Beta blockers (beta-blockers, β-blockers, etc.) are a class of medications that are predominantly used to manage abnormal heart rhythms, and to protect the heart from a second heart attack (myocardial infarction) after a first heart attack (secondary prevention).[1] They are also widely used to treat high blood pressure (hypertension), although they are no longer the first choice for initial treatment of most patients.[2]
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
Performance-enhancing use
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. Mixed α1/β-antagonist therapy is also commonly associated with orthostatic hypotension. Carvedilol therapy is commonly associated with edema.[45] 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.[46]
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.[47]
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.[48] 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.[49]
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.[50] The mixed alpha- and beta blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.[51] The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta blockers for treatment of methamphetamine toxicity.[51] 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.[52]
Contraindications
Contraindications for beta-blockers include:
- Abrupt discontinuations
- Acute bronchospasm[53]
- Acute heart failure[53]
- Asthma[citation needed]
- AV block[citation needed]
- Bradycardia[53]
- Bronchitis[53]
- Cardiogenic shock[53]
- Cerebrovascular disease[citation needed]
- Chronic obstructive pulmonary disease (COPD)[citation needed]
- Diabetes mellitus[53]
- Emphysema[53]
- Hypersensitivity to beta blockers[53]
- Hypotension[citation needed]
- Kidney failure[citation needed]
- Hepatic disease[citation needed]
- Myopathy[citation needed]
- Pheochromocytoma
- Psoriasis[citation needed]
- Stroke[citation needed]
- Vasospastic angina[citation needed]
- Wolff–Parkinson–White syndrome[53]
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 cardioselective beta blockers.[54]:182
Cardioselective beta-blocker (β1 blockers), if really required, can be prescribed at the least possible dose to those with mild to moderate respiratory symptoms.[55][56] 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.[55]
Diabetes mellitus
Epinephrine signals early warning of the upcoming hypoglycemia.[57]
Beta-blockers' inhibition on epinephrine's effect can somewhat exacerbate hypoglycemia by interfering with glycogenesis 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.[53]
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. Usage of beta-blockers in tachycardic patients with Wolff-Parkinson-White Syndrome can result in severe bradycardia, necessitating treatment with a pacemaker.
Toxicity
Glucagon, used in the treatment of overdose,[58][59] increases the strength of heart contractions, increases intracellular cAMP, and decreases renal vascular resistance. It is, therefore, useful in patients with beta blocker cardiotoxicity.[60][61] 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.[62] Stimulation of β1 receptors on the kidney causes renin release.[63] Stimulation of β2 receptors induces smooth muscle relaxation,[64] induces tremor in skeletal muscle,[65] and increases glycogenolysis in the liver and skeletal muscle.[66] Stimulation of β3 receptors induces lipolysis.[67]
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,[68] and also tremor,[69] and breakdown of glycogen. Beta blockers can have a constricting effect on the bronchi of the lungs, possibly worsening or causing asthma symptoms.[70]
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.[71]
Accordingly, nonselective beta blockers are expected to have antihypertensive effects.[72] The primary antihypertensive mechanism of beta blockers is unclear, but may involve reduction in cardiac output (due to negative chronotropic and inotropic effects).[73] 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 are not used after myocardial infarctions, 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.[45]
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.[citation needed]
Examples
Nonselective agents
Nonselective beta blockers display both β1 and β2 antagonism.[74]
- Propranolol[74]
- Bucindolol (has additional α1-blocking activity)[75]
- Carteolol[76]
- Carvedilol (has additional α1-blocking activity)[74]
- Labetalol (has additional α1-blocking activity)[74]
- Nadolol[74]
- Oxprenolol (has intrinsic sympathomimetic activity)[77]
- Penbutolol (has intrinsic sympathomimetic activity)[74]
- Pindolol (has intrinsic sympathomimetic activity)[74]
- Sotalol (not considered a "typical beta blocker")[74]
- Timolol[74]
β1-selective agents
β1-selective beta blockers are also known as cardioselective beta blockers.[74]
- Acebutolol (has intrinsic sympathomimetic activity, ISA)[74]
- Atenolol[74]
- Betaxolol[74]
- Bisoprolol[74]
- Celiprolol (has intrinsic sympathomimetic activity)[78]
- Metoprolol[74]
- Nebivolol[74]
- Esmolol[79]
β2-selective agents
- Butaxamine[80]
- ICI-118,551[81]
β3-selective agents
- SR 59230A[82]
β1 selective antagonist and β3 agonist agents
- Nebivolol[74]
Comparative information
Pharmacological differences
- Agents with intrinsic sympathomimetic action (ISA)
- Acebutolol,[83] pindolol,[83] labetalol,[83] mepindolol,[84] oxprenolol,[77] celiprolol,[78] penbutolol[74]
- Agents organized by lipid solubility (lipophilicity)[85]
- 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[86]
- Carvedilol, propranolol > oxprenolol > labetalol, metoprolol, timolol
Indication differences
- Agents specifically labeled for cardiac arrhythmia
- Esmolol,[87] sotalol,[88] landiolol (Japan)[89]
- Agents specifically labeled for congestive heart failure[74]
- Bisoprolol, carvedilol, sustained-release metoprolol
- Agents specifically labeled for glaucoma
- Betaxolol,[86] carteolol,[86] levobunolol,[86] timolol,[86] metipranolol[90]
- Agents specifically labeled for myocardial infarction[74]
- 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[91]
- 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.[45]
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.[92]
Some pre-clinical and clinical research suggests that some beta blockers may be beneficial for cancer treatment.[93][94] However, other studies do not show a correlation between cancer survival and beta blocker usage.[95][96] Also, a 2017 meta-analysis failed to show any benefit for the use of beta blockers in breast cancer.[97]
Beta blockers have also been used for the treatment of schizoid personality disorder.[98] However, there is limited evidence supporting the efficacy of supplemental beta-blocker use in addition to antipsychotic drugs for treating schizophrenia.[99]
Contrast media are not contraindicated in patients receiving beta blockers.
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