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.
Generically available beta-blockers, which subclassify based on selective aspects of their action, include: include:
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.
Generic beta-blockers with selectivity for the beta-1 adrenergic receptor:
- Hepatically metabolized by cytochrome P-450 2D6 allele
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
Generic beta-blockers with alpha blocking activity (more orthostatic hypotension):
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.
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".
G protein–coupled cell surface receptor kinase 2 (GRK2) genetic polymorphisms may also affect the response to adrenergic beta-antagonists.
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, 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.
Beta-blockers such as metoprolol that are metabolized by cytochrome P-450 CYP2D6 allele and may have more drug interactions 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.
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.
Cohort studies suggest that atenolol may or may not be better than other adrenergic beta-antagonists.
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 suggest that atenolol and carvedilol may be more effect than metoprolol for the treatment of 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
Beta-blockers may be less effective than diuretics in the treatment of elderly patients with hypertension due to reduced ability to prevent coronary heart disease.
Cocaine abuse is thought to be a contraindication, but the association between beta-blockers and adverse events among cocaine users is not certain.
- ↑ Anonymous (2023), Adrenergic beta-antagonist (English). Medical Subject Headings. U.S. National Library of Medicine.
- ↑ 2.0 2.1 Soriano JB, Hoes AW, Meems L, Grobbee DE (1997). "Increased survival with beta-blockers: importance of ancillary properties". Prog Cardiovasc Dis 39 (5): 445–56. PMID 9122425. [e]
- ↑ (2001) "Which beta-blocker?". Med Lett Drugs Ther 43 (1097): 9-11. PMID 11177223. [e]
- ↑ 4.0 4.1 4.2 4.3 (June 2005) "Drugs for hypertension". Treat Guidel Med Lett 3 (34): 39–48. PMID 15912125. [e]
- ↑ (March 2008) "Nebivolol (Bystolic) for hypertension". Med Lett Drugs Ther 50 (1281): 17–9. PMID 18323772. [e]
- ↑ Baker JG (2005). "The selectivity of beta-adrenoceptor antagonists at the human beta1, beta2 and beta3 adrenoceptors.". Br J Pharmacol 144 (3): 317-22. DOI:10.1038/sj.bjp.0706048. PMID 15655528. PMC PMC1576008. Research Blogging.
- ↑ Webb AJ, Fischer U, Rothwell PM (2011). "Effects of β-blocker selectivity on blood pressure variability and stroke: a systematic review.". Neurology 77 (8): 731-7. DOI:10.1212/WNL.0b013e31822b007a. PMID 21795649. Research Blogging.
- ↑ (January 2009) "Drugs for hypertension". Treat Guidel Med Lett 7 (77): 1–10. PMID 19107095. [e]
- ↑ 9.0 9.1 Tuininga YS, Crijns HJ, Brouwer J, et al (December 1995). "Evaluation of importance of central effects of atenolol and metoprolol measured by heart rate variability during mental performance tasks, physical exercise, and daily life in stable postinfarct patients". Circulation 92 (12): 3415–23. PMID 8521562. [e]
- ↑ Sarafidis P, Bogojevic Z, Basta E, Kirstner E, Bakris GL (February 2008). "Comparative efficacy of two different beta-blockers on 24-hour blood pressure control". J Clin Hypertens (Greenwich) 10 (2): 112–8. PMID 18259123. [e]
- ↑ Stapleton MP (1997). "Sir James Black and propranolol. The role of the basic sciences in the history of cardiovascular pharmacology". Tex Heart Inst J 24 (4): 336–42. PMID 9456487. PMC 325477. [e]
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- ↑ Shin J, Johnson JA (June 2007). "Pharmacogenetics of beta-blockers". Pharmacotherapy 27 (6): 874–87. DOI:10.1592/phco.27.6.874. PMID 17542770. Research Blogging.
- ↑ Shekelle PG, Rich MW, Morton SC, et al (2003). "Efficacy of angiotensin-converting enzyme inhibitors and beta-blockers in the management of left ventricular systolic dysfunction according to race, gender, and diabetic status: a meta-analysis of major clinical trials". J. Am. Coll. Cardiol. 41 (9): 1529–38. PMID 12742294. [e]
- ↑ Liggett, Stephen B et al. 2008. A GRK5 polymorphism that inhibits [beta]-adrenergic receptor signaling is protective in heart failure. Nat Med advanced online publication. http://dx.doi.org/10.1038/nm1750 (Accessed April 29, 2008).
- ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 600870. World Wide Web URL: http://omim.org/.
- ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 109635. World Wide Web URL: http://omim.org/.
- ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 109630. World Wide Web URL: http://omim.org/.
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- ↑ Lanfear DE, Jones PG, Marsh S, Cresci S, McLeod HL, Spertus JA (2005). "Beta2-adrenergic receptor genotype and survival among patients receiving beta-blocker therapy after an acute coronary syndrome.". JAMA 294 (12): 1526-33. DOI:10.1001/jama.294.12.1526. PMID 16189366. Research Blogging.
- ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 104250. World Wide Web URL: http://omim.org/.
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- ↑ Kaplan, Norman M.; Lieberman, Ellin (1990). “Treatment of Hypertension: Drug Therapy”, Clinical Hypertension, Fifth. Baltimore: Williams & Wilkins, 220. ISBN 0-683-04522-9. “All beta-blockers act longer on the blood pressure than the pharmacokinetic data would imply. In moderate doses, most beta-blokders will likely keep the blood pressure down when given once daily. To ensure adequate control, early morning blood pressures should be measured before the daily dose is taken”
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- ↑ Watson RD, Stallard TJ, Littler WA (June 1979). "Influence of once-daily administration of beta-adrenoceptor antagonists on arterial pressure and its variability". Lancet 1 (8128): 1210–3. PMID 87678. “Patients were treated with either propranolol 240 mg (8 patients), metoprolol 200 mg (8 patients), or acebutolol 400 mg (4 patients) taken once daily.” [e]
- ↑ Kaplan, Norman M.; Lieberman, Ellin (1994). “Treatment of Hypertension: Drug Therapy”, Clinical Hypertension, Sixth. Baltimore: Williams & Wilkins, 225. ISBN 0-683-04544-X. “In the usual doses prescribed, various beta blockers have equal antihypertensive efficacy. However, they many not all provide full 24-hour lowering of the BP which may be particularly critical in protecting against early morning cardiovascular catastrophes. Metoprolol blunted this rise, but atenolol and pindolol did not (Raftery and Carrageta, 1985). Neutel et al, (1990) found a similar lack of 24-hour effect with once-daily atenolol but a sustained effect with acebutolol. Moreover, twice-daily doses of "cardioselective" agents may preserve this cardioselectivity better than once-daily large doses (Lipworth et al, 1991).”
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- ↑ 36.0 36.1 36.2 Brandler E, Paladino L, Sinert R (2010). "Does the early administration of beta-blockers improve the in-hospital mortality rate of patients admitted with acute coronary syndrome?". Acad Emerg Med 17 (1): 1-10. DOI:10.1111/j.1553-2712.2009.00625.x. PMID 20078433. Research Blogging.
- ↑ 37.0 37.1 37.2 Chen ZM, Pan HC, Chen YP, Peto R, Collins R, Jiang LX et al. (2005). "Early intravenous then oral metoprolol in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial.". Lancet 366 (9497): 1622-32. DOI:10.1016/S0140-6736(05)67661-1. PMID 16271643. Research Blogging. Review in: ACP J Club. 2006 May-Jun;144(3):58-9 Review in: Evid Based Med. 2006 Jun;11(3):82-3
- ↑ 38.0 38.1 38.2 38.3 38.4 Freemantle N, Cleland J, Young P, Mason J, Harrison J (1999). "beta Blockade after myocardial infarction: systematic review and meta regression analysis.". BMJ 318 (7200): 1730-7. PMID 10381708. PMC PMC31101.
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- ↑ 39.0 39.1 (1986) "Randomised trial of intravenous atenolol among 16 027 cases of suspected acute myocardial infarction: ISIS-1. First International Study of Infarct Survival Collaborative Group.". Lancet 2 (8498): 57-66. PMID 2873379.
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