 Other effects

Beta blockers decrease nocturnal melatonin release, per- haps partly accounting for sleep disturbances caused by some agents. [49]

They can also be used to treat glaucoma because they de- crease intraocular pressure by lowering aqueous humor secretion. [50]

7 Examples

7.1 Nonselective agents

Carteolol

Carvedilol (has additional α-blocking activity)

Labetalol (has additional α-blocking activity)

Nadolol

Oxprenolol (has intrinsic sympathomimetic activity)

• Oxprenolol (has intrinsic sympathomimetic activity) Dichloroisoprenaline , the first beta blocker. •

Dichloroisoprenaline, the first beta blocker.

Penbutolol (has intrinsic sympathomimetic activity)

Pindolol (has intrinsic sympathomimetic activity)

Sotalol

Timolol

Eucommia bark (herb) [51]

7.2 β 1 -selective agents

Also known as cardioselective

Acebutolol (has intrinsic sympathomimetic activity)

Atenolol

Betaxolol

Esmolol [52]

Nebivolol (also increases nitric oxide release for va- sodilation)

7.3 β 2 -selective agents

Butaxamine (weak α-adrenergic agonist activity):

No common clinical applications, but used in exper- iments.

ICI-118,551: Highly selective β 2 -adrenergic recep- tor antagonist—no known clinical applications, but used in experiments due to its strong receptor speci- ficity.

7.4 β 3 -selective agents

SR 59230A (has additional α-blocking activity):

Used in experiments.

5

8 Comparative information

8.1 Pharmacological differences

Agents with intrinsic sympathomimetic action (ISA)

Acebutolol, carteolol, celiprolol, mepindolol, oxprenolol, pindolol

Agents with greater aqueous solubility (hydrophilic beta blockers)

Atenolol, celiprolol, nadolol, sotalol

Acebutolol, propranolol

8.2 Indication differences

10 References

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[2]

Cruickshank JM (August 2010). “Beta blockers in hyper- tension”. Lancet 376 (9739): 415; author reply 415–6. doi:10.1016/S0140-6736(10)61217-2. PMID 20692524.

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Betaxolol,

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Agents specifically indicated for migraine prophy- laxis

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. [25]

9 See also

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[8] van der Vring JA, Daniëls, Holwerda et al. (June 1999). “Combination of calcium channel blockers and beta blockers for patients with exercise-induced angina pectoris: a double-blind parallel-group com- parison of different classes of calcium channel block- ers. The Netherlands Working Group on Cardiovas- cular Research (WCN)". Angiology 50 (6): 447–54. doi:10.1177/000331979905000602. PMID 10378820.

336–42. PMC 325477. PMID 9456487.

[10] Lindholm LH, Carlberg B, Samuelsson O (2005). “Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis”. Lancet 366 (9496): 1545–1553. PMID 16257341.

[12] Khan, M.I. Gabriel (2007). Cardia Drug Therapy. Hu- mana Press. ISBN 1-59745-238-6.

6

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11 External links

Musicians and beta-blockers by Gerald Klickstein, March 11, 2010 (A blog post that considers “whether beta-blockers are safe, effective, and ap- propriate for performers to use.”)

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

Musicians using beta blockers by Blair Tindall. Condensed version of above article.

In Defense of the Beta Blocker by Carl Elliott, The Atlantic, August 20, 2008. (Discusses the use of propranolol by a North Korean pistol shooter in the 2008 Olympics)

beta-Adrenergic Blockers at the US National Li- brary of Medicine Medical Subject Headings (MeSH)

8

12 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

12 Text and image sources, contributors, and licenses

12.1 Text

Beta blocker Source: http://en.wikipedia.org/wiki/Beta%20blocker?oldid=640247115 Contributors: AxelBoldt, Kpjas, Edward, Patrick, Pit, GGano, Ugen64, Raven in Orbit, Pakaran, Owen, Robbot, Diberri, DocWatson42, Christopher Parham, Techelf, Jao, Ksheka, Pret- zelpaws, Jfdwolff, Eequor, Jackol, Toytoy, Mike Rosoft, MattKingston, Rich Farmbrough, Avriette, Clawed, Smyth, Neurophyre, Ver- balcontract, Ljosa, Reinyday, Davidruben, Cmdrjameson, Arcadian, Tim Smith, BillyTFried, Silverback, Gary, Arthena, Andrewpmk, Wouterstomp, Axl, Wtmitchell, Kanodin, Animated Cascade, DrGaellon, SteinbDJ, Gene Nygaard, Martian, Firsfron, Before My Ken, GregorB, Eras-mus, Dysepsion, Rjwilmsi, Smoe, NeonMerlin, Bensin, Nihiltres, Backin72, MacRusgail, Pevernagie, Dexcel, Banaticus, YurikBot, Chris Capoccia, Townba, Manop, Draeco, CHurst5841, Tsalman, Light current, Mais oui!, Andrew73, Winick88, SmackBot, Sagie, Ikip, Etherealmuse, Edgar181, Ahimsa52, Benjaminevans82, Jcarroll, Bluebot, Thumperward, Enigma55, Magnitique, Snowman- radio, Niels Olson, DR04, Monacat, Austere, Nakon, BinaryTed, Acdx, ArglebargleIV, Sbmehta, Sir Nicholas de Mimsy-Porpington, Ned- dyseagoon, Dcflyer, Dcperi, Lathrop1885, Frank Lofaro Jr., Fvasconcellos, Lighthead, Kylu, ShelfSkewed, Vzach, Tawkerbot4, MayaSim- Fan, Calorus, Thijs!bot, Barticus88, Anupam, John254, Mentifisto, Trlkly, Luna Santin, Tmopkisn, Farosdaughter, Keith111, Qwerty Binary, Ph.eyes, S@lo, VoABot II, Emhale, Cisum.ili.dilm, JaGa, MartinBot, Nikpapag, Mike6271, TheEgyptian, Lamaybe, Nbauman, Boghog, Jerry, J.A.McCoy, Lamaglama, Mikael Häggström, Dlegros, Heyitspeter, KylieTastic, Ummel, Gogobera, Alexmuller, Cpt ricard, Maf5081, VolkovBot, Easterangel, TXiKiBoT, Eowyne, Dwight666, TedColes, Teloscientist, Madhero88, Happy B., Doc James, Alle- borgoBot, SieBot, Toddyboy711, Ddxc, Mike2vil, CultureDrone, MrADHD, Scuttlebug, ClueBot, Prohlep, Inteleki, MikeVitale, Boing! said Zebedee, Lbeben, Auntof6, TheodorePreston, Adrian dakota, Carlo Banez, Arjayay, Medos2, KiraCurious, Huntthetroll, Navic- ular, Evpstud, DumZiBoT, Vanished 45kd09la13, Anonymos25, Addbot, Gxcf1, DOI bot, SpBot, Aldrich Hanssen, Zorrobot, Chaldor, Luckas-bot, Yobot, Ptbotgourou, Anypodetos, Apophenic, Goga312, AnomieBOT, KDS4444, Rubinbot, Drtedwilliams, RandomAct, Ma- terialscientist, RobertEves92, Citation bot, Jmarchn, Xqbot, Capricorn42, The Magnificent Clean-keeper, Gigemag76, Srich32977, Skaaii, RibotBOT, Sjp37, Captain-n00dle, Uchinara, FrescoBot, Citation bot 1, Nirmos, DrilBot, Prospect 2000, MusicNewz, Trappist the monk, Smr117, Vrenator, RjwilmsiBot, TjBot, Octopus.crawler, Hreid11, Dcirovic, K6ka, Hazard-SJ, Wayne Slam, Erianna, Cbaltes, MonoAV, MusicEducator, Sonicyouth86, Teaktl17, ClueBot NG, Andrei S, Vldscore, Snotbot, Frietjes, Rurik the Varangian, Helpful Pixie Bot, Iste Praetor, Godlyone, Walrus068, Adallace, Gorthian, Hopur2, Abracus, Markzuckerberggeek, Dinooka, Lady Pandora, EricEnfermero, BattyBot, Darren Travis, Ossip Groth, Jimw338, Morganson691, TylerDurden8823, 00AgentBond93, UseTheCommandLine, MEWhyte, Jodosma, ElHef, Davv321, EtymAesthete, Lilwikki, Truebreath, Lubbdubb, Monkbot, SantiLak, BethNaught, Shinyhomme, Joshw251 and Anonymous: 255

12.2 Images

File:Dichloroisoprenaline.svg Source: http://upload.wikimedia.org/wikipedia/commons/6/6a/Dichloroisoprenaline.svg License: CC BY-SA 3.0 Contributors: Self-made using BKChem and Inkscape Original artist: JaGa

12.3 Content license