Beta blockers

Beta blockers
Drug class
Propranolol
Skeletal formula of propranolol, the first beta blocker
Names
Stem-olol[1]
Other namesBeta-blocker, β-blockers, beta-adrenergic blocking agents, beta antagonists, beta-adrenergic antagonists, beta-adrenoreceptor antagonists, beta adrenergic receptor antagonists, BB
Clinical data
UsesAbnormal heart rhythms, ischemic heart disease, heart failure, hypertension[2]
Side effectsTiredness, headache, trouble sleeping, nausea, sexual dysfunction[2]
InteractionsSome calcium channel blockers[2]
SubtypesCardioselective: Atenolol, bisoprolol, metoprolol, esmolol[3]
Non-cardioselective: Carvedilol, labetalol, propranolol, sotalol[3]
External links
Drugs.comDrug Classes
WebMDMedicineNet  RxList

Beta blockers (β-blockers) are a class of medication mainly used to manage abnormal heart rhythms, ischemic heart disease, and heart failure.[2] They are also used to treat high blood pressure, though are no longer a first choice for initial treatment in most people.[2][4] Other uses may include overactive thyroid, essential tremor, glaucoma, and migraines.[3] Common agents in this class include atenolol, bisoprolol, carvedilol, and metoprolol.[2][5] They can be taken by mouth, given intravenously, or used as eye drops.[3]

Side effects may include tiredness, headache, trouble sleeping, nausea, and sexual dysfunction.[2] They may cause complications in asthma, low blood pressure, and heart block.[2] Lower doses may be required in those with liver problems and heart failure.[2] They may also interact with certain calcium channel blockers.[2] Beta blocker toxicity is associated with a high risk of a poor outcome.[6]

Beta blockers work by binding to and blocking epinephrine (adrenaline) and norepinephrine (noradrenaline) from activating beta receptors, and thus decrease sympathetic nervous system activity.[7] Some block activation at all β-adrenergic receptors while others are selective for β1- receptors.[7] β1- receptors are located mainly in the heart and kidneys.[3][8] β2-receptors are located in the smooth muscles of blood vessels and the airway.[7] β3- receptors are located in fat cells.[3]

The first medically useful beta blocker, propranolol, was made in 1964 by James Black.[9] It is considered one of the most important contributions to pharmacology of the 20th century.[10] Beta blockers are among the most widely used medications.[2] Some are available as generic medication and are relatively inexpensive.[2] Their use in particular sports is banned by the International Olympic Committee as they improve accuracy.[11][12]

Types

Dichloroisoprenaline, the first beta blocker

Nonselective

Nonselective beta blockers display both β1 and β2 antagonism.[13]

β1-selective

β1-selective beta blockers are also known as cardioselective beta blockers.[13]

β2-selective

β3-selective

β1 selective antagonist and β3 agonist

Uses

Large differences exist in the pharmacology of agents within the class, thus not all beta blockers are used for all indications listed below.

Uses for beta blockers include:

Beta blockers have also been used for:

High blood pressure

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.[40][41][42][43]

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.[44][45][46] 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. 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 extracellular volume and increasing the oxygen-carrying capacity of blood. Heart failure characteristically involves increased catecholamine activity on the heart, which is responsible for a number of 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.[47] 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.[48]

Therapeutic administration of beta blockers for congestive heart failure ought to begin at very low doses (1/8 of target) with 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.[29]

Anxiety

Officially, beta blockers are not approved for anxiolytic use by the U.S. Food and Drug Administration.[49] 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.[50] 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.[51] 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".[51]

Cardiac surgery

The use of beta blockers around the time of cardiac surgery decreases the risk of heart dysrhythmias.[39] Starting them around the time of other types of surgery, however, may worsen outcomes.

Performance-enhancement

Beta blockers lower the heart rate and reduce tremors, and as a result have been used in professional sports where high accuracy is required.[52] Such sports have included archery and shooting.[52] Golf[53] and snooker have been implicated as well.[53] Beta blockers are banned by the International Olympic Committee.[11] 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.[54]

For similar reasons, beta blockers have also been used by surgeons.[55]

Side effects

Side effects 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.[56] 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.[57] Beta blockers do not appear to affect the rate of depression.[58]

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.[59]

A 2007 study revealed diuretics and beta blockers used for hypertension increase a person's risk of developing diabetes mellitus, while ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers) actually decrease the risk of diabetes.[60] 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.[61]

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.[62] The mixed alpha- and beta blocker labetalol is especially useful for treatment of concomitant tachycardia and hypertension induced by methamphetamine.[63] The phenomenon of "unopposed alpha stimulation" has not been reported with the use of beta blockers for treatment of methamphetamine toxicity.[63] 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.[64]

Contraindications

Contraindications for beta-blockers include:

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.[66]: 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.[67][68] 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.[67]

Diabetes mellitus

Epinephrine signals early warning of the upcoming hypoglycemia.[69]

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 thyroid storm.[65]

Bradycardia or AV block

Unless a pacemaker is present, beta-blockers can severely depress conduction in the AV node, resulting in 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,[70][71] increases the strength of heart contractions, increases intracellular cAMP, and decreases renal vascular resistance. It is, therefore, useful in patients with beta blocker cardiotoxicity.[72][73] 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.

Mechanism of action

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.[74] Stimulation of β1 receptors on the kidney causes renin release.[75] Stimulation of β2 receptors induces smooth muscle relaxation,[76] induces tremor in skeletal muscle,[77] and increases glycogenolysis in the liver and skeletal muscle.[78] Stimulation of β3 receptors induces lipolysis.[79]

Beta blockers inhibit these normal epinephrine- and norepinephrine-mediated sympathetic actions,[80] 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,[81] and also tremor,[82] and breakdown of glycogen. Beta blockers can have a constricting effect on the bronchi of the lungs, possibly worsening or causing asthma symptoms.[83]

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.[84]

Accordingly, nonselective beta blockers are expected to have antihypertensive effects.[85] The primary antihypertensive mechanism of beta blockers is unclear, but may involve reduction in cardiac output (due to negative chronotropic and inotropic effects).[86] 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.[56]

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.

Pharmacological differences

  • Agents with intrinsic sympathomimetic action (ISA)
  • Agents organized by lipid solubility (lipophilicity)[89]
    • 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[90]
    • Carvedilol, propranolol > oxprenolol > labetalol, metoprolol, timolol

History

In 1964,[9] the search to find an effective drug in myocardial infarction led Sir James Black and ICI, the company with which Black worked with, to develop propranolol, the first beta blocker with beneficial effects.[9][91] Subsequent poorly designed trials failed to demonstrate benefits and beta blockers for myocardial infarction fell out of favour until the ISIS-1 trial, a landmark trial which looked at injecting beta blockers in myocardial infarction. Beta blockers were found to reduce cardiac rupture, leading to their estabishment in the use following an acute myocardial infarction.[9]

Society and culture

Commonly used β-blockers are available as generic medication and are relatively inexpensive.[2] Their use in certain precision sports is banned by the International Olympic Committee as they improve performance by reducing tremor and anxiety.[11][12][52]

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.[56]

Research

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.[97]

Some pre-clinical and clinical research suggests that some beta blockers may be beneficial for cancer treatment.[98][99] However, other studies do not show a correlation between cancer survival and beta blocker usage.[100][101] Also, a 2017 meta-analysis failed to show any benefit for the use of beta blockers in breast cancer.[102]

Beta blockers have also been used for the treatment of schizoid personality disorder.[103] However, there is limited evidence supporting the efficacy of supplemental beta-blocker use in addition to antipsychotic drugs for treating schizophrenia.[104]

Contrast media are not contraindicated in patients receiving beta blockers.[105]

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