Drugs

, Volume 15, Issue 5, pp 369–380 | Cite as

Drug Interactions with Digitalis Glycosides

  • Peter F. Binnion
Review Article

Summary

The 2 major factors affecting serum levels of the most commonly used cardiac glycoside digoxin, are patient compliance and the physical characteristics of the tablet; the latter is unimportant with the lipid soluble glycosides digitoxin and β-methyldigoxin. Several drugs interfere with the absorption of these cardiac glycosides from the gastrointestinal tract, either by adsorption, altering gut motility or other unknown mechanisms, but only mixtures containing kaolinpectin (and possibly some liquid antacids) are of potential clinical importance with tablets of a satisfactory dissolution profile.

Enzyme inducing agents can increase the rate of elimination of digitoxin and heparin-induced free fatty acid release decrease protein binding of digitoxin, but the therapeutic implications are not clear.

The biological action on the heart depends on the amount of glycoside in the myocardial tissue and the reaction of the patient’s diseased heart to the drug. Experimental work on tissue glycoside concentration is of great fundamental interest but of unknown clinical relevance, except for digoxin antibodies which are the most specific remedy for poisoning in attempts at suicide.

In the absence of specific electrocardiographic changes in digitalis overdosage, estimation of serum concentrations are mandatory. The role of hypokalaemia in digitalis toxicity is, in the author’s opinion, controversial but the role of some drugs in altering myocardial sensitivity to cardiac glycosides is important.

Interest in drug interactions with cardiac glycosides was initially raised by studies conducted in New York by Lindenbaum et al. (1971) who showed that serum digoxin levels in patients varied widely and were dependent on the particular brand of digoxin tablet. About this time, a senior hospital physician was under my care with uncontrolled atrial fibrillation; treatment with the hospital 0.25mg tablet of digoxin resulting in a zero plasma digoxin level (Binnion, 1974a). In this very practical way, we were lead into exploring factors affecting the bioavailability of digoxin. Bioavailability is concerned with the amount of a drug reaching the systemic circulation from a dosage form and has been investigated very extensively in the case of digoxin.

The term digitalis refers to steroid or steroid glycoside compounds that exert typical positive inotropic and electrophysiological effects on the heart. Over 300 compounds with these characteristics exist and all contain a steroid nucleus with a 5-or 6-membered unsaturated lactone ring attached to the C17 position (fig. 1). The double-bond of the lactone ring is essential for cardiac action, the structural requirements for activity are present in aglycones (e.g. digitoxigenin) and the addition of one or more sugar moieties at position C3modifies potency and duration of action, but not the fundamental pharmacological properties of this class of compound (Henderson, 1969).

Keywords

Glycoside Digoxin Ouabain Cardiac Glycoside Digitoxin 

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References

  1. Baskin, S.I.; Dutta, S. and Marks, B.H.: The effects of diphenylhydantoin and potassium on the biological activity of ouabain in the guinea-pig heart. British Journal of Pharmacology 47: 85–96 (1973).PubMedCrossRefGoogle Scholar
  2. Bazzano, G. and Bazzano, G.S.: Digitalis intoxication — Treatment with a new steroid-binding resin. Journal of the American Medical Association 220: 828–830 (1972).PubMedCrossRefGoogle Scholar
  3. Becker, D.J.; Nonkin, P.M.; Bennett, L.D.; Kimball, S.G.; Sternberg, M.S. and Wasserman, F.: Effect of isoproterenol on digitalis cardiotoxicity. American Journal of Cardiology 10: 242–247 (1962).PubMedCrossRefGoogle Scholar
  4. Beermann, B.: The gastrointestinal uptake of methyldigox-in-12α-3H in man. European Journal of Clinical Pharmacology 5: 28 (1972).CrossRefGoogle Scholar
  5. Beermann, B.; Hellstrom, K. and Rosen, A.: Fate of orally administered 3H-digitoxin in man with special reference to absorption. Circulation 43: 852–861 (1971).PubMedCrossRefGoogle Scholar
  6. Beermann, B.; Hellstrom, K. and Rosen, A.: The absorption of orally administered [12α-3H] digoxin in man. Clinical Science 43: 507–518 (1972).PubMedGoogle Scholar
  7. Beermann, B.; Hellstrom, K. and Rosen, A.: The gastrointestinal absorption of digoxin in seven patients with gastric or small intestinal reconstructions. Acta Medica Scandinavica 193: 293–297 (1973).PubMedCrossRefGoogle Scholar
  8. Beller, G.A.; Smith, T.W.; Abelmann, W.H.; Haber, E. and Hood, W.B.: Digitalis intoxication. New England Journal of Medicine 284: 989–997 (1971).PubMedCrossRefGoogle Scholar
  9. Bigger, J.T. and Strauss, H.C.: Digitalis toxicity: drug interactions promoting toxicity and the management of toxicity. Seminars in Drug Treatment 2: 147–177 (1972).PubMedGoogle Scholar
  10. Binnion, P.F. and McDermott, M.: Bioavailability of digoxin. Lancet ii: 592 (1972).CrossRefGoogle Scholar
  11. Binnion, P.F.: Absorption of different commercial preparations of digoxin in the normal human subject, and the influence of antacid, antidiarrhoeal and ion-exchange resins; in Storstein (Ed) Symposium on Digitalis, p.216–224 (Gyldendal Norsk Förlag, Oslo, Norway 1973a).Google Scholar
  12. Binnion, P.F.: Zero plasma digoxin levels in patients on oral digoxin therapy. Irish Journal of Medical Science 148: 346–349 (1974a).CrossRefGoogle Scholar
  13. Binnion, P.F.: The absorption of digoxin tablets. Clinical Pharmacology and Therapeutics 16: 807–812 (1974b).PubMedGoogle Scholar
  14. Binnion, P.F.; McDermott, M. and LeSher, D.: Bioavailability of digoxin. Lancet 1: 1118 (1973).PubMedCrossRefGoogle Scholar
  15. Binnion, P.F.: A comparison of the bioavailability of digoxin in capsule, tablet, and solution taken orally with intravenous digoxin. J. Clin. Pharmacol. 16: 461–467 (1976).PubMedGoogle Scholar
  16. Binnion, P.F. and Das Gupta, R.: Tritiated digoxin metabolism after prior treatment with propranolol or diphenylhydantoin sodium. International Journal of Clinical Pharmacology 12: 96–101 (1975).Google Scholar
  17. Brown, D.D. and Juhl, R.P.: Decreased bioavailability of digoxin due to antacids and kaolin pectin. New England Journal of Medicine 295: 1034–1037 (1976).PubMedCrossRefGoogle Scholar
  18. Butler, V.P.: Assay of digitalis in the blood. Progress in Cardiovascular Disease 14: 571–600 (1972).CrossRefGoogle Scholar
  19. Butler, V.P. and Chen, J.P.: Digoxin-specific antibodies. Proceedings of the National Academy of Sciences 57: 71–78 (1967).CrossRefGoogle Scholar
  20. Butler, V.P.; Schmidt, D.H.; Smith, T.W.; Haber, E.; Raynor, B.D. and Demartini, P.: Effect of Fab Fragments of Sheep Antidigoxin Antibody on serum concentrations and urinary excretion of digoxin. Circulation 48 (Suppl.): 130 (1973).Google Scholar
  21. Caldwell, J.H. and Greenberger, N.J.: Cholestyramine enhances digitalis excretion and protects against lethal intoxication. Journal of Clinical Investigation 49: 16a (1970).CrossRefGoogle Scholar
  22. Caldwell, J.H. and Greenberger, N.J.: Interruption of the enterohepatic circulation of digitoxin by cholestyramine. Journal of Clinical Investigations 50: 2626–2637 (1971).CrossRefGoogle Scholar
  23. Caldwell, J.H.; Martin, J.F.; Dutta, S. and Greenberger, N.J.: Intestinal absorption of digoxin-3H in the rat. American Journal of Physiology 217: 1747–1751 (1969).PubMedGoogle Scholar
  24. Curry, P.; Fitchett, D.; Stubbs, W. and Krikler, D.: Ventricular arrhythmias and hypokalaemia. Lancet 2: 231–233 (1976).PubMedCrossRefGoogle Scholar
  25. Das Gupta, R. and Binnion, P.F.: Tissue digoxin concentrations at digoxin intoxication in normal, acutely hypokalemic, and acutely hyperglycemic dogs. Physiological Chemistry and Physics 8: 207–220 (1976).PubMedGoogle Scholar
  26. Doherty, J.E.; Hall, W.H.; Sherwood, J.; Girkin, D. and Gammill, J.: Serum protein binding of digoxin in human subjects; in Storstein (Ed) Symposium on Digitalis, p.48–54 (Gyldendal Norsk Forlag, Oslo, Norway 1973).Google Scholar
  27. Dunbar, R.W.; Boettner, R.B.; Gatz, R.N.; Pennington, R.E. and Morrow, D.H.: The effect of mepivacaine, bupivacaine and lidocaine on digitalis-induced ventricular arrhythmias. Anesthesia and Analgesia Current Researches 49: 761–766 (1970).Google Scholar
  28. Evered, D.C. and Chapman, C.: Plasma digoxin concentrations and digoxin toxicity in hospital patients. British Heart Journal 33: 540–545 (1971).PubMedCrossRefGoogle Scholar
  29. Fisch, C. and Knoebel, S.B.: Recognition and therapy of digitalis toxicity. Progress in Cardiovascular Diseases 13: 71–96 (1970).PubMedCrossRefGoogle Scholar
  30. Frye, R. and Braunwald, E.: Studies on digitalis III. The influence of triiodothyronine on digitalis requirements. Circulation 23: 376–382 (1961).PubMedCrossRefGoogle Scholar
  31. Greenberger, N.J.; MacDermott, R.P.; Martin, J.F. and Dutta, S.: Intestinal absorption of six tritium-labelled digitalis glycosides in rats and guinea pigs. Journal of Pharmacology and Experimental Therapeutics 167: 265–273 (1969).PubMedGoogle Scholar
  32. Greenblatt, D.J.; Duhme, D.W.; Koch-Weser, J. and Smith, T.W.: Evaluation of digoxin bioavailability in single-dose studies. New England Journal of Medicine 289: 651–654 (1973).PubMedCrossRefGoogle Scholar
  33. Greenblatt, D.J.; Duhme, D.W.; Koch-Weser, J. and Smith, T.W.: Intravenous digoxin as a bioavailability standard: slow infusion and rapid injection. Clinical Pharmacology and Therapeutics 15: 510–513 (1974).PubMedGoogle Scholar
  34. Greenblatt, D.J.; Smith, T.W. and Koch-Weser, J.: Bioavailability of drugs: the digoxin dilemma. Clinical Pharmacokinetics 1: 36–51 (1976).PubMedCrossRefGoogle Scholar
  35. Hall, W.M. and Doherty, J.E.: Tritiated digoxin XXII. Absorption and excretion in malabsorption syndromes. American Journal of Medicine 56: 437–442 (1974).PubMedCrossRefGoogle Scholar
  36. Hall, W.H.; Shappell, S.D. and Doherty, J.E.: Effect of cholestyramine on digoxin absorption and excretion in man. American Journal of Cardiology 39: 213–216 (1977).PubMedCrossRefGoogle Scholar
  37. Hartel, G.; Manninen, V. and Reisell, P.: Treatment of digoxin intoxication. Lancet 2: 158 (1973).PubMedCrossRefGoogle Scholar
  38. Heizer, W.D.; Smith, T.W. and Goldfinger, S.E.: Absorption of digoxin in patients with malabsorption syndromes. New England Journal of Medicine 285: 257–259 (1971).PubMedCrossRefGoogle Scholar
  39. Heifant, R.H.; Scherlag, B.J. and Damato, A.N.: The electrophysiological properties of diphenylhydantoin sodium as compared to procaine amide in the normal and digitalis-intoxicated heart. Circulation 36: 108–118 (1976a).CrossRefGoogle Scholar
  40. Heifant, R.H.; Scherlag, B.J. and Damato, A.N.: Protection from digitalis toxicity with the prophylactic use of diphenylhydantoin sodium. Circulation 36: 119–124 (1967b).CrossRefGoogle Scholar
  41. Henderson, F.G.: Chemistry and biological activity of the cardiac glycosides; in Fisch and Surawicz (Eds) Digitalis, p.3–12 (Grune and Stratton, New York 1969).Google Scholar
  42. Hoeschen, R.J.: The effect of digoxin antibody on the washout of tritiated digoxin and its inotropic effect from perfused rabbit hearts; in Roy and Dhalla (Eds) Recent Advances in the Study of Cardiac Structure and Metabolism, p.345–353 (University Park Press, Baltimore 1976).Google Scholar
  43. Iisalo, E.: Clinical pharmacokinetics of digoxin. Clinical Pharmacokinetics 2: 1–16 (1977).PubMedCrossRefGoogle Scholar
  44. Jounela, A.J.; Pentikainen, P.J. and Sothmann, A.: Effect of particle size on the bioavailability of digoxin. European Journal of Clinical Pharmacology 8: 365–370 (1975).PubMedCrossRefGoogle Scholar
  45. Juhl, R.P.; Summers, R.W.; Guillory, J.K.; Blaug, S.M.; Cheng, F.H. and Brown, D.D.: Effect of sulphasalazine on digoxin bioavailability. Clinical Pharmacology and Therapeutics 20: 387–400 (1976).PubMedGoogle Scholar
  46. Khalil, S.A.H.: The uptake of digoxin and digitoxin by some antacids. Journal of Pharmacy and Pharmacology 26: 961–967 (1974).PubMedCrossRefGoogle Scholar
  47. Kleiger, R.E.; Vitale, J. and Lown, B.: Clinical and experimental relationships between digitalis and potassium. Proceedings of the New England Cardiovascular Society 23: 19–21 (1964-1965).Google Scholar
  48. Larbig, D.; Scheler, F.; Schmidt, H.J.; Betzien, G. and Kaufmann, B.: Untersuchungen zur enteralen Resorption von β-methyl-digoxin. (Investigations into the enterai absorption of β-methyl digoxin). Klinische Wochenschrift 49: 604–607 (1971).PubMedCrossRefGoogle Scholar
  49. Lahiri, K. and Ertel, N.: Mechanism of diphenylhydantoin (DPH) induced decrease in serum digoxin (DG) levels. Clinical Research 22: 321A (1974).Google Scholar
  50. Lindenbaum, J.; Maulitz, R.M. and Butler, V.P.: Inhibition of digoxin absorption by neomycin. Gastroenterology 71: 399–404 (1976).PubMedGoogle Scholar
  51. Lindenbaum, J.; Maulitz, R.M.; Saha, J.R.; Shea, N. and Butler, V.P.: Impairment of digoxin absorption by neomycin. Clinical Research 20: 410 (1972).Google Scholar
  52. Lindenbaum, J.; Mellow, M.H.; Blackstone, M.O. and Butler, V.P.: Variation in biologic availability of digoxin from four preparations. New England Journal of Medicine 285: 1344–1347 (1971).PubMedCrossRefGoogle Scholar
  53. Lucchesi, B.R. and Shivak, R.: Effect of quinidine and procaine amide upon acetylstrophanthidin cardiotoxicity. Journal of Pharmacology and Experimental Therapeutics 143: 366–373 (1964).Google Scholar
  54. Lukas, D.S.: The pharmacokinetics and metabolism of digitoxin in man; in Storstein (Ed) Symposium on Digitalis, p.84–102 (Gyldendal Norsk Förlag, Oslo, Norway 1973).Google Scholar
  55. Lukas, D.S. and DeMartino, A.G.: Binding of digitoxin and some related cardenolides to human plasma proteins. Journal of Clinical Investigation 48: 1041–1053 (1969).PubMedCrossRefGoogle Scholar
  56. Manninen, V.; Apajalahti, A.; Melin, J. and Karesoja, M.: Altered absorption of digoxin in patients given propantheline and metoclopramide. Lancet 1: 398–400 (1973a).PubMedCrossRefGoogle Scholar
  57. Manninen, V.; Apajalahti, A.; Simonen, H. Reissell, P.: Effect of propantheline and metoclopramide on absorption of digoxin. Lancet 1: 1118–1119 (1973b).PubMedCrossRefGoogle Scholar
  58. Marcus, F.I.: Metabolism of digoxin in normal man and factors influencing the body distribution; in Storstein (Ed) Symposium on Digitalis, p. 112–125 (Gyldendal Norsk Förlag, Oslo, Norway 1973).Google Scholar
  59. Marcus, F.I.; Kapadia, G.G. and Goldsmith, C.: Alteration of the body distribution of tritiated digoxin by acute hyperkalemia in the dog. Journal of Pharmacology and Experimental Therapeutics 165: 136–148 (1969).PubMedGoogle Scholar
  60. Marcus, F.I.; Quinn, E.J.; Horton, H.; Jacobs, S.; Pippin, S.; Stafford, M. and Zukoski, C.: The effect of jejunoileal bypass on the pharmacokinetics of digoxin in man. Circulation 55: 537–541 (1976).CrossRefGoogle Scholar
  61. Mason, D.T.; Zelis, R.; Lee, G.; Hughes, J.L.; Spann, J.F. and Amsterdam, E.A.: Current concepts and treatment of digitalis toxicity. American Journal of Cardiology 27: 545–559 (1971).CrossRefGoogle Scholar
  62. Morgan, L.M. and Binnion, P.F.: The distribution of 3H-digoxin in normal and acutely hyperkalaemic dogs. Cardiovascular Research 4: 235–241 (1970).PubMedCrossRefGoogle Scholar
  63. Morrow, D.H. and Townley, N.T.: Anesthesia and digitalis toxicity: an experimental study. Anesthesia and Analgesia Current Researches 43: 510–519 (1964).Google Scholar
  64. Morrow, D.T.; Gaffney, T.E. and Braunwald, E.: Studies on digitalis VII. Influence of hyper- and hypothyroidism on the myocardial response to ouabain. Journal of Pharmacology and Experimental Therapeutics 140: 324–328 (1963).Google Scholar
  65. Okita. G.T.: Relationship between Na+, K+-ATPase inhibition and the inotropic and cardiotoxic actions of digitalis; in Storstein (Ed) Symposium on Digitalis, p.131–143 (Gyldendal Norsk Forlag, Oslo, Norway 1973).Google Scholar
  66. Perrier, D.; Mayersohn, M. and Marcus, F.I.: Clinical pharmacokinetics of digitoxin. Clinical Pharmacokinetics 2: 292–311 (1977).PubMedCrossRefGoogle Scholar
  67. Sampson, J.J.; Alberton, E.C. and Kondo, B.: Effects on man of potassium administration in relation to digitalis glycosides with special reference to blood potassium, electrocardiogram and ectopic beats. American Heart Journal 26: 164–179 (1943).CrossRefGoogle Scholar
  68. Shaw, T.R.D. and Carless, J.E.: The effect of particle size on the absorption of digoxin. European Journal of Clinical Pharmacology 7: 269–273 (1974).PubMedCrossRefGoogle Scholar
  69. Solomon, H.M.: Interaction of digitoxin with other drugs; in Storstein (Ed) Symposium on Digitalis, p.324–329 (Gyldendal Norsk Förlag, Oslo, Norway 1973).Google Scholar
  70. Smith, T.W.; Haber, E. and Yeatman, L.: Reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. New England Journal of Medicine 294: 797–800 (1976).PubMedCrossRefGoogle Scholar
  71. Steiness, E.: Renal tubular secretion of digoxin. Circulation 50: 103–107 (1974).PubMedCrossRefGoogle Scholar
  72. Steiness, E. and Olesen, K.H.: Cardiac arrhythmias induced by hypokalaemia and potassium loss during maintenance digoxin therapy. British Heart Journal 38: 167–172 (1976).PubMedCrossRefGoogle Scholar
  73. Storstein, L.: Protein binding of cardiac glycosides in disease states. Clinical Pharmacokinetics 2: 220–233 (1977).PubMedCrossRefGoogle Scholar
  74. Sumner, D.J. and Russell, A.J.: Digoxin pharmacokinetics and multicompartmental analysis and its clinical implications. British Journal of Clinical Pharmacology 3: 221–229 (1976).PubMedCrossRefGoogle Scholar
  75. Thompson, W.G.: Relationship of in vitro binding of digoxin to its intestinal absorption in rats. Canadian Journal of Pharmacology 51: 832–834 (1973).CrossRefGoogle Scholar
  76. van Bever, R.J.; Duchateau, A.M.J.A.; Pluym, B.F.M. and Merkus, F.W.H.M.: The effect of colestipol on digitoxin plasma levels. Arzneimittel-Forschung 26: 1891–1893 (1976).PubMedGoogle Scholar
  77. Vaughan Williams, E.M. and Sekiya, A.: Prevention of arrhythmias due to cardiac glycosides by block of β-sympathetic receptors. Lancet 1: 420–421 (1963).CrossRefGoogle Scholar
  78. Vohringer, H.F.; Kuhlmann, J. and Rietbrock, N.: Der einfluss von antacida auf die plasmakonzentration von digoxin beim menschen. Deutsche Medizinische Wochenschrift 101: 106–108 (1976).PubMedCrossRefGoogle Scholar
  79. Wilkinson, P.R.; Hesp, R.; Issler, H. and Raftery, E.D.: Total body and serum potassium during prolonged thiazide therapy for essential hypertension. Lancet 1: 759–762 (1975).PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press 1978

Authors and Affiliations

  • Peter F. Binnion
    • 1
  1. 1.Section of CardiologyPennsylvania HospitalPhiladelphiaUSA

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