JANICE B. SCHWARTZ,
Many investigators have studied the potential interactions between calcium-channel antagonists and digoxin. Digoxin is usually well absorbed, and its excretion is dependent on renal mechanisms, primarily glomerular filtration. Several studies have reported a decrease in digoxtn clearance and an increase of approximately 50% in digoxin levels when verapamil was added to digoxin therapy. Because renal digoxin clearance was decreased but no concomitant change in creatinine clearance was shown, the presumed major mechanism for decreased renal digoxin clearance is an alteration in renal tubular secretion of digoxin. Although an early report described a digoxin-nifediptne interaction, several subsequent studies have shown no sfgnificant changes in digoxin kinetics during nifedipine administration. Four studies found no significant decrease in creatinine clearance of digoxin during
nifedipine administration. Thus significant changes in glomerular filtration are unlikely. Physiologic endpoints were measured by 2 groups describing a digoxin-nifedipine interaction and, although there was an increase in serum digoxin concentration, no changes were found in electrophysiologic ,correlates. Thus, if a digoxin-nifedipine interaction does exist, steady-state digoxin levels might increase from 24 to 45 % when nifedipine therapy is added. Studies to date have involved small numbers of subjects with and without cardiac disease and have used different study protocols. Nonetheless, little evidence exists for any clinically significant increase in physiologic effects and no adverse effects have been found in patients receiving combined nifedipine and digoxin.
Interactions with digoxin during concomitant drug administration have been a focus of concern and research since quinidine-digoxin interactions with potentially lethal consequences were rep0rted.l” With the recent widespread availability of the calcium or slowchannel antagonist drugs, potential interactions with digoxin have been investigated.s-2g This article will review the published reports regarding (1) the existence of a pharmacokinetic interaction between digoxin and nifedipine; (2) the mechanism of such an interaction; (3) the physiologic consequences of such an interaction, if one exists; and (4) the potential clinical implications of the pharmacodynamic changes.
during nifedipine dosing of 10 mg orally 3 times a day for 2 weeks in combination with digoxin dosing of 0.125 mg orally 3 times a day (from 0.5 f 0.16 to 0.73 f 0.23 ng/mL, mean f standard deviation [SD]) in 12 normal subjects. More detailed analyses of digoxin clearance after single intravenous (IV) administration of 1 mg to healthy individuals by Pedersen et all9 found no significant change in the biologic half-life, volume of distribution or total body clearance of digoxin during nifedipine dosing (10 mg orally 4 times a day for 10 days). They did note an insignificant but consistent lowering of cumulative urinary excretion of digoxin during nifedipine administration that was accompanied by an increased extrarenal clearance of digoxin. Thus, the result was no net change in total body digoxin clearance. In a preliminary report of another single-dose study of digoxin kinetics (0.5 mg IV) in 8 healthy volunteers,26 no significant changes were detected in the digoxin half-life, the area under the time-concentration curve or the volume of distribution during nifedipine administration (30 mg orally 3 times a day for 6 days). The lack of change in these kinetic parameters agrees with the results of Pedersen et al,lg but the renal clearance
Current existence published in mean
(Am J Cardiol
The Kinetic Interaction reports reflect the conflict regarding the of a nifedipine-digoxin interaction. The first reports by Belz et aP7 showed a 45% increase steady-state serum digoxin concentrations
From the Departments of Medicine and Pharmacy, University of California School of Medicine, San Francisco, California. Address for reprints: Janice B. Schwartz, MD, University of California, M-l 186, San Francisco, California 94143.
data differ. Zylber-Katz et alz6 reported an increase in cumulative urinary digoxin excretion, and thus renal digoxin clearance, during nifedipine coadministration. The use of differing digoxin and nifedipine doses, different urinary sampling time periods and small sample sizes may explain the seemingly conflicting results in urinary and renal digoxin clearance. In any event, the variable changes in renal elimination following IV digoxin during nifedipine coadministration were small and could be considered largely insignificant because there was no alteration in the digoxin elimination half-life or the area under the time-concentration curve. Since the reports of Belz et al,s,7J8 2 reports of digoxin and nifedipine oral coadministration have appeared. Schwartz et al have studied the effects of digoxin and nifedipine coadministration in both healthy individuals25 and patients with chest pain syndromes.24 No significant change in steady-state trough serum digoxin concentrations was seen during oral coadministration of nifedipine (18.5 f 4 mg 3 times a day, mean f SD) and digoxin (0.375 mg/day) for 2 weeks in 20 healthy subjects when compared with concentrations obtained during two 2-week periods of placebo and digoxin coadministration. They reported a rise in urinary digoxin excretion and renal digoxin clearance during nifedipine coadministration.25 In the cardiac patients (also receiving other cardiac medications), Schwartz et a124 noted no change in steady-state serum digoxin concentrations measured daily after the initiation of nifedipine therapy (41 f 15 mg/day, mean f SD) in 8 patients or after 1 and 2 weeks of nifedipine and digoxin (Lanoxine 0.25 mg/day) coadministration in 14 patients. De Cesaris et al22 studied the effects of combined oral administration of nifedipine and P-methyl digoxin (an almost completely absorbed digitalis preparation)30 in patients with congestive heart failure. They observed a 25% increase in steady-state serum concentrations of digoxin (from 0.87 f 0.16 to 1.09 f 0.18 ng/mL, mean f SD) after 7 days of nifedipine therapy (60 mg/day). Renal digoxin excretion was not measured, and no mention was made of additional cardiac medications. It is difficult to explain the discrepant results between individual studies in healthy volunteers and among studies of different groups of cardiac patients. Under the traditional -“gold standard,” single-dose, kinetic experimental conditions-IV administration to normal subjects receiving no medications other than the study drugs-the results consistently show the lack of a kinetic interaction.lgJ7 When the experiments use oral formulations in normal subjects18 or are performed in’ the clinical environment,22*24 the results have been variable. This variation may reflect differing digoxin formulations, dietary habits, dosing regimens, concomitant medications, renal elimination mechanisms or the small number of subjects studied to date. The Potential Mechanism To evaluate the possible mechanism of drug interactions with digoxin, it is necessary to briefly review
digoxin’s metabolism. The importance of the bioavailability of digitalis preparations first received attention in the 197Os, and the most commonly prescribed formulation of digitalis is digoxin (as Lanoxina). In normal subjects, digoxin has been reported to be 65 to 75% absorbed in tablet form, while the encapsulated gel (Lanoxicapk) and P-methyl digoxin are almost completely absorbed.30 Digoxin is approximately 20% protein bound, and 8 to 10% may undergo enterohepatic degradation. The majority of digoxin is excreted renally as the unchanged compound, although some individuals excrete appreciable amounts of the biotransformed, relatively inactive metabolite dihydrodigoxin.31 Urinary excretion and renal clearance of digoxin have been shown to be proportional to the glomerular filtration rate (and creatinine clearance), and algorithms have been developed to relate digoxin dosages to alterations in creatinine c1earance.s2-34 More recently, the contributions of renal tubular secretion and reabsorption of digoxin have become apparent:Renal tubular secretion of digoxin seems to be more important in patients with impaired renal blood flows5736 and in infants and children.37338 The. average elimination half-life of digoxin is 36 to 48 hours, allowing once-daily dosing, and is distributed primarily in lean body mass,3gy4o allowing largely weight-independent calculations of loading doses. Acute administration of nitroprusside and hydralazine has been reported to increase renal digoxin clearance and renal blood flow without changing glomerular filtration rate in patients with congestive heart [email protected]
In contrast, acute decreases in renal perfusion pressure have resulted in decreased glomerular filtration rates and digoxin clearance in experimental models.43 To summarize, digoxin is usually well absorbed, and its excretion is dependent on renal mechanisms-primarily glomerular filtration, but also tubular reabsorption and secretion in certain groups. Can these facts elucidate the existence and the mechanism of a digoxinlnifedipine interaction? In studies performed after IV digoxin administrationlg or with P-methyl digoxin,2‘Jp27alterations in absorption can be totally eliminated as possible factors in the results. Two of.the 3 studies report no interaction, yet one reports an increase in digoxin levels. Creatinine clearance was measured by Belz is Pedersen,ls De Cesaris,22 Schwartz25 and their co-workers, all of whom report no significant decrease in creatinine clearance during nifedipine; thus, significant changes in glomerular filtration are unlikely. Some of the same reports found decreases in digoxin clearance, pointing to the possibility of alterations in renal tubular digoxin secretion and reabsorption. The net effect of nifedipine on renal digoxin secretion/reabsorption might depend on its vasodilatory effects versus a direct effect on renal tubular exchange. No direct studies of possible alterations in tissue distribution have been performed. It is of interest to compare the reports regarding verapamil, another slow-channel antagonist. Although 1 preliminary report in a small number of patients suggested no significant interaction between verapamil
and digoxin,l all subsequent investigations have demonstrated a decrease in digoxin clearance and an increase of approximately 50% in digoxin levels when verapamil was added to digoxin therapy.71g-18 Decreases in renal digoxin clearance without concomitant change in creatinine clearance have been shown. Therefore, the presumed major mechanism is an alteration in renal tubular secretion of digoxin,13J5 although changes in extrarenal clearance may play a smaller role.11J3 Evidence to date suggests that verapamil does not affect tissue uptake or the distribution of digoxin.17 The Physiologic Consequences Possible physiologic endpoints for assessing the significance of changes in serum digoxin concentrations include: (1) electrophysiologic effects, such as sinus activity, atrioventricular conduction and supraventricular or ventricular arrhythmias; (2) inotropic effects; and (3) subjective toxic effects, such as anorexia, nausea, vomiting and visual disturbances. Physiologic endpoints were measured by 2 groups investigating the digoxinnifedipine interaction. No change in heart rate, PR intervals or QTc was found by Belz et a1,6*7J8despite the 45% increase in digoxin concentrations during nifedipine coadministration. In other words, no change in electrophysiologic correlates was seen as a consequence of the observed increase in serum digoxin concentration. Analysis of systolic time intervals showed that left ventricular ejection time shortened slightly more during nifedipine administration than during digoxin administration alone. With higher nifedipine doses, Schwartz et a126 found an increase in sinus rate (especially standing) and no change in PR interval or digoxin levels. De Cesaris et alz2 assessed the degree of adenosine triphosphatase (ATPase) inhibition by studying rubidium uptake in erythrocytes from patients with increased digoxin levels during nifedipine therapy. They found an increase in digitalis activity associated with the 25% increased digoxin levels during nifedipine coadministration. No study has reported increased subjective complaints suggestive of digitalis excess. The Clinical Implications To date, data regarding the existence of a digoxinnifedipine interaction are conflicting. If such an interaction does exist, steady-state digoxin levels might increase from 24 to 45% when nifedipine therapy is added. Despite this increase, there is little evidence for increased physiologic effects. More importantly, adverse effects have not been found in the patients studied. It is likely that the effects on digoxin metabolism in a given individual will reflect the underlying renal and cardiac function and the effects on renal blood flow during nifedipine administration. The prudent approach would be to monitor both serum digoxin concentrations and physiologic endpoints during the initiation of nifedipine therapy in a patient taking digoxin. The current evidence is too unclear to recommend routine alterations in digoxin dosage during nifedipine administration.
Addendum: Since preparation of this article, another report44 has appeared showing no interaction between nifedipine and P-acetyldigoxin in 11 patients with congestive heart failure.
Leahey EB, pelffei JA, Drusfn RE, Heissenbuttel RH, Lovejoy WP, Bigger J&lnteracbon between quinidme and digoxin. JAMA 1978;240:533-
N Engl J Med 1979;301:400-
3. Bigger JT Jr. The quinidine-digoxin interaction. N Engl J Med 1979;301: 779-781. 4. Leahey EB, Refffel JA, Heissenbuttei RH, Drusin RE, Lovejoy WP, Bigger JT. Enhanced cardiac effect of digoxin during quinidine treatment. Arch Intern Med 1979;139:519-521. 5. Hirsh PD, Weiner HJ, North RL. Further insights into digoxin-quinidine interaction: lack of correlation between serum digoxin concentration and inotropic state of the heart. Am J Cardiol 1980;46:883-867. 8. Sefz GG, Aust PE, Muwkes R. Digoxin plasma concentrations and nifedipine: correspondence. Lancet 1981;1:845. 7. Belz GO! Doerlng W, Munkes R, Aust PE, Befz 0. Effects of various calcium antagonrsts on blood level and renal clearance of digoxin (abstr). Circulation 1981;64:suppl IV:24. 9. Kieln HO, Paurner H, Di Segni E, David D, Kapiinsky E. The beneficial effects of verapamil in chronic atrial fibrillation. Arch Intern Med 1979; 139:747-749. 9. Lang R, Klein HO, Weiss E, Llbhaber C, Kapilnsky E. Effect of verapamil on blood level and renal clearance of digoxin (abstr). Circulation 1980; 62:suooI lll:83. 10. Klein ii0, Lang R, Pi Begni E, Kapllnsky E. Verapamil-digoxin interaction (abstr). N Engl J Med 1980;303:160. 11. Pedersen KE, Dorph-Pedersen A, Hvldt S, Kiitgaard NA, Pedersen KK. The long-tarm effect of verapamil on plasma digoxin concentration and renal digoxin clearance in healthy subjects. Eur J Clin Pharmacol 1982;22: 123-127. 12. Schwartz JB, Keefe D, Kates RE, Harrison DC. Verapamil and digoxin: another drug-drug interaction (abstr). Clin Res 1981;29:5OlA. 13. Pedersen KE, Dorph-Pedersen A, Hvkit S, Klftgaard NA, Nielsen-Kudrk F. Digoxin-verapamil interaction. Clin Pharmacol Ther 1981;30:31 l316. 14. Morganroth J, Chfn CC, Strum S, Dreffus LS. Oral verapamfl in the treatment of atrial fibrillation/flutter (abstr). Am J Cardiol 1982;49:981. 15. Klein HO, Lang R, Weiss E, De Segni E, Libhaber C, Guerrero J, Kaplinsky E. The influence of verapamil on serum digoxin concentration. Circulation 1982;65:998-1003. 16. Schwartz JB, Keele D, Kates RE, Kirstein E, Harrison DC. Acute and chronic pharmacodynamic interaction of verapamil and digoxin in atrial fibrillation. Circulation 1982:85:1183-l 170. 17. Koren 0, Soldin S, YacLeod SM. Digoxin-verapamil interaction: in vitro studies in rat tissue. J Cardiovasc Pharmacol 1983:5:443-445. 10. Belz GG, Doering W, Munkes R, Matthews J. Interaction between digoxin and calcium antagonists and antiarrhythmic drugs. Clin Pharmacol Ther 1983;33:410-417. 19. Pedersen KE, Dorph-Pedersen A, Huldt S, Klftgaard NA, Kjaer K, Nlelson-Kudsk F. Effect of nifedipine on digoxin kinetics in healthy subjects. Clin Pharmacol Ther 1982;32:562-565. 20. Tepper D, Hoch R, Koegler L, Kleinbaum H, Butler 8, Felder J, Torres V, Miura DS, Somberg JC. The lack of effect of bepridil on serum digoxin concentration (abstr). Clin Res 1983;31:873A. 21. Doering W. Effect of coadministration of verapamil and quinidine on serum digoxin concentration. Eur J Clin Pharmacol 1983;25:517-521. 22. De Cesaris R, Balestrazzi M, Chiarappa R, Ranier1 G. Increase of serum digoxin levels after combined administration of calcium antagonists and beta-methyldigoxin. G ltal Cardiol 1983;13: 188-191. 23. Schrager BR, Pina I, Frangi Y, Appfewhite S, Sequeira R, Chahine RA. Diltiazem. digoxin interaction? (abstr) Circulation 1983;68:suppl lll:lll368. 24. Schwartz JB, Ralzner A, Akers S. The effect of nifedipine on serum digoxin concentrations in patients. Am Heart J 1984;107:689-673. 25. Schwartz JB, Migiiore PJ. Effect of nifecfipine on serum digoxin concentr$on and renal drgoxrn clearance. Ckn Pharmacol Ther 1984:38:19-
26. Zylber-Katz E, Koren G, Levy 1111.Pharmacokinetic study of digoxin and nifedioine coadministration fabstr). Clin Pharmacol Ther 1984:35:114. 27. Oyama Y! FuJiI S, Kanda K,‘Akino E, Kawasaki H, Nagata M, Goto K. Digoxindilbazem interaction. Am J Cardiol 1984;53:1480-1481. 28. Yoshida A, Masatsugu F, Kurosawa N, Nioka M, Schlchlnohe T, Arakawa M, Fukada R, Owada E, fto K. Effects of diltiazem on olasma level and urinary excretion of digoxin in healthy subjects. Clin’Pharmacol Ther 1984:35:681-685. 29. Ram&s H, Magometschnigg D, Ganzlnger U. The diltiazemdigoxin interaction. Clin Pharmacol Ther 1984;36:183-189. 30. Schaumann W. Beta-methyl digoxin, a new lipophilic digoxin derivative. In: Scdem G, Dengler HJ, eds. Cardiac Glycosides. New York: SpringerVerlag, 1978:93-104. 31. Llndenbaum J. Rund DO. Butler VP. Tse-Ena D. Saha JR. inactivation of digoxin by the gut florai reversal by antibi%id therapy. N Engl J Med 1981;305:789-794, 32. Jeiiiiie RW. An improved method of digoxin therapy. Ann Intern Med 1966;69:703-717.
33. Jelllff RW, Buell J, Kalaba f?. Reduction of digitalis toxicity by computerassisted glycoside dosage regimens. Ann Intern Med 1972;77:891-906. Sheiner LB, Halkln H, Peck C, Rosenberg B, Yelmon KL. Improved computer-assisted digoxin therapy. Ann Intern Med 1975;62:619-627. 35. Halkin H, Shelner LB, Peck CC, Melmon KL. Determinants of the renal clearance of digoxin. Clin Pharmacol Ther 1975,17:385-394. 36. Steiness E. Renal tubular secretion of digoxm. Circulation 1974;50: 103-107. 37. Llnday LA, Engle MA, Reidenberg MM. Maturation and renal digoxin clearance. Clin Pharmacol Ther 1981;30:735-738. 38. Karen 0, Hessleln P, Macleod SM. Kinetics of amiodarone-associated digoxin toxicity in children, abstracted. Clin Pharmacol Ther 1984;35:121. 39. Abernethy DR, Greenblatt DJ, Smith TW. Digoxin disposition in obesity: clinical pharmacokinetic investigation. Am Heart J 1981;102:740-744. 34.
Ewy GA, Groves BM, Ball MF, Nlmmo L, Jackson B, Marcus F. Digoxin metabolism in obesity. Circulation 1971;44:810-814. Cogan JJ, Humphreys YH, Carlson CJ, Rapaporf E. Renal effects of nitroprusside and hydralazine in patients with congestive heart failure. Circulation 1980:61:316-323. 42. Cogan JJ, Humphreys MH, Carlson CJ, Benowltz NL, Rappaport E. Acute vasodilator therapy increases renal clearance of digoxin in patients with congestive hear-l failure. Circulation 1981;64:973-976. 43. Rlsler 1, Somberg JC, Blute RD, Smith lW. The effect of altered renal perfusion pressure on clearance of digoxin. Circulation 1980;61:521525. 44. Kuhlmann J. Effects of nifedipine and diltiazen on plasma levels and renal excretion of beta-acetyldigoxin. Clin Pharmacol Ther 1985;37:150156. 41.