Advertisement

New and Old Inotropic Drugs: Controversies and Challenges

  • G. Cocco
  • P. Jerie
Part of the Ettore Majorana International Science Series book series (volume 21)

Summary

Many studies, using different parameters for contractility, have established that some inotropic reserve exists even in severly failing myocardium. Thus, various agents (such as digitalis, sympathomimetic drugs etc.) can augment the myocardial inotropic state in heart failure to various degrees. The aim of this paper is to describe available positive inotropic drugs, classified according to their mechanism of action. Drugs with established positive inotropic effect are described first. In addition, new agents with sufficiently high oral bioavailability and long duration of action are presented. Of increasing importance are drugs which combine a positive inotropic and a vasodilator effect (e.g., methylxanthines, some ß-agonists, amrinone etc.). Indeed, it appears that one of the most favorable effects of positive inotropic drugs is the simultaneous direct or reflex peripheral vasodilation. Lastly, it remains to be determined whether or not pronounced, sustained inotropic stimulation of the myocardium can produce a potentially deleterious imbalance in the myocardial energy supply-demand relationship, or whether the potential exists for arrhythmia induction by some of these agents. Based on these considerations, it seems likely that inotropic drugs alone will not represent the most favorable therapy for the severely failing heart.

Keywords

Heart Failure Chronic Heart Failure Cardiac Glycoside Positive Inotropic Effect Isosorbide Dinitrate 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    J. Ross, Mechanisms of cardiac contraction. What roles for preload, afterload and inotropic state in heart failure? Eur.Heart J., 4 (suppl.A): 19 - 28 (1983).CrossRefGoogle Scholar
  2. 2.
    L. Storstein, Clinical and circulatory aspects of digitalis in heart failure, Eur.Heart J., 3 (suppl.D): 59 - 64 (1982).Google Scholar
  3. 3.
    H. Scholz, Pharmacological actions of various inotropic agents, Eur.Heart J., 4 (suppl.A): 161 - 172 (1983).CrossRefGoogle Scholar
  4. 4.
    K. Weber, V. Andrews, and J. S. Janicki, Cardiotonic agents in the management of chronic heart failure, Am.Heart J., 103: 639 - 649 (1982).CrossRefGoogle Scholar
  5. 5.
    P. Jerie, Behandlung der therapieresistenten Herzinsuffizienz, Schweiz.Rundschau.Med., 72: 15 - 21 (1983).Google Scholar
  6. 6.
    M. Telerman, P. Decoodt, and B. Peperstraele, The rationale of the treatment of congestive heart failure, Acta Cardiol., (Suppl. 28 ): 77 - 83 (1982).Google Scholar
  7. 7.
    M. Artman, M. D. Parrish, and T. P. Graham Jr., Congestive heart failure in childhood and adholescence: recognition and management, Am.Heart J., 105: 471 - 480 (1983).CrossRefGoogle Scholar
  8. 8.
    H. Holzgreve, Glykosidtherapie: Suche nach alternativen Behandlungsmöglichkeiten, Münch.med.Wschr., 124: 14 - 16 (1982).Google Scholar
  9. 9.
    A. M. Weissler, J. R. Syder, C. D. Schoenfeld, and S. Cohen, Assay of digitalis glycosides in man, Am.J.Cardiol., 17: 768 - 780 (1966).CrossRefGoogle Scholar
  10. 10.
    C. Davidson and D. Gibson, Clinical significance of positive inotropic action of digoxin in patients with left ventricular disease, Brit.Heart J., 85: 970 - 976 (1973).CrossRefGoogle Scholar
  11. 11.
    V. Cohn, A. Selzer, E. Kersh, L. S. Kerpmann, and N. Goldschleger, Variability of hemodynamic response of acute digitalisation in chronic cardiac failure due to cardiomyopathy and coronary artery disease, Am.J.Cardiol., 35: 461 - 468 (1975).CrossRefGoogle Scholar
  12. 12.
    G. D. Johnston and D. G. McDevitt, Is maintenance digoxin necessary in patients with sinus rhythm? Lancet, 1: 567 - 570 (1979).CrossRefGoogle Scholar
  13. 13.
    N. H. Carliner, C. A. Gilbert, A. W. Pruitt, and L. I. Goldberg, Effect of maintenance digoxin therapy on systolic time intervals and serum digoxin concentrations, Circulation, 50: 94 - 98 (1974).CrossRefGoogle Scholar
  14. 14.
    M. H. Crawford, J. S. Karliner, and R. A. O'Rourke, Favourable effect of oral maintenance digoxin therapy on left ventric-ular performance in normal subjects. Echocardiographic study, Am.J.Cardiol., 38: 843 - 848 (1976).CrossRefGoogle Scholar
  15. 15.
    J. H. Kleinmann, N. B. Ingels, G. Daughters, E. B. Stinson, E. L. Aldermann, and R. H. Goldmann, Left ventricular dynamics during long-term digoxin treatment in patients with stable coronary artery disease, Am.J.Cardiol., 41: 937 - 943 (1978).CrossRefGoogle Scholar
  16. 16.
    S. B. Arnold, C. B. Randolph, W. W. Parmley, and K. Chatterjee, Long-term digitalis therapy improves left ventricular function in heart failure, New.Engl.J.Med., 303: 1443 - 1448 (1980).CrossRefGoogle Scholar
  17. 17.
    R. G. Murray, A. C. Tweddel, W. Martin, D. Pearson, J. Hulton, and T. D. Lawrie, Evaluation of digitalis in cardiac failure, Br.med.J., 284: 1526 - 1528 (1982).CrossRefGoogle Scholar
  18. 18.
    H. Lüllmann, T. Peters, and J. Preuner, Mechanism of action of digitalis glycosides in the light of new experimental observations, Eur.Heart J., 4 (suppl.D): 45 - 51 (1982).Google Scholar
  19. 19.
    T. Go frind, The biphasic action of cardiac glycosides on the Na -K pump and its relevance in the treatment of heart failure, Eur.Heart J., 3 (suppl.D): 53 - 57 (1982).CrossRefGoogle Scholar
  20. 20.
    U. Peters, Pharmacokinetic review of digitalis glycosides, Eur.Heart J., 3 (suppl.D): 65 - 78 (1982).CrossRefGoogle Scholar
  21. 21.
    K. Kochsiek, Pharmacokinetic review of digitalis review, Eur.Heart J., 3 (suppl.D): 79 - 86 (1982).Google Scholar
  22. 22.
    G. Cocco and A. Audibert, Probleme der digitalistherapie bei patienten mit niereninsuffizienz, Schweiz. Rundschau.Med., 39: 1242 - 1245 (1975).Google Scholar
  23. 23.
    G. Cocco and A. Audibert, Digitalistherapie and niereninsuffizienz, Mediz.Monatschrift., 1: 22 - 25 (1976).Google Scholar
  24. 24.
    E. G. Krause and A. Wollenberger, Cyclic nucleotides and heart, in: “Cyclis 3’, 5’—nucleotides Mechanisms of Action,” H. Cramer and J. Schultz, eds., London (1977).Google Scholar
  25. 25.
    G. I. Drummond and D. L. Severson, Cyclic nucleotides and cardiac function, Circ.Res., 44: 145 - 153 (1979).CrossRefGoogle Scholar
  26. 26.
    H. Scholz, Effects of beta-and alpha-adrenoceptor and activators and adrenergic transmitter releasing agents on the mechanical activity of the heart, in: "Handbook of Experimental Pharmacology," Part I, L. Szekers, ed., Springer Verlag, Berlin - Heidelberg - New York, 651 - 733 (1980).Google Scholar
  27. 27.
    H. Reuter, Localization of beta adrenergic receptors and effect of noradrenaline and cyclic nucleotides on action potentials, ionic currents and tension in mammalian cardiac muscle, J.Physiol. (London), 242: 429 - 451 (1974).Google Scholar
  28. 28.
    S. I. Rajfer and L. I. Goldgerg, Dopamine in the treatment of heart failure, Eur.Heart J., 3 (suppl.D): 103 - 106 (1982).CrossRefGoogle Scholar
  29. 29.
    K. Chatterjee, A. Bendersky, and W. W. Parmley, Dobutamine in heart failure, Eur.Heart J., 3 (suppl.D): 107 - 114 (1982).Google Scholar
  30. 30.
    H. Mattson, A. Hedberg, and E. Carlsson, Basic pharmacological properties of prenalterol, Acta Med.Scand., 659 (suppl.): 9 - 37 (1982).Google Scholar
  31. 31.
    O. Ronn, E. Fellenius, C. Graffner, G. Johnsson, P. Lundborg, and L. Svensson, Metabolic and hemodynamic effects and pharmacokinetics of a new selective 81-adrenoceptor agonist, prenalterol, in man, Eur.J.Clin.Pharmacol., 17: 81 - 86 (1980).CrossRefGoogle Scholar
  32. 32.
    A. Hjalmarson, N. Abelardo, and E. Waagstein, Effects of prenalterol in congestive heart failure, Eur.Heart J., 3 (suppl.D): 115 - 121 (1982).Google Scholar
  33. 33.
    G. Cocco and C. Strozzi, Oral treatment with the beta-agonist prenalterol in patients with congestive heart failure. Unpublished data. Ciba-Geigy Basle files.Google Scholar
  34. 34.
    E. J. Ariens, Molecular pharmacology. The mode of action of biologically active compounds, Academic Press, New York, 148 - 170 (1964).Google Scholar
  35. 35.
    J. D. Harry, H. F. Marlow, A. G. Wrdleworth, and J. Young, The action of ICI 118,587 (a beta-adrenoceptor partial agonist) on the heart rate response to exercise in man, Br.J.Clin. Pharmacol., 12: 266 - 267 (1981).Google Scholar
  36. 36.
    H. F. Marlow, A. G. Wardleworth, and L. M. Booth, The haemodynamic effects of oral doses of ICI 118,587, a betaadrenoceptor partial agonist, in healthy volunteers, Br.J.Clin.Pharmacol., 13: 269 - 270 (1982).CrossRefGoogle Scholar
  37. 37.
    H. Pouleur, M. F. Rousseau, P. Mengeot, C. Veriter, M. F. Vincent, and L. A. Brasseur, Improvement of global and regional left ventricular function in patients with previous myocardial infarction by a new 81-adrenoceptor partial agonist, ICI 118,587, Eur.Heart J., 3 (suppl.D): 123 - 127 (1982).Google Scholar
  38. 38.
    B. Sharma and J. F. Goodwin, Beneficial effect of salbutamol on cardiac function in severe congestive cardiomyopathy. Effect on systolic and diastolic function of the left ventricle, Circulation, 58: 449 - 460 (1978).CrossRefGoogle Scholar
  39. 39.
    C. H. Kerr, Hemodynamic effects of oral salbutamol in patients with severe left ventricular failure, Circulation, 60 (suppl.II): 11 - 41 (1979).Google Scholar
  40. 40.
    P. D. V. Bourdillon, J. R. Dawson, R. A. Foole, A. D. Timmis, P. A. Poole-Wilson, and G. C. Sutton, Salbutamol in treatment of heart failure, Brit.Heart J., 43: 206 - 210 (1980).CrossRefGoogle Scholar
  41. 41.
    C. S. Maskin, Th. Le Jemtel, J. Kugler, and E. H. Sonnenblick, Inotropic therapy in the management of congestive heart failure, Cardiovasc.Rev.and Reports, 3: 837 - 846 (1982).Google Scholar
  42. 42.
    R. Slutsky, W. Hooper, K. Gerber, G. Cartis, J. Karliner, and W. Ashburn, The effect of terbutaline on left ventricular function and size, Am.J.Cardiol., 45: 412 - 419 (1980).CrossRefGoogle Scholar
  43. 43.
    M. Irmer, H. Wollschläger, and H. Just, Behandlung der schweren herzinsuffizienz mit dem beta-stimulator fenoterol, Klin.Wschr., 59: 639 - 645 (1981).CrossRefGoogle Scholar
  44. 44.
    W. S. Colucci, R. W. Alexander, and G. H. Mudge Jr., Acute and chronic effects of pirbuterol on left ventricular ejection fraction and clinical status in severe congestive heart failure, Am.Heart J., 102: 564 - 568 (1981).CrossRefGoogle Scholar
  45. 45.
    J. R. Dawson, R. Canepa-Anson, P. Kuan, N. H. G. Whitaker, J. Carnie, C. Warnes, S. R. Reueben, P. A. Poole-Wilson, and G. C. Sutton, Treatment of chronic heart failure with pirbuterol: acute haemodynamics responses.Google Scholar
  46. 46.
    R. E. Rude, Z. Turi, E. J. Brown, B. H. Lorell, W. S. Colucci, G. H. Mudge Jr., C. R. Taylor, and W. Grossman, Acute effects of oral pirbuterol on myocardial oxygen metabolism and systemic hemodynamics in chronic congestive heart failure, Circulation, 64: 139 - 145 (1981).CrossRefGoogle Scholar
  47. 47.
    B. Sharma, J. Hoback, G. S. Francis, M. Hodges, R. W. Asinger, J. N. Cohn, and C. R. Taylor, Pirbuterol: a new oral sympathomimetic amine for the treatment of congestive heart failure, Am.Heart J., 102: 533 - 541 (1981).CrossRefGoogle Scholar
  48. 48.
    C. R. Taylor, J. R. C. Baird, K. J. Blackburn, D. Cambridge, J. W. Constantine, M. S. Ghaly, M. L. Hayden, H. M. Mclhenny, P. F. Moore, A. Y. Olukotun, L. G. Pullman, D. S. Salsbury, C. A. P. D. Saxton, and S. Shevde, Comparative pharmacology and clinical efficacy of newer agents in treatment of heart failure, Am.Heart J., 102: 515 - 532 (1981).CrossRefGoogle Scholar
  49. 49.
    J. R. Dawson, J. Bayliss, M. S. Norell, R. Canepa-Anson, P. Kuan, S. Reuben, P. A. Poole-Wilson, and G. C. Sutton, Clinical studies with ß2-adrenoceptor agonists in heart failure, Eur.Heart J., 3 (suppl.D): 135 - 141 (1982).Google Scholar
  50. 50.
    R. Canepa-Anson, J. R. Dawson, W. S. Frankl, P. Kuan, G. C. Sutton, S. Reuben, and P. A. Poole-Wilson, ß2-Adrenoceptor agonists; pharmacology, metabolic effects and arrhythmias, Eur.Heart J., 3 (suppl.D): 129 - 134 (1982).Google Scholar
  51. 51.
    G. Cocco, F. Burkart, D. Chu, and F. Follath, Intrinsic sympathomimetic activity of beta-adrenoceptor blocking agents, Europ.J.clin.Pharmacol., 13: 1 - 4 (1978).CrossRefGoogle Scholar
  52. 52.
    W. S. Hillis and M. Been, Phosphodiesterase inhibitors: haemodynamic effects related to the treatment of cardiac failure, Eur.Heart J., 3 (suppl.D): 97 - 101 (1982).Google Scholar
  53. 53.
    M. Robert and L. Humair, Cardiotone wirkung vom glucagon. Klinische prüfung and therapeutische indikationen, Schweiz.med Wschr., 100: 1345 - 1352 (1970).Google Scholar
  54. 54.
    E. L. Kinney, B. Carlin, J. O. Ballard, J. M. Burks, W. F. Hallahan, and R. Zelis, Clinical experience with amrinone in patients with advanced congestive heart failure, J.Clin. Pharmacol., 22: 433 - 440 (1982).Google Scholar
  55. 55.
    A. A. Alousi and J. Edelson, Amrinone, in; “Pharmacological and Biochemical Properties of Drug Substances,” 3: 120 - 147 (1981).Google Scholar
  56. 56.
    J. Bayliss, M. Norell, R. Canepa-Anson, S. R. Reuben, P. A. Poole-Wilson, and G. C. Sutton, Acute haemodynamic comparison of amrinone and pirbuterol in chronic heart failure. Additional effects of isosorbide dinitrate, Brit.Heart J., 49: 214 - 221 (1983).CrossRefGoogle Scholar
  57. 57.
    P. T. Wilsmurst and M. M. Webb-Peploe, Side effects of amrinone therapy, Brit.Heart J., 49: 447 - 451 (1983).CrossRefGoogle Scholar
  58. 58.
    J. Thormann, W. Kramer, M. Schlepper, and M. Gottwick, AR-L 115BS in the treatment of heart failure, Eur.Heart J., 3 (suppl.D): 87 - 95 (1982).Google Scholar
  59. 59.
    G. Haeusler, Ro 13-6438, a new original positive inotropic agent, World Conf.Clin.Pharmacol.Ther. (London), abstract 0057 (1980).Google Scholar
  60. 60.
    S. Gasic, Preliminary experience with i.v. and oral Ro 13-6438 in healthy volunteers. Roche Clinical Unit, Univ. of Vienna. Rocher files (unpublished data ) (1980).Google Scholar
  61. 61.
    W. Kiowski, F. Burkart, M. Pfisterer, and Z. Y. Lu, Die positive inotrope wirkung von Ro13-6438, einer nicht-digitalisähnlichen/nicht sympathomimetísch wirkenden substanz bei patienten mit herzinsuffizienz: 51 Annual Meeting of the Swiss Soc. of Internal Medicine, 5-7th May 1983, abstract No.8.Google Scholar
  62. 62.
    O. A. Smiseth, Inosine infusion in dogs with acute ischemic left ventricular failure: favourable effects on myocardial performance and metabolism, Cardiovasc.Res., 17: 192 - 199 (1983).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • G. Cocco
    • 1
    • 2
  • P. Jerie
    • 1
    • 2
  1. 1.Klinik BarmelweidBarmelweidSwitzerland
  2. 2.Cardiological AmbulanceSolbadklinikRheinfeldenSwitzerland

Personalised recommendations