Beta blocker

Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack (secondary prevention).^[1] They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.^[2]

Beta blockers
Drug class
Skeletal formula of propranolol, the first clinically successful beta blocker.
Class identifiers
Synonyms	beta-blockers, β-blockers, beta-adrenergic blocking agents, beta antagonists, beta-adrenergic antagonists, beta-adrenoreceptor antagonists, beta adrenergic receptor antagonists, BB
Use	Hypertension, arrhythmia, etc.
ATC code	C07
Biological target	beta receptors
Clinical data
Drugs.com	Drug Classes
Consumer Reports	Best Buy Drugs
WebMD	MedicineNet  RxList
External links
MeSH	D000319
In Wikidata

Beta blockers are competitive antagonists that block the receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system, which mediates the fight-or-flight response.^[3][4] Some block activation of all types of β-adrenergic receptors and others are selective for one of the three known types of beta receptors, designated β₁, β₂ and β₃ receptors.^[5] β₁-adrenergic receptors are located mainly in the heart and in the kidneys.^[4] β₂-adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle.^[4] β₃-adrenergic receptors are located in fat cells.^[6]

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

In 1964, James Black^[7] synthesized the first clinically significant beta blockers—propranolol and pronethalol; it revolutionized the medical management of angina pectoris^[8] and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.^[9]

For the treatment of primary hypertension, meta-analyses of studies which mostly used atenolol have shown that although beta blockers are more effective than placebo in preventing stroke and total cardiovascular events, they are not as effective as diuretics, medications inhibiting the renin–angiotensin system (e.g., ACE inhibitors), or calcium channel blockers.^{[10][11][12][13]}

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:

• Angina pectoris^[14][15][16] (contraindicated for Prinzmetal's angina)
• Atrial fibrillation^[17]
• Cardiac arrhythmia^[18][16]
• Congestive heart failure^[19]
• Essential tremor^[20]
• Glaucoma^[16][21] (as eye drops, they decrease intraocular pressure by lowering aqueous humor secretion^[22])
• Hypertension,^[16] although they are generally not preferred as an initial treatment^[23]
• Hyperthyroidism^[16]
• Migraine prophylaxis^[24]
• Mitral valve prolapse^[25]
• Myocardial infarction^[26]
• Phaeochromocytoma, in conjunction with α-blocker^[27]
• Postural orthostatic tachycardia syndrome^[28]
• Symptomatic control (tachycardia, tremor) in anxiety and hyperthyroidism^[28]
• Theophylline overdose^[29]

Beta blockers have also been used for:^[30]

• 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 in non-cardiac surgery, but the best evidence suggests that they increase mortality when used this way^[31][32]

Congestive heart failure

Although beta blockers were once contraindicated in congestive heart failure, as they have the potential to worsen the condition due to their effect of decreasing cardiac contractility, studies in the late 1990s showed their efficacy at reducing morbidity and mortality.^[33][34][35]Bisoprolol, carvedilol, and sustained-release metoprolol are specifically indicated as adjuncts to standard ACE inhibitor and diuretic therapy in congestive heart failure, although at doses typically much lower than those indicated for other conditions. Beta blockers are only indicated in cases of compensated, stable congestive heart failure; in cases of acute decompensated heart failure, beta blockers will cause a further decrease in ejection fraction, worsening the patient's current symptoms.

Beta blockers are known primarily for their reductive effect on heart rate, although this is not the only mechanism of action of importance in congestive heart failure.^[36] Beta blockers, in addition to their sympatholytic β1 activity in the heart, influence the renin–angiotensin system at the kidneys. Beta blockers cause a decrease in renin secretion, which in turn reduces the heart oxygen demand by lowering the extracellular volume and increasing the oxygen-carrying capacity of the blood. Heart failure characteristically involves increased catecholamine activity on the heart, which is responsible for several deleterious effects, including increased oxygen demand, propagation of inflammatory mediators, and abnormal cardiac tissue remodeling, all of which decrease the efficiency of cardiac contraction and contribute to the low ejection fraction.^[37] Beta blockers counter this inappropriately high sympathetic activity, eventually leading to an improved ejection fraction, 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 numbers of hospital visits and hospitalizations were also reduced in the trials.^[38]

Therapeutic administration of beta blockers for congestive heart failure ought to begin at very low doses (1/8 of target) with a gradual escalation of the dose. The heart of the patient must adjust to decreasing stimulation by catecholamines and find a new equilibrium at a lower adrenergic drive.^[21]

Anxiety

Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration.^[39] However, many controlled trials in the past 25 years indicate beta blockers are effective in anxiety disorders, though the mechanism of action is not known.^[40] The physiological symptoms of the fight-or-flight response (pounding heart, cold/clammy hands, increased respiration, sweating, 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, representing 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.^[41] Beta blockers are inexpensive, said to be relatively safe, and on one hand, seem to improve musicians' performances on a technical level, while some, such as 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".^[41]

Surgery

Low certainty evidence indicates that the use of beta blockers around the time of cardiac surgery may decrease the risk of heart dysrhythmias and atrial fibrillation.^[42] Starting them around the time of other types of surgery, however, may worsen outcomes. For non-cardiac surgery, the use of beta blockers to prevent adverse effects may reduce the risk of atrial fibrillation and myocardial infarctions (very low certainty evidence), however, there is moderate certainty evidence that this approach may increase the risk of hypotension.^[43] Low-certainty evidence suggests that beta blockers used perioperatively in non-cardiac surgeries may increase the risk of bradycardia.^[43]

Performance-enhancing use

Because they promote lower heart rates and reduce tremors, beta blockers have been used in professional sports where high accuracy is required, including archery, shooting, golf^[44] and snooker.^[44] Beta blockers are banned in some sports by the International Olympic Committee.^[45] In the 2008 Summer Olympics, 50-metre pistol silver medalist and 10-metre air pistol bronze medalist Kim Jong-su tested positive for propranolol and was stripped of his medals.^[46]

For similar reasons, beta blockers have also been used by surgeons.^[47]

Classical musicians have commonly used beta blockers since the 1970s to reduce stage fright.^[48]

Adverse effects

Adverse drug reactions 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), abnormal vision, hallucinations, insomnia, nightmares, sexual dysfunction, erectile dysfunction and/or alteration of glucose and lipid metabolism.^{[medical citation needed]} Mixed α₁/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema.^{[49][page needed]} 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, vivid dreams and nightmares.^[50]

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, but 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 glycogen breakdown (glycogenolysis) in the liver and pancreatic release of the hormone glucagon, which work together to increase plasma glucose. Therefore, blocking β2-adrenoceptors lowers plasma glucose. β1-blockers have fewer metabolic side effects in diabetic patients; however, the fast heart rate that serves as a warning sign for insulin-induced low blood sugar may be masked, resulting in hypoglycemia unawareness. This is termed beta blocker-induced hypoglycemia unawareness. Therefore, beta blockers are to be used cautiously in diabetics.^[51]

A 2007 study revealed diuretics and beta blockers used for hypertension increase a patient's risk of developing diabetes mellitus, while ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers) actually decrease the risk of diabetes.^[52] 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.^[53]

Beta blockers must not be used in the treatment of selective alpha-adrenergic agonist overdose. The blockade of only beta receptors increases blood pressure, reduces coronary blood flow, left ventricular function, and cardiac output and tissue perfusion by means of leaving the alpha-adrenergic system stimulation unopposed.^{[medical citation needed]} Beta blockers with lipophilic properties and CNS penetration such as metoprolol and labetalol may be useful for treating CNS and cardiovascular toxicity from a methamphetamine overdose.^[54] The mixed alpha- and beta blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.^[55] The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta blockers for treatment of methamphetamine toxicity.^[55] Other appropriate antihypertensive drugs to administer during hypertensive crisis resulting from stimulant overdose are vasodilators such as nitroglycerin, diuretics such as furosemide, and alpha blockers such as phentolamine.^[56]

Contraindications

Contraindications for beta blockers include:

• Abrupt discontinuations
• Acute bronchospasm^[57]
• Acute heart failure^[57]
• Asthma
• AV block
• Bradycardia^[57]
• Bronchitis^[57]
• Cardiogenic shock^[57]
• Cerebrovascular disease
• Chronic obstructive pulmonary disease (COPD)
• Diabetes mellitus^[57]
• Emphysema^[57]
• Hypersensitivity to beta blockers^[57]
• Hypotension
• Kidney failure
• Hepatic disease
• Myopathy
• Pheochromocytoma
• Psoriasis
• Stroke
• Vasospastic angina
• Wolff–Parkinson–White syndrome^[57]

Asthma

The 2007 National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines recommend against the use of non-selective beta blockers in asthmatics, while allowing for the use of cardio selective beta blockers.^[58]: 182

Cardio selective beta blocker (β1 blockers), if really required, can be prescribed at the least possible dose to those with mild to moderate respiratory symptoms.^[59][60] β2-agonists can somewhat mitigate β-Blocker-induced bronchospasm where it exerts greater efficacy on reversing selective β-blocker-induced bronchospasm than the nonselective β-blocker-induced worsening asthma and/or COPD.^[59]

Diabetes mellitus

Epinephrine signals early warning of the upcoming hypoglycemia.^[61]

Beta blockers' inhibition on epinephrine's effect can somewhat exacerbate hypoglycemia by interfering with glycogenolysis and mask signs of hypoglycemia such as tachycardia, palpitations, diaphoresis, and tremors. Diligent blood glucose level monitoring is necessary for a patient with diabetes mellitus on beta blocker.

Hyperthyroidism

Abrupt withdrawal can result in a thyroid storm.^[57]

Bradycardia or AV block

Unless a pacemaker is present, beta blockers can severely depress conduction in the AV node, resulting in a reduction of heart rate and cardiac output. One should be very cautious with the use of beta blockers in tachycardia patients with Wolff-Parkinson-White Syndrome, as it can result in life-threatening arrhythmia in certain patients. By slowing the conduction through the AV node, preferential conduction through the accessory pathway is favored. If the patient happens to develop atrial flutter, this could lead to a 1:1 conduction with very fast ventricular rate, or worse, ventricular fibrillation in the case of atrial fibrillation.

Toxicity

Glucagon, used in the treatment of overdose,^[62][63] increases the strength of heart contractions, increases intracellular cAMP, and decreases renal vascular resistance. It is, therefore, useful in patients with beta blocker cardiotoxicity.^[64][65] Cardiac pacing is usually reserved for patients unresponsive to pharmacological therapy.

People experiencing bronchospasm due to the β₂ receptor-blocking effects of nonselective beta blockers may be treated with anticholinergic drugs, such as ipratropium, which are safer than beta agonists in patients with cardiovascular disease. Other antidotes for beta blocker poisoning are salbutamol and isoprenaline.

β-receptor antagonism

Stimulation of β₁ receptors by epinephrine and norepinephrine induces a positive chronotropic and inotropic effect on the heart and increases cardiac conduction velocity and automaticity.^[66] Stimulation of β₁ receptors on the kidney causes renin release.^[67] Stimulation of β₂ receptors induces smooth muscle relaxation,^[68] induces tremor in skeletal muscle,^[69] and increases glycogenolysis in the liver and skeletal muscle.^[70] Stimulation of β₃ receptors induces lipolysis.^[71]

Beta blockers inhibit these normal epinephrine- and norepinephrine-mediated sympathetic actions,^[3] but have minimal effect on resting subjects.^{[citation needed]} That is, they reduce the effect of excitement or physical exertion on heart rate and force of contraction,^[72] and also tremor,^[73] and breakdown of glycogen. Beta blockers can have a constricting effect on the bronchi of the lungs, possibly worsening or causing asthma symptoms.^[74]

Since β₂ adrenergic receptors can cause vascular smooth muscle dilation, beta blockers may cause some vasoconstriction. However, this effect tends to be small because the activity of β₂ receptors is overshadowed by the more dominant vasoconstricting α₁ receptors. By far the greatest effect of beta blockers remains in the heart. Newer, third-generation beta blockers can cause vasodilation through blockade of alpha-adrenergic receptors.^[75]

Accordingly, nonselective beta blockers are expected to have antihypertensive effects.^[76] The primary antihypertensive mechanism of beta blockers is unclear, but may involve reduction in cardiac output (due to negative chronotropic and inotropic effects).^[77] It may also be due to reduction in renin release from the kidneys, and a central nervous system effect to reduce sympathetic activity (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 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 water retention.

Intrinsic sympathomimetic activity

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, depending 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, labetalol and acebutolol) 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 should not be used for patients with any kind of angina as it can aggravate or after myocardial infarctions. They may also be less effective than other beta blockers in the management of angina and tachyarrhythmia.^[49]

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.^[78][79]

Examples

 

Dichloroisoprenaline, the first beta blocker

Nonselective agents

Nonselective beta blockers display both β₁ and β₂ antagonism.^[80]

• Propranolol^[80]
• Bucindolol (has additional α₁-blocking activity)^[81]
• Carteolol^[82]
• Carvedilol (has additional α₁-blocking activity)^[80]
• Labetalol (has intrinsic sympathomimetic activity and additional α₁-blocking activity)^[80]
• Nadolol^[80]
• Oxprenolol (has intrinsic sympathomimetic activity)^[83]
• Penbutolol (has intrinsic sympathomimetic activity)^[80]
• Pindolol (has intrinsic sympathomimetic activity)^[80]
• Sotalol (not considered a "typical beta blocker")^[80]
• Timolol^[80]

β₁-selective agents

β₁-selective beta blockers are also known as cardioselective beta blockers.^[80] Pharmacologically, the beta-blockade of the B1 receptors in the heart will act on cAMP. The function of cAMP as a second messenger in the cardiac cell is that it phosphorylates the LTCC and the ryanodine receptor to increase intracellular calcium levels and cause contraction. Beta-blockade of the B1 receptor will inhibit cAMP from phosphorylating, and it will decrease the ionotrophic and chronotropic effect. Note that drugs may be cardioselective, or act on B1 receptors in the heart only, but still have instrinsic sympathomimetic activity.

• Acebutolol (has intrinsic sympathomimetic activity, ISA)^[80]
• Atenolol^[80]
• Betaxolol^[80]
• Bisoprolol^[80]
• Celiprolol (has intrinsic sympathomimetic activity)^[84]
• Metoprolol^[80]
• Nebivolol^[80]
• Esmolol^[85]

Nebivolol and Bisoprolol are the most β₁ cardioselective beta blockers.^[86]

β₂-selective agents

• Butaxamine^[87]
• ICI-118,551^[88]

β₃-selective agents

• SR 59230A^[89]

β₁ selective antagonist and β₃ agonist agents

• Nebivolol^[80]

Comparative information

Pharmacological differences

• Agents with intrinsic sympathomimetic action (ISA)
  • Acebutolol,^[90] pindolol,^[90] labetalol,^[90] mepindolol,^[91] oxprenolol,^[83] celiprolol,^[84] penbutolol^[80]
• Agents organized by lipid solubility (lipophilicity)^[92]
  • 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 effect^[93]
  • Carvedilol, propranolol > oxprenolol > labetalol, metoprolol, timolol

Indication differences

• Agents specifically labeled for cardiac arrhythmia
  • Esmolol,^[94] sotalol,^[95] landiolol (Japan)^[96]
• Agents specifically labeled for congestive heart failure^[80]
  • Bisoprolol, carvedilol, sustained-release metoprolol
• Agents specifically labeled for glaucoma
  • Betaxolol,^[93] carteolol,^[93] levobunolol,^[93] timolol,^[93] metipranolol^[97]
• Agents specifically labeled for myocardial infarction^[80]
  • Atenolol, metoprolol (immediate release), propranolol (immediate release), timolol, carvedilol (after left ventricular dysfunction), bisoprolol (preventive treatment before and primary treatment after heart attacks)
• Agents specifically labeled for migraine prophylaxis^[98]
  • 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.^[49]

Other effects

Beta blockers, due to their antagonism at beta-1 adrenergic receptors, inhibit both the synthesis of new melatonin and its secretion by the pineal gland. The neuropsychiatric side effects of some beta blockers (e.g. sleep disruption, insomnia) may be due to this effect.^[99]

Some pre-clinical and clinical research suggests that some beta blockers may be beneficial for cancer treatment.^[100][101] However, other studies do not show a correlation between cancer survival and beta blocker usage.^[102][103] Also, a 2017 meta-analysis failed to show any benefit for the use of beta blockers in breast cancer.^[104]

Beta blockers have also been used for the treatment of schizoid personality disorder.^[105] However, there is limited evidence supporting the efficacy of supplemental beta blocker use in addition to antipsychotic drugs for treating schizophrenia.^[106]

Contrast agents are not contraindicated in those receiving beta blockers.^[107]

See also

• Alpha blockers

References

1. Freemantle N, Cleland J, Young P, Mason J, Harrison J (June 1999). "beta Blockade after myocardial infarction: systematic review and meta regression analysis". BMJ. 318 (7200): 1730–7. doi:10.1136/bmj.318.7200.1730. PMC 31101. PMID 10381708.
2. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC, Svetkey LP, Taler SJ, Townsend RR, Wright JT, Narva AS, Ortiz E (February 2014). "2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8)". JAMA. 311 (5): 507–20. doi:10.1001/jama.2013.284427. PMID 24352797.
3. Frishman WH, Cheng-Lai A, Nawarskas J (2005). Current Cardiovascular Drugs. Current Science Group. p. 152. ISBN 978-1-57340-221-7. Retrieved September 7, 2010.
4. Arcangelo VP, Peterson AM (2006). Pharmacotherapeutics for advanced practice: a practical approach. Lippincott Williams & Wilkins. p. 205. ISBN 978-0-7817-5784-3. Retrieved September 7, 2010.
5. Frishman WH, Cheng-Lai A, Nawarskas J (2005). Current Cardiovascular Drugs. Current Science Group. p. 153. ISBN 978-1-57340-221-7. Retrieved September 7, 2010.
6. Clément K, Vaisse C, Manning BS, Basdevant A, Guy-Grand B, Ruiz J, Silver KD, Shuldiner AR, Froguel P, Strosberg AD (August 1995). "Genetic variation in the beta 3-adrenergic receptor and an increased capacity to gain weight in patients with morbid obesity". The New England Journal of Medicine. 333 (6): 352–4. doi:10.1056/NEJM199508103330605. PMID 7609752.
7. "Sir James Black, OM". The Telegraph. March 23, 2010. from the original on March 27, 2010. Retrieved March 25, 2010.
8. van der Vring JA, Daniëls MC, Holwerda NJ, Withagen PJ, Schelling A, Cleophas TJ, Hendriks MG (June 1999). "Combination of calcium channel blockers and beta blockers for patients with exercise-induced angina pectoris: a double-blind parallel-group comparison of different classes of calcium channel blockers. The Netherlands Working Group on Cardiovascular Research (WCN)". Angiology. 50 (6): 447–54. doi:10.1177/000331979905000602. PMID 10378820. S2CID 21885509.
9. Stapleton MP (1997). "Sir James Black and propranolol. The role of the basic sciences in the history of cardiovascular pharmacology". Texas Heart Institute Journal. 24 (4): 336–42. PMC 325477. PMID 9456487.
10. Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH (January 2017). "Beta-blockers for hypertension". The Cochrane Database of Systematic Reviews. 1 (1): CD002003. doi:10.1002/14651858.CD002003.pub5. PMC 5369873. PMID 28107561.
11. Chen YJ, Li LJ, Tang WL, Song JY, Qiu R, Li Q, Xue H, Wright JM (November 2018). "First-line drugs inhibiting the renin angiotensin system versus other first-line antihypertensive drug classes for hypertension". The Cochrane Database of Systematic Reviews. 2018 (11): CD008170. doi:10.1002/14651858.CD008170.pub3. PMC 6516995. PMID 30480768.
12. Zhu, Jiaying; Chen, Ning; Zhou, Muke; Guo, Jian; Zhu, Cairong; Zhou, Jie; Ma, Mengmeng; He, Li (January 9, 2022). "Calcium channel blockers versus other classes of drugs for hypertension". The Cochrane Database of Systematic Reviews. 1 (1): CD003654. doi:10.1002/14651858.CD003654.pub6. ISSN 1469-493X. PMC 8742884. PMID 35000192.
13. Wiysonge CS, Bradley HA, Volmink J, Mayosi BM, Opie LH (January 2017). "Beta-blockers for hypertension". The Cochrane Database of Systematic Reviews. 1 (1): CD002003. doi:10.1002/14651858.cd002003.pub5. PMC 5369873. PMID 28107561.
14. Cleophas, Ton (1995). Beta-blockers in hypertension and angina pectoris: different compounds, different strategies. Kluwer Academic Publishers. ISBN 978-0-7923-3516-0.
15. Khan, M.I. Gabriel (2007). Cardia Drug Therapy. Humana Press. ISBN 978-1-59745-238-0.
16. Katzung, Bertram (2018). Basic & Clinical Pharmacology. McGraw-Hill. ISBN 9781259641152.
17. Meinertz T, Willems S (December 2008). "[Treatment of atrial fibrillation in every days [sic] practice]" [Treatment of atrial fibrillation in everyday practice]. Der Internist. 49 (12): 1437–42, 1444–45. doi:10.1007/s00108-008-2152-6. PMID 19020848.
18. "Medications for Arrhythmia". www.heart.org. Retrieved August 10, 2019.
19. "Beta Blocker Therapy". American College of Cardiology. Retrieved August 10, 2019.
20. "Essential Tremor Medications". Cleveland Clinic. Retrieved August 10, 2019.
21. Goodman & Gilman's: The Pharmacological Basic of Therapeutics. McGraw-Hill. 2018. ISBN 9781259584732.
22. Shen, Howard (2008). Illustrated Pharmacology Memory Cards: PharMnemonics. Minireview. p. 15. ISBN 978-1-59541-101-3.
23. NICE Hypertension guidance April 9, 2017, at the Wayback Machine Last updated 2013
24. "Preventive Treatment of Migraine in Adults". www.uptodate.com. Retrieved August 10, 2019.
25. "Mitral Valve Prolapse". Mayo Clinic. March 6, 2018. Retrieved August 9, 2019.
26. "Acute myocardial infarction: Role of beta blocker therapy". www.uptodate.com. Retrieved August 10, 2019.
27. "Pheochromocytoma Medication: Alpha Blockers, Antihypertensives, BPH, Alpha Blocker, Vasodilators, Beta Blockers, Nonselective, Beta Blockers, Beta1 Selective, Antihypertensives, Other, Radiopharmaceuticals". emedicine.medscape.com. Retrieved August 10, 2019.
28. . ww2.mc.vanderbilt.edu – Vanderbilt Health Institute. Nashville, TN. Archived from the original on August 10, 2019. Retrieved August 10, 2019.
29. "Theophylline Poisoning". www.uptodate.com. Retrieved August 10, 2019.
30. "When Beta Blockers Are Used". www.myoclinic.org. Retrieved September 24, 2021.
31. Bouri, Sonia; Shun-Shin, Matthew James; Cole, Graham D; Mayet, Jamil; Francis, Darrel P (March 15, 2014). "Meta-analysis of secure randomised controlled trials of β-blockade to prevent perioperative death in non-cardiac surgery". Heart. 100 (6): 456–64. doi:10.1136/heartjnl-2013-304262. ISSN 1355-6037. PMC 3932762. PMID 23904357.
32. Blessberger H, Kammler J, Domanovits H, Schlager O, Wildner B, Azar D, Schillinger M, Wiesbauer F, Steinwender C (March 2018). "Perioperative beta-blockers for preventing surgery-related mortality and morbidity". The Cochrane Database of Systematic Reviews. 9 (9): CD004476. doi:10.1002/14651858.CD004476.pub3. PMC 6494407. PMID 29533470.
33. Hjalmarson A, Goldstein S, Fagerberg B, Wedel H, Waagstein F, Kjekshus J, Wikstrand J, El Allaf D, Vítovec J, Aldershvile J, Halinen M, Dietz R, Neuhaus KL, Jánosi A, Thorgeirsson G, Dunselman PH, Gullestad L, Kuch J, Herlitz J, Rickenbacher P, Ball S, Gottlieb S, Deedwania P (March 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. doi:10.1001/jama.283.10.1295. PMID 10714728.
34. Leizorovicz A, Lechat P, Cucherat M, Bugnard F (February 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". American Heart Journal. 143 (2): 301–07. doi:10.1067/mhj.2002.120768. PMID 11835035.
35. Packer M, Fowler MB, Roecker EB, Coats AJ, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Staiger C, Holcslaw TL, Amann-Zalan I, DeMets DL (October 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): 2194–99. doi:10.1161/01.CIR.0000035653.72855.BF. PMID 12390947.
36. Fletcher, Peter (2000). "Beta blockers in heart failure". Australian Prescriber. 23 (6): 120–123. doi:10.18773/austprescr.2000.138.
37. "Use of beta-blockers and ivabradine in heart failure with reduced ejection fraction". www.uptodate.com. from the original on December 22, 2015. Retrieved December 11, 2015.
38. Pritchett AM, Redfield MM (August 2002). "Beta-blockers: new standard therapy for heart failure". Mayo Clinic Proceedings. 77 (8): 839–45, quiz 845–46. doi:10.4065/77.8.839. PMID 12173717.
39. Schneier FR (September 2006). "Clinical practice. Social anxiety disorder". The New England Journal of Medicine. 355 (10): 1029–36. doi:10.1056/NEJMcp060145. PMID 16957148.
40. Tyrer P (January 1992). "Anxiolytics not acting at the benzodiazepine receptor: beta blockers". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 16 (1): 17–26. doi:10.1016/0278-5846(92)90004-X. PMID 1348368. S2CID 24742562.
41. Tindall, Blair (October 17, 2004). . The New York Times. Archived from the original on August 26, 2015.
42. Blessberger, Hermann; Lewis, Sharon R.; Pritchard, Michael W.; Fawcett, Lizzy J.; Domanovits, Hans; Schlager, Oliver; Wildner, Brigitte; Kammler, Juergen; Steinwender, Clemens (September 23, 2019). "Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing cardiac surgery". The Cochrane Database of Systematic Reviews. 9 (9): CD013435. doi:10.1002/14651858.CD013435. ISSN 1469-493X. PMC 6755267. PMID 31544227.
43. Blessberger, Hermann; Lewis, Sharon R.; Pritchard, Michael W.; Fawcett, Lizzy J.; Domanovits, Hans; Schlager, Oliver; Wildner, Brigitte; Kammler, Juergen; Steinwender, Clemens (September 26, 2019). "Perioperative beta-blockers for preventing surgery-related mortality and morbidity in adults undergoing non-cardiac surgery". The Cochrane Database of Systematic Reviews. 9 (9): CD013438. doi:10.1002/14651858.CD013438. ISSN 1469-493X. PMC 6761481. PMID 31556094.
44. Tim Glover. "Golf: O'Grady says players use beta-blockers: Drugs 'helped win majors'". The Independent. from the original on September 25, 2015. Retrieved March 28, 2017.
45. World Anti-Doping Agency (September 19, 2005). "The World Anti-Doping Code: The 2006 Prohibited List International Standard" (PDF). World Anti-Doping Agency. (PDF) from the original on February 11, 2017. Retrieved February 10, 2017.
46. Scott, Matt (August 15, 2008). "Olympics: North Korea's Kim Jong-su loses medals after positive drugs test". The Guardian. Guardian News and Media Limited. Retrieved March 7, 2018.
47. Elman MJ, Sugar J, Fiscella R, Deutsch TA, Noth J, Nyberg M, Packo K, Anderson RJ (1998). "The effect of propranolol versus placebo on resident surgical performance". Transactions of the American Ophthalmological Society. 96: 283–91, discussion 291–4. PMC 1298399. PMID 10360293.
48. "Musicians Use Beta Blockers as Performance-Enabling Drugs". WQXR. August 16, 2013. Retrieved March 11, 2021.
49. Rossi S, ed. (2006). Australian Medicines Handbook. Adelaide: Australian Medicines Handbook.
50. Cruickshank JM (2010). "Beta-blockers and heart failure". Indian Heart Journal. 62 (2): 101–10. PMID 21180298.
51. Beta-Adrenoceptor Antagonists (Beta-Blockers); "CV Pharmacology | Beta-Adrenoceptor Antagonists (Beta-Blockers)". from the original on August 8, 2011. Retrieved August 8, 2011.
52. Elliott WJ, Meyer PM (January 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. S2CID 37044384.
53. Mayor S (July 2006). "NICE removes beta blockers as first line treatment for hypertension". BMJ. 333 (7557): 8. doi:10.1136/bmj.333.7557.8-a. PMC 1488775. PMID 16809680.
54. Richards JR, Derlet RW, Albertson TE. "Treatment & Management". Methamphetamine Toxicity. from the original on April 9, 2016. Retrieved April 20, 2016. {{cite encyclopedia}}: |website= ignored (help)
55. Richards JR, Albertson TE, Derlet RW, Lange RA, Olson KR, Horowitz BZ (May 2015). "Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review". Drug and Alcohol Dependence. 150: 1–13. doi:10.1016/j.drugalcdep.2015.01.040. PMID 25724076.
56. Handly, Neal (December 16, 2016). "Toxicity, Amphetamine". Medscape. from the original on October 13, 2007.
57. Wyeth Pharmaceuticals Inc. "Propranolol hydrochloride" (PDF). Retrieved September 3, 2020.
58. National Heart, Lung, and Blood Institute (2007). "Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma–Summary Report 2007". The Journal of Allergy and Clinical Immunology. 120 (5): S94–S138. doi:10.1016/j.jaci.2007.09.029. Retrieved December 9, 2017.{{cite journal}}: CS1 maint: multiple names: authors list (link)
59. Morales, Daniel R.; Jackson, Cathy; Lipworth, Brian J.; Donnan, Peter T.; Guthrie, Bruce (2014). "Adverse Respiratory Effect of Acute β-Blocker Exposure in Asthma". Chest. Elsevier BV. 145 (4): 779–786. doi:10.1378/chest.13-1235. ISSN 0012-3692. PMID 24202435.
60. Salpeter, Shelley R.; Ormiston, Thomas M.; Salpeter, Edwin E. (November 5, 2002). "Cardioselective β-Blockers in Patients with Reactive Airway Disease". Annals of Internal Medicine. American College of Physicians. 137 (9): 715–25. doi:10.7326/0003-4819-137-9-200211050-00035. ISSN 0003-4819. PMID 12416945.
61. Sprague, JE; Arbeláez, AM (2011). "Glucose Counterregulatory Responses to Hypoglycemia". Pediatric Endocrinology Reviews. 9 (1): 463–475. PMC 3755377. PMID 22783644.
62. Weinstein RS, Cole S, Knaster HB, Dahlbert T (February 1985). "Beta blocker overdose with propranolol and with atenolol". Annals of Emergency Medicine. 14 (2): 161–3. doi:10.1016/S0196-0644(85)81081-7. PMID 2857542.
63. "Toxicity, Beta-blocker: Treatment & Medication – eMedicine Emergency Medicine". from the original on March 17, 2009. Retrieved March 6, 2009.
64. John Gualtier. (PDF). Courses.ahc.umn.edu. Archived from the original (PDF) on March 3, 2016. Retrieved March 28, 2017.
65. USMLE WORLD 2009 Step1, Pharmacology, Q85
66. Perez, Dianne M. (2006). The Adrenergic Receptors in the 21st Century. Humana Press. p. 135. ISBN 978-1-58829-423-4. Retrieved September 8, 2010.
67. Jameson JL, Loscalzo J (2010). Harrison's Nephrology and Acid-Base Disorders. McGraw-Hill Companies. p. 215. ISBN 978-0-07-166339-7. Retrieved September 8, 2010.
68. O'Donnell JM, Nácul FE (2009). Surgical Intensive Care Medicine. Springer. p. 47. ISBN 978-0-387-77892-1. Retrieved September 8, 2010.
69. Ahrens RC (1990). "Skeletal muscle tremor and the influence of adrenergic drugs". The Journal of Asthma. 27 (1): 11–20. doi:10.3109/02770909009073289. PMID 1968452.
70. Reents, Stan (2000). Sport and exercise pharmacology. Human Kinetics. p. 19. ISBN 978-0-87322-937-1. Retrieved September 10, 2010.
71. Martini, Frederic H. (2005). Anatomy and Physiology. Pearson Education. p. 394. ISBN 978-0-8053-5947-3. Retrieved September 10, 2010.
72. Khan, M. I. Gabriel (2006). Encyclopedia of Heart Diseases. Elsevier. p. 160. ISBN 978-0-12-406061-6. Retrieved September 10, 2010.
73. Lamster IB, Northridge ME, eds. (2008). Improving Oral Health for the Elderly: An Interdisciplinary Approach. New York: Springer. p. 87. ISBN 978-0-387-74337-0. Retrieved October 23, 2010.
74. Rothfeld GS, Romaine DS (2005). The Encyclopedia of Men's Health. Amaranth. p. 48. ISBN 978-0-8160-5177-9. Retrieved October 23, 2010.
75. Manger WM, Gifford RW (2001). 100 Questions and Answers about Hypertension. Blackwell Science. p. 106. ISBN 978-0-632-04481-8. Retrieved September 10, 2010. beta blockers dilation of blood vessels.
76. Hurst, J.W. (1997). Schlant, Robert C. (ed.). Hurst's the Heart. Vol. 2. Blackwell Science. p. 1564. ISBN 978-0-07-912951-2. Retrieved October 7, 2010.
77. Reid, J.L. (2001). Lecture notes on clinical pharmacology. Vol. 6. Blackwell Science. p. 76. ISBN 978-0-632-05077-2. Retrieved March 11, 2011.
78. "Labetalol Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved March 3, 2019.
79. "Coreg - Food and Drug Administration" (PDF).
80. "Comparison of Oral Beta-Blockers". pharmacist.therapeuticresearch.com. Therapeutic Research Center. from the original on October 18, 2017. Retrieved April 30, 2017.
81. Rosendorff C (June 1993). "Beta-blocking agents with vasodilator activity". Journal of Hypertension Supplement. 11 (4): S37–40. doi:10.1097/00004872-199306003-00009. PMID 8104240.
82. "CARTEOLOL". pubchem.ncbi.nlm.nih.gov. U.S. National Library of Medicine. from the original on October 18, 2017. Retrieved October 18, 2017.
83. "oxprenolol". pubchem.ncbi.nlm.nih.gov. U.S. National Library of Medicine. from the original on October 18, 2017. Retrieved October 18, 2017.
84. "Celiprolol". pubchem.ncbi.nlm.nih.gov. U.S. National Library of Medicine. from the original on October 18, 2017. Retrieved October 18, 2017.
85. Volz-Zang C, Eckrich B, Jahn P, Schneidrowski B, Schulte B, Palm D (1994). "Esmolol, an ultrashort-acting, selective beta 1-adrenoceptor antagonist: pharmacodynamic and pharmacokinetic properties". European Journal of Clinical Pharmacology. 46 (5): 399–404. doi:10.1007/BF00191900. PMID 7957532. S2CID 12809602.
86. Sinha, Shashank S; Gurm, Hitinder S (February 2014). "The double jeopardy of chronic obstructive pulmonary disease and myocardial infarction". Open Heart. 1 (1): e000010. doi:10.1136/openhrt-2013-000010. ISSN 2053-3624. PMC 4189253. PMID 25332777.
87. "Butaxamine". pubchem.ncbi.nlm.nih.gov. U.S. National Library of Medicine. from the original on October 18, 2017. Retrieved October 18, 2017.
88. "ICI 118551". ChEBI.
89. "SR 59230A". pubchem.ncbi.nlm.nih.gov. U.S. National Library of Medicine. from the original on October 18, 2017. Retrieved October 18, 2017.
90. Larochelle P, Tobe SW, Lacourcière Y (May 2014). "β-Blockers in hypertension: studies and meta-analyses over the years". The Canadian Journal of Cardiology. 30 (5 Suppl): S16–22. doi:10.1016/j.cjca.2014.02.012. PMID 24750978.
91. Mulrow, edited by Detlev Ganten, Patrick J. (1990). Pharmacology of Antihypertensive Therapeutics. Berlin, Heidelberg: Springer Berlin Heidelberg. p. 523. ISBN 9783642742095. {{cite book}}: |first1= has generic name (help)CS1 maint: multiple names: authors list (link)
92. Zipursky JS, Macdonald EM, Luo J, Gomes T, Mamdani MM, Paterson JM, Juurlink DN (June 2017). "Lipophilic β-Blockers and Suicide in the Elderly". Journal of Clinical Psychopharmacology. 37 (3): 381–84. doi:10.1097/JCP.0000000000000695. PMID 28338548. S2CID 23355130.
93. Aronson JK (June 2008). "Changing beta-blockers in heart failure: when is a class not a class?". The British Journal of General Practice. 58 (551): 387–89. doi:10.3399/bjgp08X299317. PMC 2418988. PMID 18505613.
94. "DailyMed - BREVIBLOC- esmolol hydrochloride injection". dailymed.nlm.nih.gov. Retrieved November 9, 2022.
95. "DailyMed - BETAPACE- sotalol hydrochloride tablet BETAPACE AF- sotalol hydrochloride tablet". dailymed.nlm.nih.gov. Retrieved November 9, 2022.
96. "Announcement of Approval of Additional Indications for Onoact 50 for Injection, Short-Acting Selective ß1 Blocker". www.evaluategroup.com. Evaluate Ltd. Retrieved October 18, 2017.
97. "Metiprapanol – metipranolol solution/ drops". dailymed.nlm.nih.gov – DailyMed. NIH. from the original on October 18, 2017. Retrieved October 18, 2017.
98. "Drugs to Prevent Migraine in Adults". pharmacist.therapeuticresearch.com. Therapeutic Research Center. from the original on October 18, 2017. Retrieved April 30, 2017.
99. Fares A (July 2011). "Night-time exogenous melatonin administration may be a beneficial treatment for sleeping disorders in beta blocker patients". Journal of Cardiovascular Disease Research. 2 (3): 153–5. doi:10.4103/0975-3583.85261. PMC 3195193. PMID 22022142.
100. Choy C, Raytis JL, Smith DD, Duenas M, Neman J, Jandial R, Lew MW (June 2016). "Inhibition of β2-adrenergic receptor reduces triple-negative breast cancer brain metastases: The potential benefit of perioperative β-blockade". Oncology Reports. 35 (6): 3135–42. doi:10.3892/or.2016.4710. PMC 4869944. PMID 27035124.
101. Kokolus KM, Zhang Y, Sivik JM, Schmeck C, Zhu J, Repasky EA, Drabick JJ, Schell TD (2018). "Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice". Oncoimmunology. 7 (3): e1405205. doi:10.1080/2162402X.2017.1405205. PMC 5790362. PMID 29399407.
102. Livingstone E, Hollestein LM, van Herk-Sukel MP, van de Poll-Franse L, Nijsten T, Schadendorf D, de Vries E (December 2013). "β-Blocker use and all-cause mortality of melanoma patients: results from a population-based Dutch cohort study". European Journal of Cancer. 49 (18): 3863–71. doi:10.1016/j.ejca.2013.07.141. PMID 23942335.
103. Cardwell CR, Coleman HG, Murray LJ, O'Sullivan JM, Powe DG (June 2014). "Beta-blocker usage and prostate cancer survival: a nested case-control study in the UK Clinical Practice Research Datalink cohort". Cancer Epidemiology. 38 (3): 279–85. doi:10.1016/j.canep.2014.03.011. PMID 24786858.
104. Kim HY, Jung YJ, Lee SH, Jung HJ, Pak K (2017). "Is Beta-Blocker Use Beneficial in Breast Cancer? A Meta-Analysis". Oncology. 92 (5): 264–268. doi:10.1159/000455143. PMID 28132057. S2CID 5463335.
105. Sonny Joseph (1997). "Chapter 3, Schizoid Personality Disorder". Personality Disorders: New Symptom-Focused Drug Therapy. Psychology Press. pp. 45–56. ISBN 9780789001344.
106. Shek, Elena; Bardhan, Sabyasachi; Cheine, Maxim V; Ahonen, Juha; Wahlbeck, Kristian. "Beta-blocker supplementation of standard drug treatment for people with schizophrenia". www.cochrane.org. doi:10.1002/14651858.CD000234. S2CID 1627733. Retrieved August 9, 2019.
107. Boehm I, Morelli J, Nairz K, Silva Hasembank Keller P, Heverhagen JT (November 2016). "Beta blockers and intravenous roentgen contrast materials: Which risks do exist?" (PDF). European Journal of Internal Medicine. 35: e17–e18. doi:10.1016/j.ejim.2016.08.003. PMID 27531627.

External links

• Musicians and beta-blockers by Gerald Klickstein, March 11, 2010 (A blog post that considers "whether beta-blockers are safe, effective, and appropriate for performers to use.")
• Better Playing Through Chemistry by Blair Tindall, The New York Times, October 17, 2004. (Discusses the use of beta blockers among professional musicians)
• Musicians using beta blockers by Blair Tindall. A condensed version of the 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 U.S. National Library of Medicine Medical Subject Headings (MeSH)