Cardiovascular Drugs and Therapy 1: 441-446, 1988 © I,iluwerAcademic Publishers. Bosum. Printed in the U.S.A.

INTERACTIONBETWEEN Caz+ ANTAGONISTS AND DIGITALIS

KEY WORDS. digoxin, verapamil, nifedipine, diltiazem, drug interactions

Calcium antagonists are widely used as first-line therapy in a variety of anginal syndromes and in essential hypertension. Due to the differences in their influence on the cardiac conduction system, some calcium antagonists are also often prescribed as antiarrhythmics, especially for supraventricular tachyarrhythmias. Simultaneously, calcium channel blockers are being investigated to determine their efficacy in preventing the ischemic damage in ventricular arrhythmias, in the reversibility of atherosclerosis, and in congestive heart failure. There is also a large program underway to define their usefulness in patients with cerebrovascular disease, be it strokes, transient ischemic attacks, or subarachnoid hemorrhages. This diversification in the use of the slow channel blockers is due to the minor or major pharmacologic differences of the chemical compounds. Receptor and tissue selectivity of a compound are major determinants of how slow channel blockers are going to be used. Because of the already widespread use of calcium channel blockers and other drugs (including digitalis) common to the treatment of cardiovascular diseases, it is essential to clarify the drug interaction relationship between these two classes of drugs.

Verapamil There are several reports in the literature indicating an important interaction between verapamil and digoxin. Koren and co-workers [1] studied the characteristics of the renal cortical specific binding for digoxin in the cat kidney and the antagonistic effects of verapamil on digoxin uptake by the kidney slices. Increases in verapamil concentration resuIted in decreases in digoxin uptake by kidney tissue but not in the liver, heart, or striated muscle tissue. Knowing that verapamil causes a decrease in renal clearance of digoxin as shown by Pedersen and associates [2] without changing the glomerular filtration rate GFR (Klein and colleagues [3]), would suggest that verapamil inhibits the renal tubular secretion of digoxin. In a study by DeCesaris and co-workers [4,6] in congestive heart failure (CHF) patients, coadministration

Jan N. Lessem Institute of Clinical Medicine, Syntex Research, Palo Alto, California

of verapamil and digoxin resulted in a significant increase of 35% in steady-state concentration of digoxin. Kaplanski's group [5] reported that the digoxin concentration in plasma, heart, liver, and muscle was twice as high in animals pretreated with verapamil (p < 0.01). In a different experiment, verapamil also significantly reduced digoxin-induced atrial arrhythmias. Doering [7] showed, using Klein and associates' original observations [8] as starting points, that verapamit increased the serum digoxin concentration in nine healthy volunteers, and that a combination of verapamil and quinidine caused a further increase of 155% in serum digoxin concentration (0.62 + 0.16 to 0.95 +_ 0.29 to 1.58 +_ 0.28 mg/ml). Pedersen and co-workers [9] reported that verapamil decreased the total body clearance of even a single dose of digoxin, from 4.68 _+ 0.41 to 3.29 + 2.88 mt/ min/kg, and increased the plasma half-life of digoxin from 32.50 _+ 2.88 to 41.31 + 2.27 hours (p < 0.01). Interestingly, however, there was no synergistic negative inotropic effect assessed from systolic time intervals. It is, of course, possible that such a negative added effect will not result from administration of a single dose. The same group [10] also found that the abovedescribed changes were associated with a greater elevation of intraerythrocytic sodium concentration than was found in control subjects. This is one of the factors best correlated with digoxin-induced arrhythmias as a sign of digitalis toxicity, and therefore is an important finding. Klein et al. reported [3] on the effects of coadministration of verapamil and digoxin in 49 patients with chronic atrial fibrillation as a follow-up to their original observation [8]. They found that serum digoxin levels rose from 0.26 ± 0.54 to 1.31 ± 0.54 mg/ ml, but that the increase was doserelated to the

Address for correspondence and reprint requests: Jan Lessem, MD, PhD, Syntex Research, Institute of Clinical Medicine, Section of Cardiology, 3401 Hitlview Avenue, Palo Alto, Catitbrnia 94301,

USA

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amount of verapamil given. There was a stepwise increase in patients who first received 160 mg verapamil and where the dose was the titrated upwards to 240 mg verapamil. The effects of verapamil on serum digoxin concentrations developed gradually over a 2 week period. Seven of the 49 patients (14%) showed clinical symptoms suggesting digitalis toxicity. It is of interest to note that Carg~elli and coworkers [11] found that verapamil 80 mg three times daily improved the control of the ventricular rate by digoxin, a finding later confirmed by Klein and colleagues [12], Plumb and associates [13], Schwartz [14], and Johansson and co-workers [15]. Although effective, the combination led to an increased frequency of adverse reactions and increases in plasma digoxin levels. Gordon and Goldenberg recently described clinical symptoms of digitalis toxicity occurring in two elderly patients with concomitant administration of verapamil [16]. Clinical digitalis toxicity may result when serum digoxin levels increase substantially and have been reported by Zatuchini [41] to lead to severe cardiac arrhythmias causing death in two patients. Kounis [46] reported a case where eoadministration caused asystole in a middle-aged female patient. It may be that elderly patients with decreased renal function are more susceptible to digitalis toxicity in general, and especially if the renal clearance of digitalis is altered unfavorably, as is the case with verapamil. Not surprisingly, digoxin intoxication has been described in an uremic patient where verapamil was coadministered [17]. Using digitoxin concomitantly with verapamil, Kuhlmann [18] showed that an increase in digitoxin plasma concentration occurred in ten patients over 4 to 6 weeks of dosing and that the total body clearance and extra renal clearance of digitoxin were reduced. In summary, the evidence is unequivocal that an interaction with the cardiac glycosides and verapamil occurs, which may lead to digitalis intoxication and further cardiac adverse effects. Concomitant medication therefore needs to be carefully monitored, and dosages of the drugs may have to be adjusted.

Diltiazem Diltiazem is a calcium channel blocker with a molecular structure different from verapamil. It is, however, prescribed for approximately the same patient population, and is therefore often coadministered with digoxin. Yoshida and colleagues [19] showed in mice that coadministration led to significant increases in plasma digoxin concentration and also to an increase in digoxin concentration in brain, heart, and liver

tissue. In 24 healthy male subjects, Rameis and coworkers [20] found that diItiazem induced an average increase in steady-state plasma digoxin concentration of 22% and led to a decreased total digoxin clearance without changing diltiazem kinetics, confirming observations by Yoshida and colleagues [2I]. Gallet and associates found in ten healthy subjects that coadministration of diltiazem and digoxin resulted in a 20.4% increase in plasma digoxin levels and increases in the PR and RR interval, while no change occurred in the QRS and QTc interval [22]. North and co-worker recently confirmed these data in eight healthy volunteers [23] and also reported that urinary digoxin clearance decreased from 223.5 _+ 35.2 to 153.4 + 17.5 ml/min, a decrease of 31.4% (p = 0.05). Kuhlmann found that coadministration of diltiazem and digitoxin resulted in an increase in plasma concentration of 6% to 31% [18]. Beltrami and co-workers [24] reported conflicting results, since they found no effect of diltiazem on pharmacokinetics of digoxin, in their single-dose experiment. Elkayam and co-workers [37] reported that in nine patients treated chronically with digoxin 0.25 mg/day after 18 + 7 days of diltiazem, the highest dose being 240 mg/day, serum digoxin concentrations did not change significantly from 0.9 _+ 0.4 ng/ml at control levels to 0.8 _+ 0.0 ng/ml during therapy with the highest dose. Even renal digoxin clearance remained essentially unaltered from 44 ± 15 to 46 _+ 13 ml/min during administration of 240 mg diltiazem. These data, although in contrast with some previously reported data, were confirmed by Boden and colleagues [38], who found that in eight healthy subjects with steady-state plasma digoxin concentration, a daily administration of 360 mg diltiazem resulted in significant decrease in heart rate from 68 + 9 to 61 + 10 beats/min (P < 0.05). Simultaneously a marginal increase occurred in the P-R interval, a finding similar to the results of Gallat and associates [22]. Boden's group found no significant change in trough serum digoxin concentrations from 0.85 ± 0.08 ng/ml to 0.90 _+ 0.08 ng/ml [P= not significant (NS)]. In summary, these studies have produced somewhat conflicting data. Elkayam [37] and Schrager and co-workers [39] both have demonstrated that a clinically significant interaction between digoxin and diltiazem does not seem to occur in patients with coronary artery disease, while Yoshida and co-workers [21] and Oyama and associates [40], working with Japanese subjects and patients, have found an interaction confirmed by other studies. If an interaction does occur between diltiazem and digoxin it seems marginal and probably physiologically insignificant. It would, however, still warrant close clinical observation when the

Ca2+ Antagonists and Digitalis

two drugs are coadministered, especially in a population at risk, such as elderly patients and those with abnormal renal function.

Dihydropyridines The dihydropyridines are a group of calcium channel blockers t h a t all have a related molecular structure but with a heterogeneous pharmacologic action. They are, however, being widely used in the t r e a t m e n t of a variety of cardiovascular diseases. Nitrendipine, which has a prolonged duration of action, was coadministered with digoxin 0.5 mg daily and digitoxin 0.1 mg daily for a week, respectively, in six healthy volunteers. Neither of these drugs affected nitrendipine kinetics, but increased plasma levels for digoxin were recorded [25]. In a recent study, Ziegler and co-workers [48] found that coadministration caused a slight decrease in digoxin concentration and t h a t urinary excretion remained virtually unchanged, as did renal digoxin clearance. In one study, nicardipine was shown to increase mean plasma digoxin levels in patients significantly (P < 0.05) without concomitant changes in nicardipine pharmacokinetics [26]. In a more pharmacokinetic-oriented study with coadministration of nicardipine and digoxin, no significant changes in plasma digoxin levels were seen. The data with nifedipine are conflicting. Hansen and co-workers [27] found in six healthy volunteers that coadministration did not alter plasma digoxin concentration, renal digoxin clearance, or creatinine clearance. Similar results were obtained by Schwartz and Misliore [28] who in a controlled study compared 20 subjects while on placebo and in steady state. With regard to nifedipine, they found that no changes oc-

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curred in digoxin concentration or renal clearance, when digoxin and nifedipine were coadministered. Schwartz also studied the changes in 14 cardiac patients and found that after 1 week of coadministration, the mean level had changed from 0.78 _+ 0.4 to 0.8 +_ 0.4 mg/ml and t h a t a slight further increase to 0.84 +_ 0.5 mg/ml occurred after 1 additional week of coadministration. None of these increases was statistically significant, and occurred in a clinically u n i m p o r t a n t range in this particular patient population [29]. Belz and associates [30] found that plasma digoxin concentration rose 45% in 36 healthy men when 0.375 mg/day digoxin was coadministered with 30 mg/day nifedipine for 2 weeks. They also showed t h a t increases in plasma digoxin concentration correlated closely to decreases in renal digoxin clearances, as well as with shortening of systolic time intervals and flattening of the T wave, and therefore concluded t h a t changes in plasma digoxin levels were reflected in cardiac activity. Pedersen and co-workers [31] studied the singledose kinetics of coadministration and found no significant changes of renal digoxin clearance. They also performed a study in steady-state patients [32] and found a small insignificant increase in m e a n plasma digoxin concentration from 0.68 _+ 0.15 to 0.74 +_ 0.13 mg/ml. These data confirm similar data from normal subjects as reported by Koren and colleagues [33]. While Garty and associates found no interaction in cardiac patients [34], Kleinbloesem and colleagues reported that in nine patients with atrial fibrillation given sustained release nifedipine (20 mg), a 15% increase occurred in plasma digoxin levels. Although statistically significant, this slight elevation was considered without any clinical relevance [35]. In a study by Johnson and colleagues [42], the effects in 24 healthy subjects of a new d i h y d r o p y r i d i n e - -

Table 1. Effects of Calcium Antagonist Drugs on Serum Digoxin Levels (Serum Digoxin Concentration, ng/mt)

Author Boden et al. [38] Belz et ai. [30] Ziegler et al. [48, 49] Klein et al. [8] Belz et al. [30] Schwartz et al. [29]

Drugs Dig + Dig + Dig + Dig + Dig + Dig + Dig + Dig + Dig +

diltiazem verapamil gallopamil nifedipine nifedipine verapamil verapamil nifedipine verapamil

Baseline 0.85 +_0.08 0.58 _+0.257 0.58 _+0.257 0.50 _+0.162 0.70 + 0.15 0.96 +_0.08 0.50 _+0.16 0.50 _+0.16 1.60 _+0.4

Peak Therapy 0.90 _+0.08 0.94 _+0.308 0.67 +_0.312 0.73 _+0.228 0.64 _+0.14 1.63 + 0.12 0.89 +_0.30 0.73 _+0.23 2.70 +_0.9

This table illustrates and summarizes some of the previouslydescribed results. The dosages of the combinations were the highest chosen in the pertinent report, and peak therapy was defined as total length of the coadministratlon. The table emphasizes some of the discrepant results obtained in different studies. Abbreviations: Dig, digoxin.

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isradipine 15 mg/day--were evaluated on the pharmacokinetic of 1 mg intravenous digoxin. Isradipine caused a 9% reduction in volume of distribution of steady state (which was statistically significant (P < 0.05), a significant increase (P < 0.05) in zero time intercept of the elimination phase of the concentrationtime curve, and a trend toward increased distribution rate constant, when a compartmental analysis model was utilized. Simultaneously, the mean serum digoxin concentration over time decreased marginally when the subjects took isradipine. Ziegler and coIleagues [49] reported that a 9% increase occurred in plasma digoxin concentration, when that drug was given with nisoldipine. In summary, although a small increase in plasma digoxin concentration sometimes occurs, this does not seem to be followed by any detrimental clinical digitalis toxicity, and therefore the combination of digoxin and dihydropyridines can be given without anticipation of a clinical significant interaction.

Other Calcium Channel Blockers Lessem and Bellinetto reported that with tiapamil, a congener to verapamil, there was a significant (P <: 0.01) increase in plasma digoxin levels [26]. Similar results have been reported for gallopamil, another verapamil congener [18]. With bepridil, Benet [36] found no significant pharmacokinetic interaction with digoxin. Keren and co-workers [43] studied the lidoflazine digoxin interaction in dogs and found that simultaneous injection of the two drugs for several days did not cause any significant increases or changes in mean serum digoxin concentration. It should be stated that for some of these newer calcium antagonists the data are not complete enough to define whether a clinically important drug interaction occurs.

Discussion Since a relative narrow margin exists between therapeutic and toxic doses and serum levels of digitalis glycosides, as pointed out by Antman and Smith [44], all drugs that can effect this margin negatively, should be used with clinical caution in combination with cardiac glycosides. From the previous review it is evident that an interaction between calcium channel blocking agents and cardiac glycosides occur. The only clinically important interaction so far identified exists with verapamil, where a pharmacokinetic interaction o c -

curs. It is important to remember that in patients with renal impairment, elderly patients, and patients undergoing anesthesia, as pointed out by Jenkins and Scoates [45], a pharmacodynamic interaction may occur between these two classes of drugs when given concomitantly. This may lead to severe and in some cases malignant cardiac arrhythmias, while in other cases it may result in sinus bradycardia, atrioventricular (A-V) block, or other subtle electrocardiographic changes. Individually adjusting either the cardiac glycoside dose or the calcium antagonist dose may help to prevent some of the pharmacodynamic interactions, while probably not influencing the pharmacokinetic interaction. When considering the dihydropyridine group, conflicting results are presented. Metzantonakis [50], for example, did not report significant increase in serum digoxin levels when patients were on coadministration with nitrendipine. However, this increase was transient and levels returned to pretreatment values. From these data and from the above review, it seems clear that the picture with cardiac glycoside interaction with dihydropyridine is very complex. The differences in results may be due to methodologic differences, but since the different calcium antagonists differ in chemical structure, it is not totally surprising that they may differ in their influence on the pharmacokinetic and pharmacodynamic parameters of digoxin. Even small differences in structure in the dihydropyridine family may account for the spread of the results. The clinical importance of the changes seen with agents of this class may be greater in patients with severe renal failure, where even a small increase in serum digoxin concentration could precipitate digoxin toxicity. In spite of all these cautions, however, a combination of these drugs can be used safely in a large patient population, and patients may even benefit from coatiministration, a judgment that should be left to the physician. Adjusting the individual dosages, as described by Piepho [47] and others will assist in obtaining maximum coadministration benefit for the patient.

References 1. Koren G, McLeod SM. Characteristics of the digoxinquinidine and digoxin-verapamilinteractions in the rat kidney. Res Commun Chem Pathot Pharmacol 1984;95:3-18. 2. Pedersen KE, Dorph-Pedersen A, Hvidt S, et al. The longterm effect of verapamil on plasma digoxin concentrations and renal digoxin clearance in healthy subjects. Eur J Clin Pharmacol 1982;22:123-127~ 3. Klein HO, Long R, Weiss E, et al. The influence of verapamil on serum digoxin concentrations. Circulation 1982; 65:998-1003.

Ca 2+ Antagonists and Digitalis

4. DeCesaris R, Balestrazzi M, Chiarappa R, Rainieri G. Interaction between verapamil and beta-methyl digoxin. Study by 86 rubidium uptake in erythrocytes. Int J Clin Pharmacol Res 1983;2:107-109. 5. Kaplanski J, Weinhouse E, Topaz M, Genchik G, Verapamil and digoxin: Interactions in the rat. Res Cammun Chem Pathol Pharmacol 1983;42:377-388. 6. DeCesaris R, Balestrazzi M, Chiarappa R, Ranieri G. Increased digitalisqike activity in combined administration of calcium antagonists and digitalis preparations. G Ital Cardial I983;13:188-19I. 7. Doering W. Effect of coadministration of verapamil and quinidine on serum digoxin concentration_ E u r J Ctin Pharmacol 1983;25:517-521. 8. Klein Ha, Lang R, Weiss E, et al. Verapamil-digoxin interaction. New Engl J Med 1980;303:160. 9. Pedersen KE, Thayssen P, Klitgaard NA, et al. Influence of verapamil on the inotropism and pharmacokinetics of digoxin. Eur J Clin Pharmacol 1983;25:199-206. 10. Pedersen KE, Christiansen BD, Kaer K, et al. Verapamilinduced changes in digoxin kinetics and intraerythrocytic sodium concentration. Clin Pharmacol Ther 1983;34:8183. 11. Cargnelli G, Domeneghetti F, Ferrari M, et al. Plasma digoxin concentrations in patients with atrial fibrillation and indications for the association with other antiarrhythmic agents. Int J Clin Pharmacol Biphharmacol 1977;15:384-388. 12. Klein Ha, Kaplinsky E. Verapamil and digoxin: Their respective effects on atrial fibrillation and their interaction. Am J Cardiol 1982;50:894-902. 13. Plumb VJ, Karp RB, Kouchoukos NT, et al. Verapamil therapy of atrial fibrillation and atrial flutter foIIowing cardiac operation. J Thorac Cardiovasc Surg 1982;83: 590-596. 14. Schwartz JB. Verapamil in atrial fibrillation: The expected, the unexpected, and the unknown. Am Heart J 1983;106: 173-176. I5. Johansson PA, Olsson SB. Long-term oral treatment with high doses of verapamil in lone atrial fibrillation. Clin Cardial 1984;7:163-170, 16. Gordon M, Goldenberg LM. Clinical digoxin toxicity in the aged in association with coadministered verapamil: A report of two cases and review of the literature. J Am Geriatr Sac 1986;34:659-662. 17. Johannessen A, Rendtorff C, Poulsen S. Digoxin intoxication induced by verapamil in an uremic patient. Clin Nephrol 1985;24:158-159. 18. Kuhhnann J. Effects of verapamil, diltiazem, and nifedipine on plasma levels and renal excretion of digitoxin. Clin Pharmacot Ther 1985;38:667-673. 19. Yoshida A, Fujita M, Owada E, Ito K. Effects of diltiazem on plasma and tissue digoxin levels in mice. J Pharmacobiodyn 1984;7:511-516. 20. Rameis H, Magometschnigg D, Ganzinger U. The diltiazem-digoxin interaction. Ctin Pharmacot Ther 1984;36:183189. 21. Yoshida A, Fujita M, Kurasawa N, et al. Effects of diltiazem on plasma level and urinary excretion of digoxin in healthy subjects. Clin Pharmacol Ther 1984;35:681-685. 22. Gallet M, Aupetit IF, Lopez M, et ah Interaction diltiazemdigoxin: Evolution de La digoxinemie et des param6tres electroeardiographiques chez le sutet sain. Arch Mal Coeur 1986;79:1216-1220,

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23. North DS, Mattern AL, Hiser WW. The influence of diltiazero hydroehloride on through serum digoxin concentrations, Drug Intell Clin Pharmacol 1986;20:500-503. 24. Beltrami TR, May J J, Bertino JS Jr. Lack of effects of dilliazem on digoxin pharmacokinetics. J Clin Pharmacol 1985;25:390-392. 25. Kirch W, Huff HI, Heidemann H, et al. Drug interactions with nitrendipine. J Cardiovasc Pharmacol 1984;6:(Suppl 7):$982-$985. 26. Lessem J, Bellinetto A. Interactions between dignxin and the calcium antagonists nicardipine and tiapamil. Clin Ther 1983;5:595-692. 27. Hansen PB, Buch J. Rasmussen O. et al. Influence of atenolol and nifedipine on digoxin-induced inotropism in humans. Br J Clin Pharmacol 1984;18:817-822. 28. Schwartz JB, Misliore PJ. Effect of nifedipine on serum digoxin concentration and renal digoxin clearance. Clin Pharmacol Ther 1984;36:19-24. 29. Schwartz JB, Raizner A, Akers S. The effect of nifedipine on serum digoxin concentrations in patients. Am Heart J 1984;107:669-673. 30. Belz GG, Doering W, Munkes R, Matthews J. Interaction between digoxin and calcium antagonists and antiarrhythmic drugs. Clin Pharmacol Ther 1983;33: 410-417. 31. Pedersen KE, Dorph-Pedersen A, Hvidt S, et al. Effect of nifedipine on digoxin kinetics in healthy subjects. Clin Pharmacol Ther 1982;32:562-565. 32. Pedersen KE, Madsen JL, Klitgaard NA, et al. Noninteraction between nifedipine and digoxin. Dan Mad Bull 1986; 33:109-110. 33. Koran G, Zylher-Katz E, Granit L, Levy M. Pharmacokinetie studies of nifedipine and digoxin coadministration. Int d Clin PharmacoI Ther Toxicol 1986;24:39-42. 34. Garty M, Shamir E, Ilfeld D, et aL Noninteraction of digoxin and nifedipine in cardiac patients. J Clin Pharmacot 1986;26:304-305. 35. Kleinbloesem CH, van Brummelen P, Hillers J. et al. Interaction between digoxin and nifedipine at steady state in patients with atrial fibrillation. Ther Drug Monit 1985; 7:372-376. 36. Benet LZ. Pharmacokinetics and metabolism of bepridil. Am d Cardiol 1985;55:8c-13c. 37. Elkayam U, Parikh K, Torkan B, et al. Effect of diltiazem on renal clearance and serum concentration of digoxin in patients with cardiac disease. Am d Cardio 1985;55:13931395. 38 Baden WE, Moore G, Sharma S, et al. No increase in serum digoxin concentration with high-dose diltiazem. Am J Mad 1986;81:425-428. 39. Schrager BR, Pina I, Frargi M, et al. Dilitazem-digoxin interaction (abstr). Circulation 1983;68(Suppl 3):368. 40. Oyama Y, Fujii S, Kandak, et al. Digoxin-diltiazem interaction. Am J Cardiol 1984;53:1480-1481. 41. Zatuchni J. Verapamil-digoxin interaction. Am Heart J I984;108:412-413. 42. Johnson BF, Wilson J, Marwaha R, et al. The comparative effects of verapamil and a new dihydropyridine calcimn channel blocker on digoxin pharmacokinetics. Clinical Pharmacol Ther 1987;42:66-71. 43. Keren G, Tapper D, Butler B, et al. Studies on the possible mechanisms of lidoflazine arrhythmogenicity. J Am Call Cardiol 1984;4:742-747. 44. Antman EM, Smith TW. Digitalis toxicity. Annu Rev Mad

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1985:36:357-367. 45. Jenkins LC, Scoates PJ. Anaesthetic implications of calcium channel blockers. Can Anaesth Soc J 1985;32:436-447. 46. Kounis NY. Asystole after verapamil and digoxin. BrJClin Pract 1980;34:57-58. 47. Peipho RW. Individualization of calcium en|ry-blocker dosage for systemic hypertension. Am J Cardiol 1985;56:105HIIIH. 48. Zieg[er R, Wingender W, Boehme K, et al. Study of phar-

macokinetic and pharmacodynamic interaction between nitrendipine and digoxin. J Cardiovasc Pharmacol 1987; 9:SI01-S105. 49. Ziegter R, Wingender W, Kuhlmam~ J. Influence of niso|dipine on plasma levels, renal excretion of beta-actyl-digoxin on ECG (abstr). Naunyn Schmiedeberg's Arch PharmacoI 1985;330:R77. 50. Metzantonakis. Discussion. J Cardiovasc Pharmacot 1987; 9:S105 -$106.