The Cornerstone of Cardiac Drug Therapy
Part of the Contemporary Cardiology book series (CONCARD)


This chapter tells you
  • Which beta-blocker is best for your patients.

  • The pharmacodynamic reasons why atenolol is a relatively ineffective beta-blocker and why the use of atenolol should be curtailed.

  • More about the important indication for heart failure (HF), New York Heart Association (NYHA) class II-III and now compensated class IV, and for all with left ventricular (LV) dysfunction regardless of functional class; thus, in class I patients with an ejection fraction (EF) < 40% and in those with myocardial infarction (MI) with HF or LV dysfunction without HF, beta-blockers are recommended at the same level as angiotensin-converting enzyme (ACE) inhibitors.

  • Why beta-blockers should be recommended for diabetic patients with hypertension with or without proteinuria and for diabetic patients with coronary heart disease (CHD). From about 1990 to 2002, most internists proclaimed in editorials and to trainees that these agents were a poor choice in this setting.

  • More recently, their use as initial agents for the treatment of primary hypertension has been criticized, particularly for diabetics with hypertension; do beta-blocking drugs cause diabetes or is the condition observed, simply, benign glucose intolerance in some? (See  Chapter 2, Beta-Blocker Controversies.)

  • Why is it incorrect to say that beta-blockers are not advisable for hypertensive patients over age 65, as many teachers, textbooks, and editorials state. This was reiterated in an editorial by Cruickshank entitled “Beta-blockers continue to surprise us” (1).

  • The results of randomized clinical trials (RCTs) that prove the lifesaving properties of these agents.

  • All their indications.

  • Salient points that relate to each beta-blocker and show the subtle and important differences confirming that beta-blockers are not all alike. Beta-blockade holds the key, but lipophilic versus hydrophilic features may be important, and brain concentration may enhance cardioprotection.


Heart Rate Variability Calcium Antagonist Essential Tremor Coronary Heart Disease Event Rate Pressure Product 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cruickshank JM. Beta-blockers continue to surprise us. Eur Heart J 2000;21:355.CrossRefGoogle Scholar
  2. 2.
    Sixth Report of Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1997;157:2413.Google Scholar
  3. 3.
    Khan M Gabriel. Hyperlipidemia. In: Heart Disease, Diagnosis and Therapy. Baltimore, Williams & Wilkins, 1996, p. 384.Google Scholar
  4. 4.
    Frishman WH. Beta-adrenergic blocking drugs. Am Coll Cardiol Curr J Rev 1997;23.Google Scholar
  5. 5.
    Black JW, Crowther AF, Shanks RG, et al. A new adrenergic beta-receptor-antagonist. Lancet 1964; 2:1080.CrossRefGoogle Scholar
  6. 6.
    Pritchard BNC, Gillam PMS. The use of propranolol in the treatment of hypertension. BMJ 1964;2:725.Google Scholar
  7. 7.
    Multi Center Diltiazem Postinfarction Trial Research Group. The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 1988;319:385.CrossRefGoogle Scholar
  8. 8.
    Estacio RO, Barrett WJ, Hiatt WR. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin dependent diabetes and hypertension. N Engl J Med 1998;338:645.PubMedCrossRefGoogle Scholar
  9. 9.
    Kaumann AJ. Some aspects of heart beta adrenoceptor function. Cardiovasc Drugs Ther 1991;5:549.PubMedGoogle Scholar
  10. 10.
    Motomura S, Zerkowski HR, Daul A, et al. On the physiologic role of beta-2 adrenoceptors in the human heart: in vitro and in vivo studies. Am Heart J 1990;l19:608.CrossRefGoogle Scholar
  11. 11.
    Krum H, Gu A, Wiltshire-Clement M, et al. Changes in plasma endothelin-1 levels reflects clinical response to P-blockade in chronic heart failure. Am Heart J 1996;131:337.PubMedCrossRefGoogle Scholar
  12. 12.
    Cruickshank JM, Degaute JP, Kuurne T, et al. Reduction of stress/catecholamine induced cardiac necrosis by Bl selective blockade. Lancet 1987;2:585.PubMedCrossRefGoogle Scholar
  13. 13.
    Cockcroft JR, Chowienczyk PJ, Brett SE, et al. Nebivolol vasodilates human forearm vasculature: Evidence for a L-arginine/No-dependent mechanism. J Pharmacol Exp Ther 1995;274:1067.PubMedGoogle Scholar
  14. 14.
    Man in’t Veld AJ, Van den Meiracker AH, Schalekamp MA. Do beta-blockers really increase peripheral vascular resistance? Review of the literature and new observations under basal conditions. Am J Hypertens 1988;1:91.Google Scholar
  15. 15.
    Braunwald E. Mechanism of action of calcium-channel-blocking agents. N Engl J Med 1982;307:1618.PubMedCrossRefGoogle Scholar
  16. 16.
    The Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med 1981;304:801.CrossRefGoogle Scholar
  17. 17.
    Pratt CM, Roberts R. Chronic beta-blockade therapy in patients after myocardial infarction. Am J Cardiol 1983;52:661.PubMedCrossRefGoogle Scholar
  18. 18.
    Khan MI, Hamilton JT, Manning GW. Protective effect of beta adrenoceptor blockade in experimental coronary occlusion in conscious dogs. Am J Cardiol 1972;30:832.PubMedCrossRefGoogle Scholar
  19. 19.
    United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703.Google Scholar
  20. 20.
    Breckenridge A. Jogger’s blockade. BMJ 1982;284:532.PubMedGoogle Scholar
  21. 21.
    Johansson BW. Effect of beta-blockade on ventricular fibrillation and tachycardia induced circulatory arrest in acute myocardial infarction. Am J Cardiol 1986;57:34F.PubMedCrossRefGoogle Scholar
  22. 22.
    Raeder EA, Verrier RL, Lown B. Intrinsic sympathomimetic activity and the effects of beta-adrenergic blocking drugs on vulnerability to ventricular fibrillation. J Am Coll Cardiol 1983;1:1442.PubMedGoogle Scholar
  23. 23.
    Pitt B. Regression of left ventricular hypertrophy in patients with hypertension: Blockade of the reninangiotensin-aldosterone system. Circulation 1998;98:1987.PubMedGoogle Scholar
  24. 24.
    Kostis JB, Rosen RC. Central nervous system effects of beta-adrenergic blocking drugs: The role of ancillary properties. Circulation 1987;75:204.PubMedGoogle Scholar
  25. 25.
    Engler RL, Conant J, Maisel A, et al. Lipid solubility determines the relative CNS effects of beta-blocking agents. J Am Coll Cardiol 1986;7:25A.Google Scholar
  26. 26.
    Pitt B. The roleof beta-adrenergic blocking agents in preventing sudden cardiac death. Circulation 85(Suppl I): 1992;I107.PubMedGoogle Scholar
  27. 27.
    Deanfield J, Wright C, Krikler S. Cigarette smoking and the treatment of angina with propranolol, atenolol and nifedipine. N Engl J Med 1984;310:951.PubMedCrossRefGoogle Scholar
  28. 28.
    Valimaki ML, Harno K. Lipoprotein lipids and apoproteins during beta-blocker administration: Comparison of penbutolol and atenolol. Eur J Clin Pharmacol 1986;30:17.PubMedCrossRefGoogle Scholar
  29. 29.
    Pasotti C, Zoppi A, Capra A. Effect of beta-blockers on plasma lipids. Int J Clin Pharmacol Ther Toxicol 1986;24:448.PubMedGoogle Scholar
  30. 30.
    Khan M Gabriel. Angina. In: Heart Disease, Diagnosis and Therapy. Baltimore, Williams & Wilkins, 1996.Google Scholar
  31. 31.
    Beta-Blocker Heart Attack Study Group. The beta-blocker heart attack trial. JAMA 1981;246:2073.CrossRefGoogle Scholar
  32. 32.
    Shore SJ, Berger KR, Murphy EA, et al. Progression of aortic dilation and the benefit of long-term betaadrenergic blockade in Marfan’s syndrome. N Engl J Med 1994;330:1335.CrossRefGoogle Scholar
  33. 33.
    BHAT: Peters RW, Muller JE, Goldstein S, et al. for the BHAT Study Group. Propranolol and the morning increase in the frequency of sudden cardiac deaths (BHAT Study). Am J Cardiol 1990;63:1518.Google Scholar
  34. 34.
    Kleiger RE, Miller JP, Bigger JT, et al. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987;59:256.PubMedCrossRefGoogle Scholar
  35. 35.
    Malik M, Farrell T, Camm J. Circadian rhythm of heart rate variability with clinical and angiographic variables and late mortality after coronary angiography. Am J Cardiol 1990;66:1049.PubMedCrossRefGoogle Scholar
  36. 36.
    Niemelä MJ, Juhani Airaksinen KE, Huikuri HV, et al. Effect of beta-blockade on heart rate variability in patients with coronary artery disease. J Am Coll Cardiol 1994;23:1370.PubMedGoogle Scholar
  37. 37.
    Kjekshus JK. Importance of heart rate in determining beta-blocker efficacy in acute and long-term myocardial infarction intervention trials. Am J Cardiol 1986;57:43F.PubMedCrossRefGoogle Scholar
  38. 38.
    Singh BN. Advantages of beta-blockers versus antiarrhythmic agents and calcium antagonists in secondary prevention after myocardial infarction. Am J Cardiol 1990;66:9C.PubMedCrossRefGoogle Scholar
  39. 39.
    Boissel JP, Leizorovicz A, Picolet H, et al. Efficacy of acebutolol after acute myocardial infarction (the APSI Trial). Am J Cardiol 1990;66:24C.PubMedCrossRefGoogle Scholar
  40. 40.
    Weintraub WS, Akizuki S, Agarwal JB, et al. Comparative effects of nitroglycerin and nifedipine on myocardial blood flow and contraction during flow-limiting coronary stenosis in the dog. Am J Cardiol 1982;50:281.PubMedCrossRefGoogle Scholar
  41. 41.
    Warltier DC, Hardman HJ, Brooks HL, et al. Transmural gradient of coronary blood flow following dihydropyridine calcium antagonists and other vasodilator drugs. Basic Res Cardiol 1983;78:644.PubMedCrossRefGoogle Scholar
  42. 42.
    Sloman G, Robinson JS, McLean K. Propranolol (Inderal) in persistent ventricular fibrillation. BMJ 1965;5439:895.Google Scholar
  43. 43.
    Rothfield EL, Lipowitz M, Zucker IR, et al. Management of persistently recurring ventricular fibrillation with propranolol hydrochloride. JAMA 1968;204:546.CrossRefGoogle Scholar
  44. 44.
    Ryden L, Ariniego R, Arnman K, et al. A double-blind trial of metoprolol in acute myocardial infarction: Effects on ventricular tachyarrhythmias. N Engl J Med 1983;308:614.PubMedCrossRefGoogle Scholar
  45. 45.
    Julian DG. Is the use of beta-blockade contraindicated in the patient with coronary spasm? Circulation 1983;67(Suppl):1.Google Scholar
  46. 46.
    Steinbeck G, Andresen D, Bach P, et al. A comparison of electrophysiologically guided anti-arrhythmic drug therapy with beta-blocker therapy in patients with symptomatic sustained ventricular tachy arrhythmias. N Engl J Med 1992;327:987.PubMedCrossRefGoogle Scholar
  47. 47.
    Steinbeck G, Andresen D, Bach P, et al. A comparison of electrophysiologically guided antiarrhythmic drug therapy with beta-blocker therapy in patients with symptomatic, sustained ventricular tachy arrhythmias. N Engl J Med 1992;327:987 [erratum: N Engl J Med 1993;328:71].PubMedCrossRefGoogle Scholar
  48. 48.
    Matterson BJ, Reda DJ, Cushman WC, et al. Single drug therapy for hypertensive men: A comparison of 6 hypertensive agents with placebo. N Engl J Med 1993;328:914.CrossRefGoogle Scholar
  49. 49.
    Medical Research Council Working Party. MRC trial of treatment of hypertension in older adults: Principal results. BMJ 1992;304:405.CrossRefGoogle Scholar
  50. 50.
    Phillips T, Anlauf M, Distler A, et al. Randomised, double blind, multicentre comparison of hydrochlorothiazide, atenolol, nitrendipine, and enalapril in antihypertensive treatment: Results of the HANE study. BMJ 1997;315:154.Google Scholar
  51. 51.
    Devreux RB. Do antihypertensive drugs differ in their abilities to regress left ventricular hypertrophy? Circulation 1997;95:1983.Google Scholar
  52. 52.
    International Collaborative Study Group. Reduction of infarct size with early use of timolol in acute myocardial infarction. N Engl J Med 1984;310:9.CrossRefGoogle Scholar
  53. 53.
    CAPRICORN: The Capricorn Investigators: Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction. Lancet 2001;357:1385.CrossRefGoogle Scholar
  54. 54.
    Second Cardiac Insufficiency Bisoprolol Study (CIBIS II). Presented by E. Merck at the 20th Congress of the European Society of Cardiology, August 1998, Vienna, Austria.Google Scholar
  55. 55.
    COPERNICUS: Packer M, Coast JS, Fowler MB, et al. for the Carvedilol Prospective Randomized Cumulative Survival Study Group: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651.CrossRefGoogle Scholar
  56. 56.
    MERIT-HF Study Group. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure. Analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF). J Am Coll Cardiol 2002;40:491–498.CrossRefGoogle Scholar
  57. 57.
    Chan AW, Quinn MJ, Bhatt DL, et al. Mortality benefit of beta-blockade after successful elective percutaneous coronary intervention. J Am Coll Cardiol 2002;40:669–675.PubMedCrossRefGoogle Scholar
  58. 58.
    Wheat MW Jr. Treatment of dissecting aneurysms of the aorta: Current status. Prog Cardiovasc Dis 1973; 16:87.PubMedCrossRefGoogle Scholar
  59. 59.
    Ponce FE, Williams LC, Webb HM, et al. Propranolol palliation of tetralogy of Fallot: Experience with long-term drug treatment in pediatric patients. Pediatrics 1973;52:100.PubMedGoogle Scholar
  60. 60.
    Brophy CM, Tilson JE, Tilson MD. Propranolol stimulates the crosslinking of matrix components in skin from the aneurysm-prone blotchy mouse. J Surg Res 1989;46:330.PubMedCrossRefGoogle Scholar
  61. 61.
    Boucek RJ, Gunja-Smith Z, Noble NL, et al. Modulation by propranolol of the lysyl cross-links in aortic elastin and collagen of the aneurysm-prone turkey. Biochem Pharmacol 1983;32:275.PubMedCrossRefGoogle Scholar
  62. 62.
    Handlin LR, Kindred LH, Beauchamp GD, et al. Reversible left ventricular dysfunction after subarachnoid hemorrhage. Am Heart J 1993;126:235.PubMedCrossRefGoogle Scholar
  63. 63.
    Mangano DT, Layug EL, Wallace A, et al. Effect of atenolol on mortality and cardiovascular morbidity after non-cardiac surgery. N Engl J Med 1996;335:1713.PubMedCrossRefGoogle Scholar
  64. 64.
    Theodorakis JM, Kremastinos T, Stephanokis GS, et al. The effectiveness of beta-blockade and its influence on heart rate variability in vasovagal patients. Eur Heart J 1993; 14:1499.PubMedGoogle Scholar
  65. 65.
    SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in a symptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327:685.CrossRefGoogle Scholar
  66. 66.
    Cunnane JG, Blackwood GW. Psychosis with propranolol: Still not recognized? Postgrad Med J 1987; 63:57.PubMedGoogle Scholar
  67. 67.
    Savola J, Vehvilainen O, Vaatainen NJ. Psoriasis as a side effect of beta-blockers. BMJ 1987;295:637.PubMedGoogle Scholar
  68. 68.
    Medical Research Council Working Party on Mild to Moderate Hypertension. Bendrofluazide and propranolol for the treatment of mild hypertension. Lancet 1981;2:359.Google Scholar
  69. 69.
    Hjalmarson A, Herlitz J, Malek I. Effect on mortality of metoprolol in acute myocardial infarction. Lancet 1981;ii:823.CrossRefGoogle Scholar
  70. 70.
    Wallin JD, O’Neill WM. Labetalol: Current research and therapeutic status. Arch Intern Med 1983;143: 485.PubMedCrossRefGoogle Scholar
  71. 71.
    Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. N Engl J Med 1999;341:1789.PubMedCrossRefGoogle Scholar
  72. 72.
    GEMINI: Bakris GL, Fonseca V, Katholi RE, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: arandomized controlled trial. JAMA 2004;292: 2227–2236.PubMedCrossRefGoogle Scholar
  73. 73.
    Packer M, Bristol MR, Cohn JN, et al. for the US Carvedilol Heart Failure Study Group: The effect of carvedilol onmorbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349.PubMedCrossRefGoogle Scholar
  74. 74.
    Gorczynski RJ. Basic pharmacology of esmolol. Am J Cardiol 1985;56:3F.PubMedCrossRefGoogle Scholar
  75. 75.
    Cray RJ, Bateman TM, Czer LS, et al. Esmolol: A new ultrashort-acting beta-adrenergic blocking agent for rapid control of heart rate in post-operative supraventricular tachyarrhythmias. J Am Coll Cardiol 1985;5:1451.CrossRefGoogle Scholar
  76. 76.
    Platia EV, Michelson EL, Porterfield JK, et al. Esmolol versus verapamil in the acute treatment of atrial fibrillation or atrial flutter. Am J Cardiol 1989;63:925.PubMedCrossRefGoogle Scholar
  77. 77.
    Morganroth J, Horowitz LN, Anderson J, et al. Comparative efficacy and tolerance of esmolol to propranolol for control of supraventricular tachyarrhythmia. Am J Cardiol 1985;56:33F.PubMedCrossRefGoogle Scholar
  78. 78.
    Clark JA, Zimmerman HF, Tanner LA. Labetalol hepatotoxicity. Ann Intern Med 1990;l13:210.Google Scholar
  79. 79.
    MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomized Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001.CrossRefGoogle Scholar
  80. 80.
    Juul-Möller S, Edvardsson N, Rehnqvist-Ahlberg N. Sotalol versus quinidine for the maintenance of sinus rhythm after direct current conversion of atrial fibrillation. Circulation 1990;82:1932–1939.PubMedGoogle Scholar
  81. 81.
    Neutel JM, Smith DHG, Ram CVS. Application of ambulatory blood pressure monitoring in differentiating between antihypertensive agents. Am J Med 1993;94:181.PubMedCrossRefGoogle Scholar

Suggested Reading

  1. Cominacini L, Fratta Pasini A, Garbin U, et al. Nebivolol and its 4-keto derivative increase nitric oxide in endothelial cells by reducing its oxidative inactivation. J Am Coll Cardiol 2003;42:1838–1844.PubMedCrossRefGoogle Scholar
  2. GEMIMI: Bakris GL, Fonseca V, Katholi RE, et al. Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: A randomized controlled trial. JAMA 2004;292:2227–2236.PubMedCrossRefGoogle Scholar
  3. Kokkinos P, Chrysohoou C, Panagiotakos D, et al. Beta-blockade mitigates exercise blood pressure in hypertensive male patients. J Am Coll Cardiol 2006;47:794–798.PubMedCrossRefGoogle Scholar
  4. Nihat K, Emrullah B, Ibrahim O, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol 2006;48:2258–2262.CrossRefGoogle Scholar
  5. Remme WJ, Torp-Pedersen C, Cleland JGF, et al. Carvedilol protects better against vascular events than metoprolol in heart failure: results from COMET. J Am Coll Cardiol 2007;49:963–971.PubMedCrossRefGoogle Scholar
  6. Takemoto Y, Hozumi T, Sugioka K, et al. Beta-blocker therapy induces ventricular resynchronization in dilated cardiomyopathy with narrow QRS complex. J Am Coll Cardiol 2007;49:778–783.PubMedCrossRefGoogle Scholar
  7. Van Melle JP, Verbeek DE, van den Berg MP, et al. Beta-blockers and depression after my ocardial infarction: A multicenter prospective study. J Am Coll Cardiol 2006;48:2209–2214.PubMedCrossRefGoogle Scholar
  8. Wilkinson IB, McEniery CM, Cockcroft JR. Atenolol and cardiovascular risk: An issue close to the heart. Lancet 2006;367:627–629.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2007

Personalised recommendations