Adrenergic beta-antagonist
Encyclopedia
Adrenergic beta-receptor blockaders (beta-blockers) are "drugs that bind to but do not activate beta-adrenergic receptor
s thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension
, cardiac arrhythmias, angina pectoris, glaucoma, migraine
headaches, and anxiety".
Beta-blockers vary within the class regarding their properties. Beta-blockers that have low intrinsic sympathomimetic activity (ISA), low membrane stabilizing activity, high beta 1-selectivity
, and high lipophilicity may be more effective.
They further divide by frequency of dosing, cost, and other factors.
, drugs vary in their selectivity. Generic beta-blockers with selectivity for the beta-1 adrenergic receptor
:
Non-generic:
lipid changes):
Non-generic:
):
G protein–coupled cell surface receptor kinase 2 (GRK2) genetic polymorphisms may also affect the response to adrenergic beta-antagonists.
Single-nucleotide polymorphism of the beta-1 (ADRB1) adrenergic receptor
, specifically c.389A>G, may increase cardiac ischemia and SNP of the beta-2 (ADRB2) adrenergic receptor
, specifically, c.16G>A SNP of the 4 SNPs studied, may increase hypotension in perioperative care.
Single-nucleotide polymorphism of the beta-2 (ADRB2) adrenergic receptor
, specifically c.46G>A and c.79C>G of the four SNPs studied, may affect the response to adrenergic beta-antagonist treatment of acute coronary syndrome
.
Genetic polymorphisms of alpha-2C (ADRA2C) may affect the response to adrenergic beta-antagonist treatment of heart failure.
that are metabolized by cytochrome P-450 CYP2D6 allele
and may have more drug interaction
s and inherited variations in metabolism.
Although poor metabolism due to CYP2D6 polymorphisms may be present in patients with drug toxicity due to metoprolol
, small studies suggest that careful, slow titration and avoidance of other drugs metabolized by CYP2D6 may avoid drug toxicity from polymorphisms of cytochrome P-450.
may be more predictive than the amount of drug in predicting the drug's benefit or harm. This may be due to invidual molecular variations in adrenergic receptor
s, G-protein-coupled receptor kinases, and metabolism by cytochrome P-450.
The individual beta-blockers have been compared in the treatment of various diseases.
Adrenergic beta-antagonists were first shown to be effective in 1981.
Adrenergic beta-antagonists do not definitely reduce short term mortality while in the hospital (see evidence table), but may improve long germ mortality. Metoprolol
may or may not be the best beta-blocker for secondary prevention of myocardial infarction
s according to meta-analyses
of randomized controlled trials.
Cohort studies
suggest that atenolol may or may not be better than other adrenergic beta-antagonists.
Two cohort studies
suggest that atenolol and carvedilol
may be more effective than metoprolol
for the treatment of heart failure.
Drugs with intrinsic sympathomimetic activity may be less beneficial. A systematic review
of randomized controlled trial
s concluded "metoprolol, carvedilol, and bisoprolol all exhibited statistically significant mortality rate reductions compared with placebo, the data were inconclusive for nebivolol or atenolol" and "for every heart rate reduction of 5 beats/min with β-blocker treatment, a commensurate 18% reduction in the risk for death occurred."
. A meta-analysis
and accompanying editorial have concluded that the more the drug lowers the heart rate
, the lower the benefit of the drug. The harm may be confined to elderly patients. Alternatively, or in addition:
Beta-blockers may be less effective than diuretic
s in the treatment of elderly patients with hypertension
due to reduced ability to prevent coronary heart disease
.
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
s thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, cardiac arrhythmias, angina pectoris, glaucoma, migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
headaches, and anxiety".
Beta-blockers vary within the class regarding their properties. Beta-blockers that have low intrinsic sympathomimetic activity (ISA), low membrane stabilizing activity, high beta 1-selectivity
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
, and high lipophilicity may be more effective.
Classification
Generically available beta-blockers, which subclassify based on selective aspects of their action, include:- Acebutolol
- Atenolol
- BisoprololBisoprololBisoprolol is a drug belonging to the group of beta blockers, a class of drugs used primarily in cardiovascular diseases. More specifically, it is a selective type β1 adrenergic receptor blocker. The FDA approved Duramed Pharmaceutical's application for Zebeta Oral Tablets as a new molecular...
- MetoprololMetoprololMetoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...
- Nadolol
- Propranolol
- Timolol
They further divide by frequency of dosing, cost, and other factors.
| Selectivity | Agents | Applications |
|---|---|---|
| Nonselective | propranolol, timolol Timolol Timolol maleate is a non-selective beta-adrenergic receptor blocker.-Uses:In its oral form , it is used:* to treat high blood pressure* to prevent heart attacks* to prevent migraine headaches... , nadolol Nadolol Nadolol is a non-selective beta blocker used in the treatment of high blood pressure, migraine headaches, and chest pain.-Pharmacology:... , pindolol Pindolol Pindolol is a beta blocker.... , penbutolol Penbutolol Penbutolol is a medication in the class of beta blockers, used in the treatment of high blood pressure.-External links:*... , carteolol Carteolol Carteolol is a non-selective beta blocker used to treat glaucoma.... |
migraine Migraine Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea... (propranolol) |
| Cardioselective/beta 1-selectivity | Atenolol, Metoprolol Metoprolol Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate... , Bisoprolol Bisoprolol Bisoprolol is a drug belonging to the group of beta blockers, a class of drugs used primarily in cardiovascular diseases. More specifically, it is a selective type β1 adrenergic receptor blocker. The FDA approved Duramed Pharmaceutical's application for Zebeta Oral Tablets as a new molecular... , Metoprolol Metoprolol Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate... , Acebutolol Acebutolol Acebutolol is a beta blocker for the treatment of hypertension and arrhythmias.-Pharmacology:Acebutolol is a cardioselective beta blocker with ISA... , Betaxolol Betaxolol Betaxolol is a selective beta1 receptor blocker used in the treatment of hypertension and glaucoma. Being selective for beta1 receptors, it typically has fewer systemic side effects than non-selective beta-blockers, for example, not causing bronchospasm as timolol may... |
myocardial infarction Myocardial infarction Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die... (metoprolol), heart failure (Carvedilol) |
| Intrinsic sympathomimetic activity | Acebutolol Acebutolol Acebutolol is a beta blocker for the treatment of hypertension and arrhythmias.-Pharmacology:Acebutolol is a cardioselective beta blocker with ISA... , Pindolol Pindolol Pindolol is a beta blocker.... , Penbutolol Penbutolol Penbutolol is a medication in the class of beta blockers, used in the treatment of high blood pressure.-External links:*... |
row 2, cell 3 |
| Beta-blockers with alpha blocking activity | Carvedilol Carvedilol Carvedilol is a non-selective beta blocker/alpha-1 blocker indicated in the treatment of mild to moderate congestive heart failure . It is marketed under various trade names including Carvil , Coreg , Dilatrend , Eucardic , and Carloc as a generic drug ., and as a... , Labetalol Labetalol Labetalol is a mixed alpha/beta adrenergic antagonist, which is used to treat high blood pressure.-Indications:... |
Heart failure (Carvedilol) |
Cardioselective/beta 1-selectivity
Even among drugs selective for the beta-1 adrenergic receptorAdrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
, drugs vary in their selectivity. Generic beta-blockers with selectivity for the beta-1 adrenergic receptor
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
:
- Atenolol
- Renally excreted
- Hydrophilic
- May require twice daily dosing
- BisoprololBisoprololBisoprolol is a drug belonging to the group of beta blockers, a class of drugs used primarily in cardiovascular diseases. More specifically, it is a selective type β1 adrenergic receptor blocker. The FDA approved Duramed Pharmaceutical's application for Zebeta Oral Tablets as a new molecular...
- MetoprololMetoprololMetoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...
- Acebutolol
Non-generic:
- Betaxolol
Non-selective
Non-selective drugs include propranolol, timolol, nadolol, pindolol, penbutolol, and carteolol.Intrinsic sympathomimetic activity
Generic beta-blockers with intrinsic sympathomimetic activity (less resting bradycardia andlipid changes):
- Acebutolol
- Pindolol
Non-generic:
- Penbutolol
Beta-blockers with alpha blocking activity
Generic beta-blockers with alpha blocking activity (more orthostatic hypotensionOrthostatic hypotension
Orthostatic hypotension, also known as postural hypotension, orthostasis, and colloquially as head rush or dizzy spell, is a form of hypotension in which a person's blood pressure suddenly falls when the person stands up or stretches. The decrease is typically greater than 20/10 mm Hg, and may be...
):
- Carvedilol
- Labetalol
History
Propranolol was developed by James Black who later received the Nobel Prize for this and other work.Mechanism of action
Beta-blockers may have reduced effect due to inability to lower central blood pressure as well as other antihypertensives.G-protein-coupled receptor kinase
Regarding the treatment of heart failure, there is conflicting evidence whether beta-blockers are as effective in African-American patients as in Anglo patients. This may be due to a polymorphism in African-American patients of the G-protein-coupled receptor kinase (GRK5) that confers a natural "genetic beta-blockade".G protein–coupled cell surface receptor kinase 2 (GRK2) genetic polymorphisms may also affect the response to adrenergic beta-antagonists.
Adrenergic receptor
Genetic polymorphisms of beta-1 (ADRB1) may affect the response to adrenergic beta-antagonist treatment of heart failure.Single-nucleotide polymorphism of the beta-1 (ADRB1) adrenergic receptor
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
, specifically c.389A>G, may increase cardiac ischemia and SNP of the beta-2 (ADRB2) adrenergic receptor
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
, specifically, c.16G>A SNP of the 4 SNPs studied, may increase hypotension in perioperative care.
Single-nucleotide polymorphism of the beta-2 (ADRB2) adrenergic receptor
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
, specifically c.46G>A and c.79C>G of the four SNPs studied, may affect the response to adrenergic beta-antagonist treatment of acute coronary syndrome
Acute coronary syndrome
Acute coronary syndrome is usually one of three diseases involving the coronary arteries: ST elevation myocardial infarction , non ST elevation myocardial infarction , or unstable angina ....
.
Genetic polymorphisms of alpha-2C (ADRA2C) may affect the response to adrenergic beta-antagonist treatment of heart failure.
Cytochrome P-450
Beta-blockers such as metoprololMetoprolol
Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...
that are metabolized by cytochrome P-450 CYP2D6 allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
and may have more drug interaction
Drug interaction
A drug interaction is a situation in which a substance affects the activity of a drug, i.e. the effects are increased or decreased, or they produce a new effect that neither produces on its own. Typically, interaction between drugs come to mind...
s and inherited variations in metabolism.
Although poor metabolism due to CYP2D6 polymorphisms may be present in patients with drug toxicity due to metoprolol
Metoprolol
Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...
, small studies suggest that careful, slow titration and avoidance of other drugs metabolized by CYP2D6 may avoid drug toxicity from polymorphisms of cytochrome P-450.
Dosage
In the 1980s, beta-blockers were thought to be effective if given once daily. However, in the 1990s and even the 1980s recognition occurred that beta-blockers varied on their duration of action.| Cost | |
|---|---|
| Atenolol 100 mg - 90 tablets | $34.97 |
| Bisoprolol Bisoprolol Bisoprolol is a drug belonging to the group of beta blockers, a class of drugs used primarily in cardiovascular diseases. More specifically, it is a selective type β1 adrenergic receptor blocker. The FDA approved Duramed Pharmaceutical's application for Zebeta Oral Tablets as a new molecular... 10 mg - 90 tablets |
$94.05 |
| Metoprolol Metoprolol Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate... succinate 200 mg - 90 tablets |
$204.58 |
| Metoprolol Metoprolol Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate... tartrate 100 mg - 180 tablets |
$25.97 |
Clinical uses
The effect of adrenergic beta-antagonists on heart rateHeart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
may be more predictive than the amount of drug in predicting the drug's benefit or harm. This may be due to invidual molecular variations in adrenergic receptor
Adrenergic receptor
The adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
s, G-protein-coupled receptor kinases, and metabolism by cytochrome P-450.
The individual beta-blockers have been compared in the treatment of various diseases.
Coronary heart disease
| Study | Patients | Intervention | Authors' conclusions | Notes |
|---|---|---|---|---|
| Brandler Meta-analysis Meta-analysis In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the... of randomized controlled trial Randomized controlled trial A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of... s 2010 |
72,249 patients in 18 trials (Includes 45,852 patients from the COMMIT trial) |
Various | "This systematic review failed to demonstrate a convincing in-hospital mortality benefit for using beta-blockers early in the course of patients with an acute or suspected MI." | |
| COMMIT (Chen) Randomized controlled trial Randomized controlled trial A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of... 2000 |
45,852 patients | Metoprolol Metoprolol Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate... 5-15 mg IV immediately then 50 mg orally every 6 hr for 2 days, then 200 mg controlled release orally once a day for 28 days |
"The use of early beta-blocker therapy in acute MI reduces the risks of reinfarction and ventricular fibrillation, but increases the risk of cardiogenic shock, especially during the first day or so after admission." | Cardiogenic shock increased 3.9% to 5%. Stroke increased from 1% to 1.1% (no statistical significance Statistical significance In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher.... ) |
| Freemantle Meta-analysis Meta-analysis In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the... of randomized controlled trial Randomized controlled trial A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of... s 2000 |
29,260 patients in 51 trials (Does not include the COMMIT trial) |
Various | "...4% reduction in the odds of death in short term trials (-8% to 15%)." | |
| ISIS-1 Randomized controlled trial Randomized controlled trial A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of... 2000 |
45,852 patients | Atenolol 5-10 mg IV immediately, followed by 100 mg/day (either 50 mg twice a day or 100 mg once a day) orally for 7 days | "...highly significant (2p less than 0.0002) evidence of an effect on the combined end-point of death, arrest, or reinfarction, suggesting that treatment of about 200 patients would lead to the avoidance of 1 reinfarction, 1 arrest, and 1 death during days 0-7." | Use of inotrope Inotrope An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions... s increased from 3.3% to 5% Strokes not recorded. |
Adrenergic beta-antagonists were first shown to be effective in 1981.
Adrenergic beta-antagonists do not definitely reduce short term mortality while in the hospital (see evidence table), but may improve long germ mortality. Metoprolol
Metoprolol
Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...
may or may not be the best beta-blocker for secondary prevention of myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
s according to meta-analyses
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
of randomized controlled trials.
Cohort studies
Cohort study
A cohort study or panel study is a form of longitudinal study used in medicine, social science, actuarial science, and ecology. It is an analysis of risk factors and follows a group of people who do not have the disease, and uses correlations to determine the absolute risk of subject contraction...
suggest that atenolol may or may not be better than other adrenergic beta-antagonists.
Heart failure
Beta-blockers were originally thought to be contraindicated in patients with heart failure. However, trials eventually showed benefit of the drugs. Metoprolol can benefit patients with heart failure.Two cohort studies
Cohort study
A cohort study or panel study is a form of longitudinal study used in medicine, social science, actuarial science, and ecology. It is an analysis of risk factors and follows a group of people who do not have the disease, and uses correlations to determine the absolute risk of subject contraction...
suggest that atenolol and carvedilol
Carvedilol
Carvedilol is a non-selective beta blocker/alpha-1 blocker indicated in the treatment of mild to moderate congestive heart failure . It is marketed under various trade names including Carvil , Coreg , Dilatrend , Eucardic , and Carloc as a generic drug ., and as a...
may be more effective than metoprolol
Metoprolol
Metoprolol is a selective β1 receptor blocker used in treatment of several diseases of the cardiovascular system, especially hypertension. The active substance metoprolol is employed either as metoprolol succinate or metoprolol tartrate...
for the treatment of heart failure.
Drugs with intrinsic sympathomimetic activity may be less beneficial. A systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
of randomized controlled trial
Randomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
s concluded "metoprolol, carvedilol, and bisoprolol all exhibited statistically significant mortality rate reductions compared with placebo, the data were inconclusive for nebivolol or atenolol" and "for every heart rate reduction of 5 beats/min with β-blocker treatment, a commensurate 18% reduction in the risk for death occurred."
Hypertension
Beta-blockers may not be a good first choice medication in treating hypertension - at least for patients without coronary heart diseaseCoronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
. A meta-analysis
Meta-analysis
In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. In its simplest form, this is normally by identification of a common measure of effect size, for which a weighted average might be the output of a meta-analyses. Here the...
and accompanying editorial have concluded that the more the drug lowers the heart rate
Heart rate
Heart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
, the lower the benefit of the drug. The harm may be confined to elderly patients. Alternatively, or in addition:
- beta-blockers may not lower the central aortic pressure as much other anti-hypertensive agents despite similar effects on the brachial systolic pressure.
- beta-blocker trials suffer from not doing beta-blockers often enough. Most trials in the meta-analysis used atenolol once per day. Only in the INVEST trial, atenolol was dosed twice a day if needed and in this trial atenolol was as effective as a calcium channel blocker.
Beta-blockers may be less effective than diuretic
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
s in the treatment of elderly patients with hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
due to reduced ability to prevent coronary heart disease
Coronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
.