Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1981 Oct;68(4):1065–1074. doi: 10.1172/JCI110329

Effect of quinidine on the digoxin receptor in vitro.

W J Ball Jr, D Tse-Eng, E T Wallick, J P Bilezikian, A Schwartz, V P Butler Jr
PMCID: PMC370894  PMID: 6270193

Abstract

To investigate the basis for a clinically important digitalis-quinidine interaction that is characterized by increases in serums digoxin concentrations when quinidine is administered to digoxin-treated patients, we have studied in vitro the interaction of quinidine with the digoxin receptor. Evidence has been obtained that quinidine is capable of decreasing the affinity for digoxin of cardiac glycoside receptor sites on purified Na,K-ATPase and on intact human erythrocyte membranes. As others have shown, quinidine is capable of inhibiting Na,K-ATPase activity, and evidence has been obtained in the current study that, while quinidine can reduce the affinity of the enzyme for digoxin, it is also capable of acting together with digoxin in inhibiting enzyme activity to a degree greater than the inhibitory effect of digoxin alone. The concentrations of digoxin and quinidine used in this study were considerably greater than their therapeutic serum concentrations. Nevertheless, these observations are consistent with the hypothesis that the increases in serum digoxin concentrations and the decreases in volumes of digoxin distribution observed clinically when quinidine is administered to digoxin-treated patients may reflect, at least in part, a decrease in the affinity of tissue receptors for digoxin. The possibility must also be considered that enhanced cardiac effects of digoxin may occur clinically as the result of an augmentation, by quinidine, of digoxin effects, which more than compensates for the modest reduction in digoxin binding.

Full text

PDF
1065

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. ACIERNO L. J., GUBNER R. Utility and limitations of intravenous quinidine in arrhythmias. Am Heart J. 1951 May;41(5):733–741. doi: 10.1016/0002-8703(51)90262-1. [DOI] [PubMed] [Google Scholar]
  2. Bernstein J. C., Israel Y. Active transport of Rb86 in human red cells and rat brain slices. J Pharmacol Exp Ther. 1970 Aug;174(2):323–329. [PubMed] [Google Scholar]
  3. Besch H. R., Jr, Watanabe A. M. Binding and effect of tritiated quinidine on cardiac subcellular enzyme systems: sarcomplasmic reticulum vesicles, mitochondria and Na+, K+-adenosine triphosphatase. J Pharmacol Exp Ther. 1977 Aug;202(2):354–364. [PubMed] [Google Scholar]
  4. CROSBY W. H., MUNN J. I., FURTH F. W. Standardizing a method for clinical hemoglobinometry. U S Armed Forces Med J. 1954 May;5(5):693–703. [PubMed] [Google Scholar]
  5. Caldwell R. W., Nash C. B. Comparison of the effects of aminosugar cardiac glycosides with ouabain and digoxin on Na+, K+ -adenosine triphosphatase and cardiac contractile force. J Pharmacol Exp Ther. 1978 Jan;204(1):141–148. [PubMed] [Google Scholar]
  6. Cho Y. W. Quantitative correlation of plasma and myocardial quinidine concentrations with biochemical and electrocardiographic changes. Am Heart J. 1973 May;85(5):648–654. doi: 10.1016/0002-8703(73)90170-1. [DOI] [PubMed] [Google Scholar]
  7. Choi S. J., Roberts J., Kelliher G. J. The effect of propranolol and quinidine on 22 Na- and 42 K-exchange in the cat papillary muscle. Eur J Pharmacol. 1972 Oct;20(1):10–21. doi: 10.1016/0014-2999(72)90210-5. [DOI] [PubMed] [Google Scholar]
  8. Dahlqvist R., Ejvinsson G., Schenck-Gustafsson K. Effect of quinidine on plasma concentration and renal clearance of digoxin. A clinically important drug interaction. Br J Clin Pharmacol. 1980 Apr;9(4):413–418. doi: 10.1111/j.1365-2125.1980.tb01070.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Doering W., König E. Anstieg der Digoxinkonzentration im Serum unter Chinidinmedikation. Med Klin. 1978 Jul 28;73(30):1085–1088. [PubMed] [Google Scholar]
  10. Doering W. Quinidine-digoxin interaction: Pharmacokinetics, underlying mechanism and clinical implications. N Engl J Med. 1979 Aug 23;301(8):400–404. doi: 10.1056/NEJM197908233010803. [DOI] [PubMed] [Google Scholar]
  11. Doherty J. E. The clinical pharmacology of digitalis glycosides: a review. Am J Med Sci. 1968 Jun;255:382–414. doi: 10.1097/00000441-196806000-00006. [DOI] [PubMed] [Google Scholar]
  12. Eaton D. L., Klaassen C. D. Carrier-mediated transport of ouabain in isolated hepatocytes. J Pharmacol Exp Ther. 1978 May;205(2):480–488. [PubMed] [Google Scholar]
  13. Ejvinsson G. Effect of quinidine on plasma concentrations of digoxin. Br Med J. 1978 Feb 4;1(6108):279–280. doi: 10.1136/bmj.1.6108.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gardner J. D., Kilno D. R., Swartz T. J., Butler V. P., Jr Effects of digoxin-specific antibodies on accumulation and binding of digoxin by human erythrocytes. J Clin Invest. 1973 Aug;52(8):1820–1833. doi: 10.1172/JCI107364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gibson T. P., Nelson H. A. Digoxin alters quinidine and quinidine alters digoxin pharmacokinetics in dogs. J Lab Clin Med. 1980 Mar;95(3):417–428. [PubMed] [Google Scholar]
  16. HOLLAND W. C., KLEIN R. L. Effects of temperature, Na and K concentration and quinidine on transmembrane flux of K42 and incidence of atrial fibrillation. Circ Res. 1958 Jul;6(4):516–521. doi: 10.1161/01.res.6.4.516. [DOI] [PubMed] [Google Scholar]
  17. Hager W. D., Fenster P., Mayersohn M., Perrier D., Graves P., Marcus F. I., Goldman S. Digoxin-quinidine interaction Pharmacokinetic evaluation. N Engl J Med. 1979 May 31;300(22):1238–1241. doi: 10.1056/NEJM197905313002202. [DOI] [PubMed] [Google Scholar]
  18. Holt D. W., Hayler A. M., Edmonds M. E., Ashford R. F. Clinically significant interaction between digoxin and quinidine. Br Med J. 1979 Dec 1;2(6202):1401–1401. doi: 10.1136/bmj.2.6202.1401. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hooymans P. M., Merkus F. W. Effect of quinidine on plasma concentration of digoxin. Br Med J. 1978 Oct 7;2(6143):1022–1022. doi: 10.1136/bmj.2.6143.1022-b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. KAHN J. B., Jr The entry of rubidium into human erythrocytes. J Pharmacol Exp Ther. 1962 May;136:197–204. [PubMed] [Google Scholar]
  21. KARKI N., BURN G. P., BURN J. H. The effect of quinidine on potassium flux. Lancet. 1957 Mar 16;272(6968):565–565. doi: 10.1016/s0140-6736(57)90927-3. [DOI] [PubMed] [Google Scholar]
  22. Kennedy K. G., Nayler W. G. The effect of quinidine on the activity of a sodium-potassium activated, magnesium-dependent ATPase enzyme isolated from toad cardiac muscle. Biochim Biophys Acta. 1965 Oct 25;110(1):174–180. doi: 10.1016/s0926-6593(65)80106-0. [DOI] [PubMed] [Google Scholar]
  23. Koch-Weser J. Drug therapy. Serum drug concentrations as therapeutic guides. N Engl J Med. 1972 Aug 3;287(5):227–231. doi: 10.1056/NEJM197208032870505. [DOI] [PubMed] [Google Scholar]
  24. Lane L. K., Anner B. M., Wallick E. T., Ray M. V., Schwartz A. Effect of phospholipase A treatment on the partial reactions of and ouabain binding to a purified sodium and potassium activated adenosine triphosphatase. Biochem Pharmacol. 1978 Jan 15;27(2):225–231. doi: 10.1016/0006-2952(78)90305-2. [DOI] [PubMed] [Google Scholar]
  25. Leahey E. B., Jr, Reiffel J. A., Drusin R. E., Heissenbuttel R. H., Lovejoy W. P., Bigger J. T., Jr Interaction between quinidine and digoxin. JAMA. 1978 Aug 11;240(6):533–534. [PubMed] [Google Scholar]
  26. Leahey E. B., Jr, Reiffel J. A., Heissenbuttel R. H., Drusin R. E., Lovejoy W. P., Bigger J. T., Jr Enhanced cardiac effect of digoxin during quinidine treatment. Arch Intern Med. 1979 May;139(5):519–521. [PubMed] [Google Scholar]
  27. Lowry K., Rao S. N., Pitts B. J., Askari A. Effects of quinidine on some reactions and ion translocations catalyzed by the Na+, K+ -ATPase complex. Biochem Pharmacol. 1973 Jun 1;22(11):1369–1377. doi: 10.1016/0006-2952(73)90310-9. [DOI] [PubMed] [Google Scholar]
  28. McCall D. Effect of quinidine on cation exchange in cultured cells. J Pharmacol Exp Ther. 1976 Jun;197(3):605–614. [PubMed] [Google Scholar]
  29. Mungall D. R., Robichaux R. P., Perry W., Scott J. W., Robinson A., Burelle T., Hurst D. Effects of quinidine on serum digoxin concentration: a prospective study. Ann Intern Med. 1980 Nov;93(5):689–693. doi: 10.7326/0003-4819-93-5-689. [DOI] [PubMed] [Google Scholar]
  30. Parker R. B., Waud D. R. Pharmacological estimation of drug-receptor dissociation constants. Statistical evaluation. I. Agonists. J Pharmacol Exp Ther. 1971 Apr;177(1):1–12. [PubMed] [Google Scholar]
  31. Pedersen K. E., Hastrup J., Hvidt S. The effect of quinidine on digoxin kinetics in cardiac patients. Acta Med Scand. 1980;207(4):291–295. doi: 10.1111/j.0954-6820.1980.tb09723.x. [DOI] [PubMed] [Google Scholar]
  32. RODENSKY P. L., KATHE J. H., WASSERMAN F. The effect of quinidine on tolerance to digoxin. Am J Cardiol. 1960 Apr;5:498–505. doi: 10.1016/0002-9149(60)90108-9. [DOI] [PubMed] [Google Scholar]
  33. Risler T., Peters U., Grabensee B., Seipel L. Untersuchungen zur Interaktion von Chinidin und Digoxin beim Menschen. Dtsch Med Wochenschr. 1979 Oct 26;104(43):1523–1526. doi: 10.1055/s-0028-1129135. [DOI] [PubMed] [Google Scholar]
  34. Risler T., Somberg J. C., Blute R. D., Jr, Smith T. W. The effect of altered renal perfusion pressure on clearance of digoxin. Circulation. 1980 Mar;61(3):521–525. doi: 10.1161/01.cir.61.3.521. [DOI] [PubMed] [Google Scholar]
  35. SCHERLIS L., GONZALEZ L. F., BESSMAN S. P. Quinidine: arterial, venous, coronary sinus and myocardial concentrations. J Clin Invest. 1961 Jan;40:60–65. doi: 10.1172/JCI104237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. SELZER A., WRAY H. W. QUINIDINE SYNCOPE. PAROXYSMAL VENTRICULAR FIBRILLATION OCCURRING DURING TREATMENT OF CHRONIC ATRIAL ARRHYTHMIAS. Circulation. 1964 Jul;30:17–26. doi: 10.1161/01.cir.30.1.17. [DOI] [PubMed] [Google Scholar]
  37. Schenck-Gustafsson K., Dahlqvist R. Pharmacokinetics of digoxin in patients subjected to the quinidine-digoxin interaction. Br J Clin Pharmacol. 1981 Feb;11(2):181–186. doi: 10.1111/j.1365-2125.1981.tb01122.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schwartz A., Allen J. C., Harigaya S. Possible involvement of cardiac Na+, K+-adenosine triphosphatase in the mechanism of action of cardiac glycosides. J Pharmacol Exp Ther. 1969 Jul;168(1):31–41. [PubMed] [Google Scholar]
  39. Smith T. W., Butler V. P., Jr, Haber E. Determination of therapeutic and toxic serum digoxin concentrations by radioimmunoassay. N Engl J Med. 1969 Nov 27;281(22):1212–1216. doi: 10.1056/NEJM196911272812203. [DOI] [PubMed] [Google Scholar]
  40. Song S. Y., Scheuer J. The effects of pharmacologic agents on myocardial sodium (Na+) and potassium (K+) stimulated ATPase. Pharmacology. 1968;1(4):209–217. doi: 10.1159/000135967. [DOI] [PubMed] [Google Scholar]
  41. Steiness E. Renal tubular secretion of digoxin. Circulation. 1974 Jul;50(1):103–107. doi: 10.1161/01.cir.50.1.103. [DOI] [PubMed] [Google Scholar]
  42. Steiness E., Waldorff S., Hansen P. B., Kjaergård H., Buch J., Egeblad H. Reduction of digoxin-induced inotropism during quinidine administration. Clin Pharmacol Ther. 1980 Jun;27(6):791–795. doi: 10.1038/clpt.1980.112. [DOI] [PubMed] [Google Scholar]
  43. Storstein O., Hansteen V., Hatle L., Hillestad L., Storstein L. Studies on digitalis. XIII. A prospective study of 649 patients on maintenance treatment with digitoxin. Am Heart J. 1977 Apr;93(4):434–443. doi: 10.1016/s0002-8703(77)80405-5. [DOI] [PubMed] [Google Scholar]
  44. Wallick E. T., Lindenmayer G. E., Lane L. K., Allen J. C., Pitts B. J., Schwartz A. Recent advances in cardiac glycoside-Na+,K+-ATPase interaction. Fed Proc. 1977 Aug;36(9):2214–2218. [PubMed] [Google Scholar]
  45. Wallick E. T., Pitts B. J., Lane L. K., Schwartz A. A kinetic comparison of cardiac glycoside interactions with Na+,K+-ATPases from skeletal and cardiac muscle and from kidney. Arch Biochem Biophys. 1980 Jul;202(2):442–449. doi: 10.1016/0003-9861(80)90448-8. [DOI] [PubMed] [Google Scholar]
  46. Wallick E. T., Schwartz A. Thermodynamics of the rate of binding of oubain to the sodium, potassium-adenosine triphosphatase. J Biol Chem. 1974 Aug 25;249(16):5141–5147. [PubMed] [Google Scholar]
  47. Watson J. F., Butler V. P., Jr Biologic activity of digoxin-specific antisera. J Clin Invest. 1972 Mar;51(3):638–648. doi: 10.1172/JCI106853. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES