Beta blocker

Beta blockers
β-blockers
Drug class

Skeletal formula of propranolol, the first clinically successful beta blocker
ATC code C07
MeSH D000319
AHFS/Drugs.com Drug Classes
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WebMD medicinenet   rxlist
Biological target beta receptors

Beta blockers (sometimes written as β-blockers) or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction[1] (heart attack), and hypertension.[2] As beta adrenergic receptor antagonists, they diminish the effects of epinephrine (adrenaline) and other stress hormones. In 1958 the first beta blocker, dichloroisoproterenol, was synthesised by Eli Lilly Laboratories,[3] but it was Sir James W. Black in 1962,[4] who found the first clinically significant use of beta blockers with propranolol and pronethalol; it revolutionized the medical management of angina pectoris[5] and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.[6]

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.[7][8] There are three known types of beta receptor, designated β1, β2 and β3 receptors.[9] β1-adrenergic receptors are located mainly in the heart and in the kidneys.[8] β2-adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle.[8] β3-adrenergic receptors are located in fat cells.[10]

Contents

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:

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 efficacy at reducing morbidity and mortality in congestive heart failure.[11][12][13] 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 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 secretion, which in turn reduce the heart oxygen demand by lowering extracellular volume and increasing the oxygen carrying capacity of blood. Beta blockers sympatholytic activity reduce heart rate, thereby increasing the ejection fraction of the heart despite an initial reduction in ejection fraction.

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.[14]

Anxiety and performance enhancement

There is clear evidence from many controlled trials in the past 25 years that beta blockers are effective in anxiety disorders, though the mechanism of action is not known.[15] Some people have used beta blockers for performance enhancement, and especially to combat performance anxiety. In particular, musicians, public speakers, actors, and professional dancers, have been known to use beta blockers to avoid stage fright and tremor during public performance and especially auditions.

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 that 27 percent of its musicians had used beta blockers and that 70 percent obtained them from friends, not physicians.[16] Beta blockers are inexpensive, said to be relatively safe and, on one hand, seem to improve musicians performances on a technical level while some say the performance may be perceived as "soulless and inauthentic".[16]

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. Stutterers also use beta blockers to avoid fight/flight responses, hence reducing the tendency to stutter. Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration.[17]

Since they promote a 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).[18] Although they have no recognisable benefit to most sports, it is acknowledged that they are beneficial to sports such as archery and shooting. 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 positive for propranolol and was stripped of his medal.

Preventing PTSD

Posttraumatic stress disorder (PTSD) is theorized to be the result of neurological patterns caused by adrenaline and fear in the brain. By administering beta blockers immediately following a traumatic event, as well as over the next couple weeks, the formation of PTSD has been reduced in clinical studies.

Adverse effects

Adverse drug reactions (ADRs) associated with the use of beta blockers include: nausea, diarrhoea, 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. Mixed α1/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema.[19]

Central nervous system (CNS) adverse effects (hallucinations, insomnia, nightmares) 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. 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 glucose. Therefore, blocking β2-adrenoceptors lowers plasma glucose. β1-blockers have fewer metabolic side effects in diabetic patients; however, the tachycardia which serves as a warning sign for insulin-induced hypoglycemia may be masked. Therefore, beta-blockers are to be used cautiously in diabetics. [20]

A 2007 study revealed that diuretics and beta-blockers used for hypertension increase a patient's risk of developing diabetes while ACE inhibitors and Angiotensin II receptor antagonists (Angiotensin Receptor Blockers) actually decrease the risk of diabetes.[21] 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.[22]

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.[23] 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.[24]

Contraindications

They are contraindicative to patients with asthma as stated in the BNF 2011. Beta blockers should also be avoided in patients with history of cocaine use or in cocaine-induced tachycardia or MI.

Toxicity

Glucagon has been used in the treatment of overdose.[25][26] Glucagon has a positive inotropic action on the heart and decreases renal vascular resistance. It is therefore useful in patients with beta-blocker cardiotoxicity. Glucagon is the specific antidote for beta-blocker poisoning, because it increases intracellular cAMP and cardiac contractility. [27] [28] Cardiac pacing should be reserved for patients unresponsive to pharmacological therapy.

Patients who experience bronchospasm due to the B2 blocking effects of non-selective beta-blockers may be treated with anticholinergic drugs such as Ipratropium, which are safer than beta agonists in patients with cardiovascular disease.

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.[29] Stimulation of β1 receptors on the kidney causes renin release.[30] Stimulation of β2 receptors induces smooth muscle relaxation,[31] induces tremor in skeletal muscle,[32] and increases glycogenolysis in the liver and skeletal muscle.[33] Stimulation of β3 receptors induces lipolysis.[34]

Beta blockers inhibit these normal epinephrine-mediated sympathetic actions,[7] but have minimal effect on resting subjects. That is, they reduce excitement/physical exertion on heart rate and force of contraction,[35] and also tremor[36] and breakdown of glycogen, but increase dilation of blood vessels[37] and constriction of bronchi.[38]

It is therefore expected that non-selective beta blockers have an antihypertensive effect.[39] The primary antihypertensive mechanism of betablockers is unclear but it may involve reduction in cardiac output (due to negative chronotropic and inotropic effects).[40] 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 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. 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 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 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 and tachyarrhythmia.[19]

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.[41]

They can also be used to treat glaucoma because they decrease intraocular pressure by lowering aqueous humor secretion.[42]

Examples of beta blockers

Non-selective agents

β1-Selective agents

β2-Selective agents

β3-Selective agents

Comparative information

Pharmacological differences

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.[19]

See also

References

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  28. ^ USMLE WORLD 2009 Step1, Pharmacology, Q85
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