Effect of diltiazem on renal clearance and serum concentration of digoxin in patients with cardiac disease

Effect of diltiazem on renal clearance and serum concentration of digoxin in patients with cardiac disease

CARDIOVASCULAR PHARMACOLOGY Effect of Diltiazem on Renal Clearance and Serum Concentration of Digoxin in Patients with Cardiac Disease URI ELKAYAM, ...

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Effect of Diltiazem on Renal Clearance and Serum Concentration of Digoxin in Patients with Cardiac Disease URI ELKAYAM, MD, KEYUR PARIKH, MD, BEHROOZ TORKAN, MD, LAURA WEBER, RN, JORDAN L. COHEN, PhD, and SHAHBUDIN H. RAHIMTOOIA, MB, FRCP

The effect of diltiatem on digoxln serum concentration was evaluated in 9 patients who had been treated chronically for heart disease with digoxln, 0.25 mg/day. The indications for digoxin therapy were arrhythmias In 5 patients and mild heart failure in the other 4. Renal digoxin clearance was also evaluated in 8 of these patients. Serum dlgoxin concentration was measured at control, 7 f 2 days afler initiation of 120 mg/day of diltiazem and 11 f 5 days after increasing the dose of diltiazem to 240 mg/day. Serum digoxin concentration was 0.9 f 0.4 rig/ml at control, 0.8 f 0.4 ng/mi with 120 mg/day of diltiazem, and 0.8 f 0.3 rig/ml during therapy with

240 mg/day. The dtfferences between these values were not significant. Renal digoxin clearance also did not show a significant change after diltiarem therapy (44 f 15 ml/min before diltiazem and 48 f 13 ml/min with 240 mg/day of dlltiazem). This study shows no effect of diltiazem in doses of 120 to 240 mg/day on serum digoxin concentration or renal digoxin clearance in patients who are treated chronically for heart disease with dlgoxin. In this dose range, diltiazem has advantages over verap amil, which markedly elevates digoxln levels.

Diltiazem is a calcium channel-blocking agent that is being used frequently for the treatment of coronary artery disease,‘-3 arrhythmias,4 systemic hypertension,5 primary pulmonary hypertension6 and heart failure.7 Many patients who benefit with use of this agent are also treated with digoxin. Other calcium blockers such as verapamil and nifedipine have an interaction with digoxinalO; verapamil may lead to marked elevation of serum digoxin concentration and to clinical signs of digoxin toxicity. We evaluated the effect of diltiazem on serum digoxin level and on renal digoxin clearance in a group of patients with heart disease.

goxin (Lanoxin”, Burroughs Wellcome) (Table I). The indication for digoxin therapy wassupraventricular arrhythmias in 5 patients and heart failure in 4. Eight patients received medicationsother than digoxin beforethe study (Table I). The indication for diltiazem therapy wascoronary artery disease in 4 patients and supraventricular arrhythmias in 5. Study protocol: The patients were instructed to continue to take 0.25 mglday of digoxin between 8 and 9 P.M. Five to 29days (mean11 f 8) later the patients wereadmitted to the Clinical ResearchCenter of the University of Southern California-Los AngelesCounty Medical Center for examination of 24-hour renal digoxin clearanceand determination of digoxin serum concentration; this evaluation was done in the morning 12 to 14 hours after the ingestion of digoxin. After completionof the initial evaluationtherapy wasbegun with 120mg/day of diltiazem (30 mg 4 times daily.) Digoxin and other drugswerecontinued at the prestudy dose.Four to 11days (mean7 f 2) after initiation of diltiazem therapy, the serumdigoxin concentration wasdetermined in all but 1 patient and the diltiazem dosewasincreasedin all 9 patients to 240 mg/day (60 mg, 4 times daily). The patients wererehospitalized 5 to 20 days (mean11 f 5) later and determination of serumdigoxin concentration and renal digoxin clearance was repeated. Digoxin concentrations in the serum and urine were de-

(Am J Cardiol

Methods Patients: We studied 9 patients (8 women and 1 man, aged

34 to 66 years, mean f standard deviation 52 f

10) who


treated chronically for heart disease with 0.25 mg/day of diFrom the Section of Cardiology, Department of Medicine, University of Southern California School of Medicine. and the Clinical pharmacokinetic Laboratory, University of Southern California School of Pharmacy, Los Angeles, California. This study was supported in part by grant 8RR-43 from the General Clinical Research Center, National Institutes of Health, Bethesda, Maryland. Manuscript received September 28, 1984; revised manuscript received January 25, 1985, accapted January 29.1985. Address for reprints: thi Elkayam. MD, Director, Inpatient Cardblogy. Section of Cardiology, University of Southern California School of Medicine, 2025 Zonal Avenue, Los Angeles, California 90033.


termined after the appropriate dilution by a radioimmunoassaytechnique usinga digoxin (1*5I)radioimmunoassaykit (Abbott Laboratories). Data analysis: Analysis of variance for the repeatedmeasureswasused to analyze the statistical significance of the 1393




TABLE I Patient Characteristics,

Digoxln Dose, Serum Digoxin Concentrations and Renal Digoxin Clearance Renal Digoxin Clearance (mUmin)

Concomitant Medications

Age W) & Sex

I3 1

66M SOF 41F 54F 57F 62F 34F 44F 56F

f t 6 3 9

Cardiovascular Disease

H, I, C, ASA S, T, P








L, I, NQ, TN, TO w, IS ii kN W w’, L, KCI I

T + -


7 +

; + -

Serum Digoxin Concentration 0W-W






:: 46

:; 36 32

Ai 017 1.0


2 0:s 1.0

5: -

E 1:s



8.: 1:s 0.7 0.5

El 46 26 56


2 if 0:4

Digoxin Dose MWday) 0.250 0.250 0.250 0.250 0.250 0.250 0.250 0.250 0.250

l Status after mitral valve replacement. A = aldomet; AF = atrial fibrillation; ASA = aspirin; C = control; CAD = coronary artery disease; CHF = congestive heart failure; Cl = clonidine; 0120 and D240 = diltiiem 120 and 240 mgklay; H = hydrochlorothiazlde; HYP = systemic hypertension; I = isosorbide dinitrate; IS = iron sulfate; KCL = potassium chloride; L = lasix; RMVD = rheumatic mitral valve disease; NG = transderm nitroglycerin; P = prazosin; PEN = penicillin; Q = quinidine; S = spironolactone; T = tolazamide; TN = tolectin; TO = tolinase; W = warfarin; -F = present; - = absent.

changes in serum digoxin concentration from control during therapy with 120 and 240 mglday of diltiazem. Renal digoxin clearances before and during diltiazem therapy (240 mg/day) were compared using a paired t test. A p value ~0.05 is considered statistically significant. Values are expressed as mean f standard deviation. Results Figure 1 shows individual values of serum digoxin concentration before and during therapy with 120 mg/day (8 patients) and 240 mg/day of diltiazem. Serum digoxin concentration increased 33% (from 0.6 to 0.8 rig/ml) in patient 3 during therapy, but failed to change substantially in any other patient. Mean group values for serum digoxin were 0.9 f 0.4 mg/ml at baseline, 0.8 f 0.4 mg/ml during therapy with 120 mg/day and 0.8 f 0.3 mg/ml during therapy with 240 mg/day of diltiazem. The differences between these values were not statistically significant. Digoxin renal clearance after diltiazem therapy was measured in 8 patients (Fig. 1) demonstrating a more than 20% decrease in 2 patients (nos. 3 and 9) and a more than 20% increase in 2 patients (nos. 4 and 5). These changes in renal digoxin clearance resulted in a substantial effect on serum digoxin levels SERUM 2.0









sor 60


141 20-




# D240

FIGURE 1. Serum digoxin concentration during digoxin therapy alone and during


I, c


and renal digoxin clearance dlltiazem (D) therapy.

in 1 patient only (patient 3). Mean values for renal digoxin clearance were 44 f 15 ml/min at control and 46 f 13 ml/min during diltiazem therapy (difference not significant). The absence of interference of diltiazem with the radioimmunoassay for digoxin has been documented by the following experiments: The in vitro addition of 100 or 500 rig/ml of diltiazem to known digoxin samples showed no difference in the concentration of digoxin determined by the radioimmunoassay procedure. In addition, serum blanks to which 100 and 500 rig/ml of diltiazem were added and serum samples taken from 2 patients treated with 240 mg/day of diltiazem, but not treated with digoxin, showed no cross-reactivity with the digoxin radioimmunoassay kit used in this study. Diltiazem therapy was associated with a significant decrease in heart rate, from 83 f 18 at control to 69 f 10 beats/min (p = 0.035) during 240 mg/day of diltiazem. Discussion The wide use of calcium channel-blocking agents in the treatment of a variety of cardiac diseases results in a concomitant use of these drugs and digoxin. Because elevated digoxin serum concentration may lead to significant adverse effects, a drug interaction with digoxin is of great clinical importance. Klein et al8 demonstrated a marked increase in serum digoxin concentration secondary to verapamil administration in a large group of patients. The effects of verapamil were dosedependent and resulted in symptoms suggestive of mild-to-moderate digoxin toxicity in some patients. The effect of verapamil on the serum digoxin level has largely been attributed to a decrease in renal clearance due to alteration of tubular secretion of digoxin. A preliminary report by Doeringll in some patients appeared to conflict with these data, showing no significant change in serum digoxin concentration after verapamil. However, a further study by the same investigators12 and by othersgJ0J3J4 have supported the existence and reinforced the clinical importance of the interaction between verapamil and digoxin. Nifedipine,

May I,1985

another widely used calcium channel blocker, was also reported to increase serum digoxin concentration in healthy subjects. 1~s However, other studies failed to show an interaction between nifedipine and digoxin both in normal subjects16 and in patients with heart disease.i7 Several investigators recently studied the interaction between digoxin and diltiazem. Rameis et al18 reported no significant effect of diltiazem on renal digoxin clearance in healthy subjects, but found a small increase in digoxin concentration after diltiazem therapy, which they suspected to be of limited clinical importance. In contrast, a significant digoxin-diltiazem interaction was reported by Yoshida et all9 in healthy Japanese subjects. Our study shows that in patients with heart disease, diltiazem in doses reported to exert significant hemodynamic and antianginal effectszO doe8 not alter either serum digoxin concentration or renal digoxin clearance. The value of our findings may be limited by the relatively few patients studied. However, the consistent and almost uniformly seen minimal change in digoxin level after diltiazem therapy substantiates the validity of the data and rules out an important interaction between the 2 drugs. The results of our study are at variance with recent studies demonstrating a significant digoxin-diltiazem interaction in Japanese patients with chronic atria1 fibrillation.21 The explanation for this discrepancy is not apparent. Our results, however, are in agreement with data reported by Schrager et al,22 showing a lack of interaction between diltiazem and digoxin in patients with coronary artery disease. These data may, therefore, suggest an advantage of diltiazem over verapamil when a calcium channel blocker is indicated in patients who are already treated with digoxin. References 1. Hossack KF,. Pool PE, Steele P, Crawford YH, DeMarla AN, Cohen LS, Ports TA. Efficacy of diltiazem in angina on effort: a multicenter trial. Am


J Cardiol

2. Rosenthal



SJ, Ginsburg

diltiazem for control 1980;46:1027-1032.



R, Lamb IH, Balm DS, Schroeder

of symptoms

3. Petru MA, Crawford


of coronary


MH, Sorensen SG, Chaudhurl


JS. Efficacy



Am J Cardioi

TK, Levine S, O’Rourke

RA. Short- and long-term efficacy of high-dose oral diltiazem for angina due to coronarv arterv disease: a olacebc-controlled. randomized. double-blind crossover study. Circulation 1983;68:139-147. 4. Roranskl JJ, Zaman L, Castellanos A. Electrophysiologic effects of diltiazem hydrochloride on supraventricuiar tachycardia. Am J Cardiol 1982; 49:621-628. 5. fnouve IK, Ma&s BM, Senowftz N, Simpson P, Logs D. Antihyoertensive therapy with diltiazem and comparison with hydrochlorothiazide. Am J Cardioi 1984:53:1588-1592. 6. Kambara H, Fujlmoto K, Wakabayashl A, Kawal C. Primary pulmonary hypertension: beneficial therapy with diltiazem. Am Heart J 1981;lOl:

230-231. 7. Walsh RW, Porter effects JACC

DB, Starling MR, O’Rourke

of intravenous 1984;3:1044-1050.

and oral diitiazem

RA. Beneficial

in severe

hsmodynamic heart failure.


8. Klein HO, Lang R, Weiss E, DlSegni E, Libhaber C, Guerrero E. The influence of verapamil on serum digoxin concentration.

J, Kapllnsky Circulation


9. Schwartz

JB, Keefe D, Kates RE, Klrsten E, Harrlson DC. Acute and chronic pharmacodynamic interaction of verapamil and digoxin in atrial fibrillation. Circulation 1982:65:1163-l 170. 10. Selz 00, Aust PE, Mu&es R. Digoxin plasma concentrations and nifedipine. Lancet 1981;2:844-845. 11. Doarlng W. Quinidinedigoxin interaction: pharmacokinetics, underlying mechanism and clinical implications. N Engl J Med 1979;301:400-404. 12. Belz GG, Doarlng R, Munkes PE, Belts 0. Effects of various calcium antagonists on blood level and renal clearance of digoxin (abstr). Circulation 1980;64:24. 13. Morganroth J, Chen CC, Stomt S, Drlfus LS. Oral verapamil in the treatment of atrial fibrillation/flutter (abstr). Am J Cardiol 1982;49:981. 14. Pedersen

KE, Dorph-Pedersen

A, Hvldt S, Klltgaard

NA, Pedersen


The long-term effect of verapamil cm piasma diixin ccncentratkw and renal digoxin clearance in healthy subjects. Eur J Clin Pharmacol 1982;22: 123-127. between digoxin 15. Belz GG, Doerlng W, Munkes R, Matthews J. Interaction and calcium antagonists and antiarrhythmic drugs. Clin Pharmacol Ther

1983;33:410-417, 16. Schwartz JB, Mlgllore tration


24. 17. Schwartz


PJ. Effect



of nifedipine on serum digoxin concenClin Pharmacol Ther 1984;38:19-

JB, Ralznar A, Akers

S. The effect of nifedipine on serum Am Hear-l J 1984;107:669-673. 18. Ramels H, Magometschnlgg D, Ganzinger U. The diltiazemdigoxin action. Clin Pharmacol Ther 1984;36:183-189. concentrations

19. Yoshlda A, Fujlta M, Kurosawa N, Nioka M, Shlchlnohe Fukuda R, Owada E, Kelji I. Effects of diltiiem on plasma excretion

of digoxin

681-685. 20. Subramanlan

in healthy




of diitiazem

in patients

Y, Fuji1 S, Kanda K, Aklno E, Kawasakl


22. 0 chrager



T, Arakawa


level and urinary Ther 1984;35:

YB, Khurml NS, Bowlas NJ, O’Hara M, Raftery EB. objective

evaluation of three dose levels angina. JACC 1983;1:1144-1153.

21. Oyama


in patients.


Am J Cardiol

BR, Pina t, Brangi M, Apellwhlte drgoxrn




with chronic 1480-1481.

S, Sequelra



H, Nagata M, Goto K. DiR, Chahlne


RA. i1i:ill-