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
beta-blockers, β-blockers, beta-adrenergic blocking agents, beta antagonists, beta-adrenergic antagonists, beta-adrenoreceptor antagonists, beta adrenergic receptor antagonists, BB
Hypertension, arrhythmia, etc.
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]: 152 [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.[3]: 153 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.[5]
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[6] synthesized the first clinically significant beta blockers—propranolol and pronethalol; it revolutionized the medical management of angina pectoris[7] and is considered by many to be one of the most important contributions to clinical medicine and pharmacology of the 20th century.[8]
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.[9][10][11][12]
Performance-enhancing use[edit]
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[34] and snooker.[34] Beta blockers are banned in some sports by the International Olympic Committee.[35] 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.[36]
For similar reasons, beta blockers have also been used by surgeons.[37]
Classical musicians have commonly used beta blockers since the 1970s to reduce stage fright.[38]
Pharmacology[edit]
Intrinsic sympathomimetic activity[edit]
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.[39]
β-Adrenergic receptor antagonism[edit]
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.[56] Stimulation of β1 receptors on the kidney causes renin release.[57] Stimulation of β2 receptors induces smooth muscle relaxation,[58] induces tremor in skeletal muscle,[59] and increases glycogenolysis in the liver and skeletal muscle.[60] Stimulation of β3 receptors induces lipolysis.[61]
Beta blockers inhibit these normal epinephrine- and norepinephrine-mediated sympathetic actions,[3] but have minimal effect on resting subjects.
That is, they reduce the effect of excitement or physical exertion on heart rate and force of contraction,[62] and also tremor,[63] and breakdown of glycogen. Beta blockers can have a constricting effect on the bronchi of the lungs, possibly worsening or causing asthma symptoms.[64]
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.[65]
Accordingly, nonselective beta blockers are expected to have antihypertensive effects.[66] The primary antihypertensive mechanism of beta blockers is unclear, but may involve reduction in cardiac output (due to negative chronotropic and inotropic effects).[67] 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.
α1-Adrenergic receptor antagonism[edit]
Some beta blockers (e.g., labetalol and carvedilol) exhibit mixed antagonism of both β- and α1-adrenergic receptors, which provides additional arteriolar vasodilating action.[68][69]
Blood–brain barrier permeability[edit]
Beta blockers vary in their lipophilicity (fat solubility) and in turn in their ability to cross the blood–brain barrier and exert effects in the central nervous system.[70] Beta blockers with greater blood–brain barrier permeability can have both neuropsychiatric therapeutic benefits and side effects, as well as adverse cognitive effects.[70] Central nervous system-related side effects and risks of beta blockers may include fatigue, depression, sleep disorders (namely insomnia) and nightmares, visual hallucinations, delirium, psychosis, Parkinson's disease, and falling.[70] Conversely, central nervous system-related benefits of beta blockers may include prevention and treatment of migraine, essential tremor, akathisia, anxiety, post-traumatic stress disorder, aggression, and obsessive–compulsive disorder.[70]
Most beta blockers are lipophilic and can cross into the brain, but there are a number of exceptions.[70] Highly lipophilic beta blockers include penbutolol, pindolol, propranolol, and timolol, moderately lipophilic beta blockers include acebutolol, betaxolol, bisoprolol, carvedilol, metoprolol, and nebivolol, and low lipophilicity or hydrophilic beta blockers include atenolol, carteolol, esmolol, labetalol, nadolol, and sotalol.[70] It is thought that highly lipophilic beta blockers are able to readily cross into the brain, moderately lipophilic beta blockers are able to cross to a lesser degree, and low lipophilicity or hydrophilic beta blockers are minimally able to cross.[70] More lipophilic beta-blockers are known to suppress melatonin release by 50-80%.[71][72][73] The preceding beta blockers also vary in their intrinsic sympathomimetic activity and β1-adrenergic receptor selectivity (or cardioselectivity), resulting in further differences in pharmacological profiles and suitability in different contexts between them.[70]
Other effects[edit]
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.[93]
Some pre-clinical and clinical research suggests that some beta blockers may be beneficial for cancer treatment.[94][95] However, other studies do not show a correlation between cancer survival and beta blocker usage.[96][97] Also, a 2017 meta-analysis failed to show any benefit for the use of beta blockers in breast cancer.[98]
Beta blockers have also been used for the treatment of schizoid personality disorder.[99] However, there is limited evidence supporting the efficacy of supplemental beta blocker use in addition to antipsychotic drugs for treating schizophrenia.[100][101]
Contrast agents are not contraindicated in those receiving beta blockers.[102]