Adrenergic beta-antagonist

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Beta-blockers timeline.

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".[1]

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.[2]

Classification

Generically available beta-blockers, which subclassify based on selective aspects of their action, include: include:[3][4][5]

They further divide by frequency of dosing, cost, and other factors.

Selectivity Agents Applications
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)


Cardioselective/beta 1-selectivity

Even among drugs selective for the beta-1 adrenergic receptor, drugs vary in their selectivity.[6] Generic beta-blockers with selectivity for the beta-1 adrenergic receptor:[4][7]

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 and lipid changes):[4]

  • Acebutolol
  • Pindolol

Non-generic:

  • Penbutolol

Beta-blockers with alpha blocking activity

Generic beta-blockers with alpha blocking activity (more orthostatic hypotension):[4]

History

Propranolol was developed by James Black who later received the Nobel Prize for this and other work.[10]

Mechanism of action

Beta-blockers may have reduced effect due to inability to lower central blood pressure as well as other antihypertensives.[11]

Pharmacogenetics

The pharmacogenetics of beta-blockers have been reviewed.[12]

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.[13] 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".[14][15]

G protein–coupled cell surface receptor kinase 2 (GRK2) genetic polymorphisms may also affect the response to adrenergic beta-antagonists.[16]

Adrenergic receptor

Genetic polymorphisms of beta-1 (ADRB1) may affect the response to adrenergic beta-antagonist treatment of heart failure.[17]

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.[18]

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.[19]

Genetic polymorphisms of alpha-2C (ADRA2C) may affect the response to adrenergic beta-antagonist treatment of heart failure.[20]

Cytochrome P-450

Beta-blockers such as metoprolol that are metabolized by cytochrome P-450 CYP2D6 allele and may have more drug interactions[21] and inherited variations in metabolism.[22]

Although poor metabolism due to CYP2D6 polymorphisms may be present in patients with drug toxicity due to metoprolol[23], small studies suggest that careful, slow titration [24][25] and avoidance of other drugs metabolized by CYP2D6[26] 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.[27][28][29] However, in the 1990s[30] and even the 1980s[31] recognition occurred that beta-blockers varied on their duration of action.

Costs of selected beta-blockers from DrugStore.com
  Cost
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

Clinical uses

The effect of adrenergic beta-antagonists on heart rate may be more predictive than the amount of drug in predicting the drug's benefit[32] or harm[33]. 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.[34]

Coronary heart disease

Selected studies of early adrenergic beta-antagonists for reducing hospital mortality after acute myocardial infarction.[35][36][37][38]
Study Patients Intervention Authors' conclusions Notes
Brandler[35]
Meta-analysis of randomized controlled trials
2010		 72,249 patients in 18 trials
(Includes 45,852 patients from the COMMIT trial[36])		 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)[36]
Randomized controlled trial
2000		 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)
Freemantle[37]
Meta-analysis of randomized controlled trials
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[38]
Randomized controlled trial
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 inotropes increased from 3.3% to 5%
Strokes not recorded.
For more information, see: Coronary heart disease.


Adrenergic beta-antagonists were first shown to be effective in 1981.[39]

Adrenergic beta-antagonists do not definitely reduce short term mortality while in the hospital (see evidence table), but may improve long germ mortality.[35][37]. Metoprolol may[2] or may not[37] 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[40] or may not[41] be better than other adrenergic beta-antagonists.

Heart failure

For more information, see: 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.[42][43]

Two cohort studies suggest that atenolol and carvedilol may be more effect than metoprolol for the treatment of heart failure.[44][45]

Drugs with intrinsic sympathomimetic activity may have less benefit[37] 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."[32]

Hypertension

For more information, see: Hypertension.

Beta-blockers may[46] or may not[47] be a good first choice medication in treating hypertension - at least for patients without coronary heart disease. A meta-analysis[33] and accompanying editorial[48] 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.[49] 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.[50]
  • 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.[51]

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.[52]

Contraindications

Cocaine abuse is thought to be a contraindication, but the association between beta-blockers and adverse events among cocaine users is not certain.[53]

References

  1. ↑ Anonymous (2024), Adrenergic beta-antagonist (English). Medical Subject Headings. U.S. National Library of Medicine.
  2. ↑ 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]
  3. ↑ (2001) "Which beta-blocker?". Med Lett Drugs Ther 43 (1097): 9-11. PMID 11177223. [e]
  4. ↑ 4.0 4.1 4.2 4.3 (June 2005) "Drugs for hypertension". Treat Guidel Med Lett 3 (34): 39–48. PMID 15912125. [e]
  5. ↑ (March 2008) "Nebivolol (Bystolic) for hypertension". Med Lett Drugs Ther 50 (1281): 17–9. PMID 18323772. [e]
  6. ↑ 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.
  7. ↑ (January 2009) "Drugs for hypertension". Treat Guidel Med Lett 7 (77): 1–10. PMID 19107095. [e]
  8. ↑ 8.0 8.1 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]
  9. ↑ 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]
  10. ↑ 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]
  11. ↑ Mackenzie IS, McEniery CM, Dhakam Z, Brown MJ, Cockcroft JR, Wilkinson IB. Comparison of the effects of antihypertensive agents on central blood pressure and arterial stiffness in isolated systolic hypertension. Hypertension. 2009 Aug;54(2):409-13. Epub 2009 Jun 1. PMID 19487582
  12. ↑ 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.
  13. ↑ 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]
  14. ↑ 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).
  15. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 600870. World Wide Web URL: http://omim.org/.
  16. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 109635. World Wide Web URL: http://omim.org/.
  17. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 109630. World Wide Web URL: http://omim.org/.
  18. ↑ Zaugg M, Bestmann L, Wacker J, et al (July 2007). "Adrenergic receptor genotype but not perioperative bisoprolol therapy may determine cardiovascular outcome in at-risk patients undergoing surgery with spinal block: the Swiss Beta Blocker in Spinal Anesthesia (BBSA) study: a double-blinded, placebo-controlled, multicenter trial with 1-year follow-up". Anesthesiology 107 (1): 33–44. DOI:10.1097/01.anes.0000267530.62344.a4. PMID 17585213. Research Blogging.
  19. ↑ 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.
  20. ↑ Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 104250. World Wide Web URL: http://omim.org/.
  21. ↑ Onalan O, Cumurcu BE, Bekar L (May 2008). "Complete atrioventricular block associated with concomitant use of metoprolol and paroxetine". Mayo Clin. Proc. 83 (5): 595–9. PMID 18452693. [e]
  22. ↑ Nozawa T, Taguchi M, Tahara K, et al (November 2005). "Influence of CYP2D6 genotype on metoprolol plasma concentration and beta-adrenergic inhibition during long-term treatment: a comparison with bisoprolol". J. Cardiovasc. Pharmacol. 46 (5): 713–20. PMID 16220080. [e]
  23. ↑ Wuttke H, Rau T, Heide R, et al. (October 2002). "Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects". Clin. Pharmacol. Ther. 72 (4): 429–37. DOI:10.1067/mcp.2002.127111. PMID 12386645. Research Blogging.
  24. ↑ Terra SG, Pauly DF, Lee CR, et al. (March 2005). "beta-Adrenergic receptor polymorphisms and responses during titration of metoprolol controlled release/extended release in heart failure". Clin. Pharmacol. Ther. 77 (3): 127–37. DOI:10.1016/j.clpt.2004.10.006. PMID 15735607. Research Blogging.
  25. ↑ Zineh I, Beitelshees AL, Gaedigk A, et al. (December 2004). "Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension". Clin. Pharmacol. Ther. 76 (6): 536–44. DOI:10.1016/j.clpt.2004.08.020. PMID 15592325. Research Blogging.
  26. ↑ Fux R, Mörike K, Pröhmer AM, et al. (October 2005). "Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study". Clin. Pharmacol. Ther. 78 (4): 378–87. DOI:10.1016/j.clpt.2005.07.004. PMID 16198657. Research Blogging.
  27. ↑ 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” 
  28. ↑ Johansson SR, McCall M, Wilhelmsson C, Vedin JA (May 1980). "Duration of action of beta blockers". Clin. Pharmacol. Ther. 27 (5): 593–601. PMID 6102896. [e]
  29. ↑ 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]
  30. ↑ 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).” 
  31. ↑ Raftery EB, Carrageta MO (April 1985). "Hypertension and beta-blockers. Are they all the same?". Int. J. Cardiol. 7 (4): 337–46. DOI:10.1016/0167-5273(85)90089-0. PMID 2859251. Research Blogging.
  32. ↑ 32.0 32.1 McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW (June 2009). "Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure". Ann. Intern. Med. 150 (11): 784–94. PMID 19487713. [e]
  33. ↑ 33.0 33.1 Bangalore S, Sawhney S, Messerli FH (October 2008). "Relation of beta-blocker-induced heart rate lowering and cardioprotection in hypertension". J. Am. Coll. Cardiol. 52 (18): 1482–9. DOI:10.1016/j.jacc.2008.06.048. PMID 19017516. Research Blogging.
  34. ↑ Dean L (2007). “Comparing Beta Blockers”, PubMed Clinical Q&A. Bethesda (MD): National Library of Medicine (US), National Center for Biotechnology Information. “Based on Oregon Drug Effectiveness Review Project” 
  35. ↑ 35.0 35.1 35.2 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.
  36. ↑ 36.0 36.1 36.2 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
  37. ↑ 37.0 37.1 37.2 37.3 37.4 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. Cite error: Invalid <ref> tag; name "pmid10381708" defined multiple times with different content Cite error: Invalid <ref> tag; name "pmid10381708" defined multiple times with different content Cite error: Invalid <ref> tag; name "pmid10381708" defined multiple times with different content
  38. ↑ 38.0 38.1 (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.
  39. ↑ (April 1981) "Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction". N. Engl. J. Med. 304 (14): 801–7. PMID 7010157. [e]
  40. ↑ Rinfret S, Abrahamowicz M, Tu J, Humphries K, Eisenberg MJ, Richard H et al. (2007). "A population-based analysis of the class effect of beta-blockers after myocardial infarction.". Am Heart J 153 (2): 224-30. DOI:10.1016/j.ahj.2006.11.008. PMID 17239680. Research Blogging.
  41. ↑ Andersen SS, Hansen ML, Gislason GH, Folke F, Schramm TK, Fosbøl E et al. (2009). "Mortality and reinfarction among patients using different beta-blockers for secondary prevention after a myocardial infarction.". Cardiology 112 (2): 144-50. DOI:10.1159/000143389. PMID 18612201. Research Blogging.
  42. ↑ Waagstein F, Bristow MR, Swedberg K, et al (December 1993). "Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group". Lancet 342 (8885): 1441–6. PMID 7902479. [e]
  43. ↑ Packer M, Bristow MR, Cohn JN, et al (May 1996). "The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group". N. Engl. J. Med. 334 (21): 1349–55. PMID 8614419. [e]
  44. ↑ Kramer JM, Curtis LH, Dupree CS, et al (December 2008). "Comparative effectiveness of beta-blockers in elderly patients with heart failure". Arch. Intern. Med. 168 (22): 2422–8; discussion 2428–32. DOI:10.1001/archinternmed.2008.511. PMID 19064824. Research Blogging.
  45. ↑ Go AS, Yang J, Gurwitz JH, Hsu J, Lane K, Platt R (December 2008). "Comparative effectiveness of different beta-adrenergic antagonists on mortality among adults with heart failure in clinical practice". Arch. Intern. Med. 168 (22): 2415–21. DOI:10.1001/archinternmed.2008.506. PMID 19064823. Research Blogging.
  46. ↑ Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR et al. (1997). "Health outcomes associated with antihypertensive therapies used as first-line agents. A systematic review and meta-analysis.". JAMA 277 (9): 739-45. PMID 9042847. [e]
  47. ↑ Lindholm LH, Carlberg B, Samuelsson O (2005). "Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis". Lancet 366 (9496): 1545–53. DOI:10.1016/S0140-6736(05)67573-3. PMID 16257341. Research Blogging.
  48. ↑ Kaplan NM (October 2008). "Beta-blockers in hypertension: adding insult to injury". J. Am. Coll. Cardiol. 52 (18): 1490–1. DOI:10.1016/j.jacc.2008.08.008. PMID 19017517. Research Blogging.
  49. ↑ Khan N, McAlister FA (2007). "-examining the efficacy of beta-blockers for the treatment of hypertension: a meta-analysis.". CMAJ 176 (7): 976. PMID 16754904. PMC 1471831. [e]
  50. ↑ Williams B, Lacy PS, Thom SM, et al. (March 2006). "Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study". Circulation 113 (9): 1213–25. DOI:10.1161/CIRCULATIONAHA.105.595496. PMID 16476843. Research Blogging.
  51. ↑ Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. (December 2003). "A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial". JAMA 290 (21): 2805–16. DOI:10.1001/jama.290.21.2805. PMID 14657064. Research Blogging.
  52. ↑ Messerli FH, Grossman E, Goldbourt U (June 1998). "Are beta-blockers efficacious as first-line therapy for hypertension in the elderly? A systematic review". JAMA 279 (23): 1903–7. PMID 9634263. [e]
  53. ↑ Rangel C, Shu RG, Lazar LD, Vittinghoff E, Hsue PY, Marcus GM (2010). "Beta-blockers for chest pain associated with recent cocaine use.". Arch Intern Med 170 (10): 874-9. DOI:10.1001/archinternmed.2010.115. PMID 20498415. Research Blogging.
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