Adrenergic beta-receptor blockaders (beta-blockers) are "drugs that bind to but do not activate beta-adrenergic receptors 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.
|Nonselective||propranolol, timolol, nadolol, pindolol, penbutolol, carteolol||migraine (propranolol)|
|Cardioselective/beta 1-selectivity||Atenolol, Metoprolol, Bisoprolol, Metoprolol, Acebutolol, Betaxolol||myocardial infarction (metoprolol), heart failure (Carvedilol)|
|Intrinsic sympathomimetic activity||Acebutolol, Pindolol, Penbutolol||row 2, cell 3|
|Beta-blockers with alpha blocking activity||Carvedilol, Labetalol||Heart failure (Carvedilol)|
Even among drugs selective for the beta-1 adrenergic receptor, drugs vary in their selectivity. Adrenergic beta-antagonists that are selective for the beta-1 adrenergic receptor may be better for patients at risk of stroke.
Non-selective drugs include propranolol, timolol, nadolol, pindolol, penbutolol, and carteolol.
Intrinsic sympathomimetic activity
Generic beta-blockers with intrinsic sympathomimetic activity (less resting bradycardia and lipid changes):
Beta-blockers with alpha blocking activity
Mechanism of action
Beta-blockers may have reduced effect due to inability to lower central blood pressure as well as other antihypertensives.
The pharmacogenetics of beta-blockers have been reviewed.
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".
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.
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.
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.
|Atenolol 100 mg - 90 tablets||$34.97|
|Bisoprolol 10 mg - 90 tablets||$94.05|
|Metoprolol succinate 200 mg - 90 tablets||$204.58|
|Metoprolol tartrate 100 mg - 180 tablets||$25.97|
The effect of adrenergic beta-antagonists on heart rate 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 receptors, 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
Meta-analysis of randomized controlled trials
|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."|
Randomized controlled trial
|45,852 patients||Metoprolol 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)
Meta-analysis of randomized controlled trials
|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%)."|
Randomized controlled trial
|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 inotropes 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 may or may not be the best beta-blocker for secondary prevention of myocardial infarctions according to meta-analyses of randomized controlled trials.
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.
Drugs with intrinsic sympathomimetic activity may have less benefit A systematic review of randomized controlled trials 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."
Beta-blockers may or may not be a good first choice medication in treating hypertension - at least for patients without coronary heart disease. 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 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.
Additional physiologic problems with beta-blockers are:
- decrease heart rate which increases stroke volume and increases pulse pressure
- decrease heart rate allow for more prolonged diastolic perfusion of the coronary arteries
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