Abnormal quinidine binding in arrest survivors
11. Kessler KM, Ho-Tung P, Steele B, Silver J, Pickoff A Narayanan S, Myerburg RJ: Simultaneous quantitation 01 quinidine, procainamide, and N-acetylprocainamide in serum by gas-liquid chromatography with a nitrogen-phosphorus selective detector. Clin Chem 28:1187, 1982. 12. Kessler KM, Lowenthal DT, Warner H, Gibson T, Briggs W, Reidenberg MM: Quinidine elimination in patients with congestive heart failure or poor renal function. N Engl J Med 290:206, 1974. 13. Snedecor GW, Cochran WG: Statistical methods. Ames, Iowa, 1967, Iowa State University Press. 14. Routledge PA, Stargel WW, Wagner GS, Shand DG: Increased alpha-l-acid glycoprotein and lidocaine disposition in myocardial infarction. Ann Intern Med 93:701, 1980. 15. Edwards DJ, Lalka D, Cerra F, Slaughter RL: Alpha-l-acid glycoprotein concentration and protein binding in trauma. Clin Pharmacol Ther 31:62, 1982. 16. Piafsky KM, Borga 0, Odar-Cederlof I, Johansson C, Sjoqvist
F: Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma alpha-l-acid glycoprotein. N. Engl J Med 299:1435, 1978. DeLeve LD, Piafsky KM: Pharmacokinetic consequences of variations in plasma propranolol binding due to rheumatoid arthritis. Clin Pharmacol Ther 29:239, 1981. Koch-Weser J, Sellers EM: Drug therapy-binding of drugs to serum albumin. N Engl J Med 294:311, 1976. Conrad KA, Molk BL, Chidsey CA: Pharmacokinetic studies of quinidine in patients with arrhythmias. Circulation 5&l, 1977. Myerburg RJ, Kessler KM, Kiem I, Pefkaros KC, Conde CA, Cooper D, Castellanos A: The relationship between plasma levels of procainamide, suppression of premature ventricular contractions and prevention of recurrent ventricular tachycardia. Circulation 84:280, 1981.
The effect of nifedipine on serum digoxin concentrations in patients Drug interactions with digoxin are being increasingly recognized. Some calcium antagonists have been shown to alter digoxin kinetics and changes in digoxin dosage have been recommended. To determine whether nifedipine affects serum digoxin concentrations in patients during combined drug administration, serum digoxin concentrations were determined before and during concomitant drug administration in 14 cardiac patients. The mean (-t-SD) digoxin concentration was 0.92 f 0.5 rig/ml before and 0.96 + 0.5 rig/ml after 4 days of nifedipine therapy in eight inpatients. For the group of 14 patients, the mean level was 0.78 & 0.4 rig/ml before nifedipine and 0.8 i- 0.4 rig/ml after 1 week of combined drug administration, and 0.84 ?C 0.5 rig/ml after 2 weeks of combined drug administration. These data suggest that nifedipine does not significantly alter serum digoxin concentrations in cardiac patients receiving combined digoxin and nifedipine in the clinical setting. (AM HEART J 107:669, 1984.)
Janice B. Schwartz, M.D., Albert Raizner, Houston,
M.D., and Susan Akers, R.N.
Since the initial reports of an interaction between digoxin and quinidine during clinical coadministration,‘e5 drug interactions with digoxin have been increasingly recognized.6 Although an initial report of combined verapamil and digoxin administration
the Department of Internal Medicine, Section of Cardiology, Section of Clinical Pharmacology-Hypertension, Baylor College of Medicine. Supported in part by a Faculty Development Award in Clinical Pharmacology of the Pharmaceutical Manufacturers Association Foundation, Inc.
(Dr Schwartz). Received Reprint College
requests: Janice B. Schwartz, M.D., Section of Cardiology, of Medicine, 6565 Fannin, MSF 905, Houston, TX 77030.
failed to show any significant effect on digoxin concentrations,3 a number of subsequent studies have demonstrated a verapamil-induced decrease in renal and extrarenal digoxin clearance, which results in an almost twofold elevation of the serum digoxin concentration.?-‘* This finding has been constant whether the study population has been normal volunteers or patients. In the first study of the combined use of nifedipine and digoxin in normal volunteers,*3 a 45% increase in steady-state plasma digoxin concentrations was reported after a f-week period. In a more recent study in healthy subjects, oral nifedipine had no effect on digoxin kinetics following a single intravenous dose of digoxin.14 669
Raizner, and Akers
characteristics Cardiac disease
CAD S/F CABG S/F MI
CAD S/P CABG SIP MI
Hypertension, adult onset diabetes, peripheral vascular disease
CAD S/P CABG S/F MI
CAD SIP CABG SIP MI
COPD, adult onset diabetes
CAD SIP CABG
Carotid vascular disease
CAD SIP MI CAD SIP MI SIP CABG CAD S/P MI
Furosemide 60 mg/day Isosorbide dinitrate 15 mg/day Levothyroxine 0.1 mg/day KC1 20 mEq/day Furosemide 80 mg/day Isosorbide dinitrate 30 mg/day Nitroglycerin ointment 1%” hs Metoprolol 150 mg/day Acetohexamide 250 mg/day Oxazepam 120 mg/day Docusate sodium 200 mg/day Lorazepam 1 mg hs Hydrochlorothiazide 100 mg/day Isosorbide dinitrate 80 mg/day Nitroglycerin ointment 4”lday Propranolol 80 mg/day Hydrochlorothiazide 25 mg/day Isosorbide dinitrate 80 mglday Nitroglycerin ointment 1 ‘/z’ hs Metoprolol 100 mg/day Isosorbide dinitrate 10 mg/day Nitroglycerin ointment 1 ‘/z * hs Propranolol 120 mg/day Dipyridamole 100 mg/day Isosorbide dinitrate 60 mg/day Nitroglycerin ointment 4”lday Isosorbide dinitrate 90 mg/day Propranolol 80 mg/day Prazosin 3 mglday Furosemide 40 mg/day Isosorbide dinitrate 160 mg/day Nitroglycerin ointment 6”/day KC1 20 mEq/day Propranolol 40 mg/day
Abbreviations: CABG = coronary artery bypass graft; CAD = coronary artery disease; CHF = congestive pulmonary disease; hs = at bedtime; MI = myocardial infarction; S/p = status post.
Because of the apparently varying effects of the calcium antagonists on digoxin metabolism and clearance in normal subjects, and because there has been no previous available data regarding patients receiving nifedipine and digoxin in the clinical setting, we report the results of the following study to determine the effect of oral nifedipine on serum digoxin concentrations in patients during combined drug administration. METHODS Patient population. Our study population was comprised of 14 patients (10 male and 4 female, ages 49 to 75 years, mean 64.1 * 8.4 [X + SD]). Eleven were inpatients and three were outpatients when nifedipine therapy was instituted. All patients had received chronic oral digoxin and had stable digoxin doses prior to entry into the study.
Nifedipine dose (mglda y)
The chronic dose of digoxin was 0.25 mg per day in 13 of the patients and 0.375 mg per day in one of the patients. The clinical indication for nifedipine therapy was coronary artery disease in 13 and hypertension in one patient. Additional patient characteristics are presented in Table I. Patients took numerous concomitant medications. All patients received long-acting nitrates and the majority received beta-blockers and diuretics (Table I). Study protocol. All patients gave written informed consent to the protocol, which had been approved by the Institutional Review Boards of the Baylor College of Medicine and the Methodist Hospital. Following entry into the study, trough (immediately prior to the daily dose) serum concentrations of digoxin were measured prior to nifedipine therapy, daily until hospital discharge in the inpatients, and after 1 and 2 weeks of chronic oral nifedipine therapy. The dosages of concomitant medications (Table I) were held constant with the exception of
effects on serum digoxin
Table Putient No.
CAD SIP MI SIP CABG
Diabetes, colon PolYPa
S/P Hepatitis, degenerative arthritis
CAD S/P MI S/P CABG
CAD SIP MI
Chronic urinary tract infection
Furosemide 40 mg/day Isosorbide dinitrate 60 mg/day Hydralazine 50 mg/day KC1 20 mEq/day Timolol (optic) Hydrochlorothiazide 50 mg/day (Furosemide x 3 days) Isosorbide dinitrate Metoprolol 50 mg/day Prazosin 6 mg/day Insulin 40 U/day KC1 20 mEq/day Furosemide 40 mg/day Isosorbide dinitrate 60 mg/day KC1 40 mEq/day Indomethacin 50 mg/day Methocarbamol5OOmg/day Hydrochlorothiazide 50 mg/day Isosorbide dinitrate 160 mg/day Nitroglycerin ointment 2” hs Propranolol 160 mg/day Furosemide 40 mg/day Isosorbide 40 mg/day Nitroglycerin ointment 3”/day Propranolol 40 mg/day Furosemide 40 mg/day Isosorbide dinitrate 180 mg/day KC1 40 mEq/day Penicillin 2 gm/day
Nifedipine dose (mglday)
data. Daily serum digoxin concentrations before and for at least 4 days after the initiation of nifedipine therapy were measured in
tion for these eight patients prior to the initiation of nifedipine therapy was 0.92 + 0.5 rig/ml (X + SD). The serum digoxin concentration was essentially unchanged after 1, 2, 3, and 4 days of combined nifedipine plus digoxin therapy (Fig. 1). The mean serum digoxin concentration after 4 days of combined therapy was 0.96 + 0.5 rig/ml (Z f SD). An analysis of the data points in individual patients showed changes in three patients. In one patient a transient rise in the serum digoxin concentration was seen at 3 days of combined therapy but had returned to the baseline pre-nifedipine level after 2 weeks of combined therapy (patient No. 1, Table I). In the second patient the serum digoxin concentration rose at the time of an increase in serum creatinine following vigorous diuresis and 5 days of combined therapy. When the serum creatinine returned to baseline levels, the serum digoxin concentration returned to the baseline pre-nifedipine levels despite 9 days of combined therapy. A third patient demonstrated a change over time in the serum digoxin concentration, but was excluded from
eight patients. The mean serum digoxin concentra-
group analysis. In this patient (Fig. 2) serum digoxin
one patient in whom diuretics were used intermittently and in one patient (excluded from group data analysis) who received quinidine for 5 days. Nitroglycerin was also used as required for chest pain and was consumed in variable amounts. Nifedipine was administered in an initial dose of 30 mg per day (10 mg orally thrice daily) and wastitrated to a favorable clinical responseor clinical tolerance. The mean dose was 41 f 15 mg/day (X +- SD, range 30 to 60 mglday). Serum drug assay. Five milliliters of blood were drawn to determine serum digoxin concentrations at the same time of day (trough) at each testing point. Digoxin determinations were made by radioimmunoassay. Statistical analysis. Changes in measurementsover time were analyzed using the Friedman nonpsrsmetric analysis of variance with multiple comparisons.i5 Values are given as the mean plus or minus the standard devia-
tion. RESULTS lnhospital
Fig. 1. Serum digoxin concentrations (mean ? SD) for eight hospitalized patients before and during the first 4 days of nifedipine coadministration.
Fig. 2. Serum digoxin concentrations in one patient before and during nifedipine coadministration. The addition of quinidine on day 4 resulted in an almost twofold elevation of digoxin concentration over the next 5 days.
concentrations were stable prior to the initiation of nifedipine therapy and during the first 4 days of combined digoxin and nifedipine therapy. When quinidine was added on the fifth day of combined drug therapy, however, a steady rise in the serum digoxin concentration over the ensuing 5 days was seen. The quinidine administration was associated with a rise in the serum digoxin concentration from 0.6 to 1.1 rig/ml. Outpatient data. The mean serum digoxin concentration for the entire group of 14 patients was 0.78 + 0.4 rig/ml (X f SD) prior to the initiation of nifedipine therapy. After 1 and 2 weeks of combined digoxin and nifedipine administration, there was no significant change in the serum digoxin concentration, with the mean level for the group of 0.64 + 0.5 rig/ml after 2 weeks of combined therapy (Fig. 3). DISCUSSION Absence of nifedipine effect. Our study indicates that nifedipine has no influence on serum digoxin concentrations in patients receiving combined nifedipine and digoxin therapy in the clinical setting
TIME Fig. 3. Serum digoxin concentrations (mean k SD) for all 14 patients before and after 1 and 2 weeks of nifedipine coadministration.
with the presence of other cardiovascular medications. Statistical analysis reveals that this statement can be made with a greater than 90% certainty of detecting an effect greater than or equal to 20%. Presence of verapamil effect. The influence of another calcium antagonist, verapamil, on serum digoxin concentrations has been investigated in several categories of cardiac patients receiving digoxin and verapamil in the clinical setting.7-10~12 Concomitant medications have included diuretics but are not reported to have included nitrates or &blockers.1o Verapamil induced consistent increases in the serum digoxin concentrations, with an approximate twofold increase after 1 to 2 weeks of combined drug administration. Elevated digoxin concentrations were maintained throughout the periods of combined therapy. These findings are in concordance with that of Pedersen et al.,” who have demonstrated that verapamil induces a 35% decrease in the total body clearance of digoxin, due to impairment of both renal and extrarenal digoxin elimination. The decrease in renal clearance is postulated to be due to a reduction in the renal tubular secretion of digoxin. Verapamil and nifedipine are structurally quite different and have been shown to have varying effects on hemodynamics and on electrophysiologic parameters in humans despite falling within the calcium antagonist classification schema for drugs. Therefore it is not unreasonable to anticipate differing effects on digoxin clearance. Previous nifedipine studies. The data with nifedipine and digoxin in normal subjects are conflicting. Belz et al.13 showed a 45% increase in steady-state serum digoxin concentrations during nifedipine dosing of 10 mg orally thrice daily in combination with
digoxin dosing of 0.125 mg orally thrice daily (from 0.5 f 0.16 to 0.73 + 0.23 rig/ml, E f SD). The effects of placebo, verapamil, and nifedipine were studied in the same 12 normal subjects using a modified Latin square design. Whereas increases in digoxin concentrations were seen in 12 of 12 volunteers during verapamil plus digoxin administration, rises in the serum digoxin concentration were noted by Belz et all3 in only 9 of the 12 normal subjects during combined nifedipine and digoxin. Pedersen et al. have reported more detailed analyses of digoxin clearance in healthy volunteers during verapamil” and during nifedipine14 administration. They documented verapamil-induced decreases in digoxin clearance secondary to changes in the volume of distribution and renal clearance. In conflict with the findings of Belz et al., they found that nifedipine had no influence on renal digoxin or creatinine clearance but increased the extrarenal clearance of digoxin. Significantly, they observed no changes in the biologic half-life of digoxin or the distribution volume of digoxin during nifedipine dosing. No obvious explanation was offered for the differences between these findings14 and those of Belz et all3 Conclusions. Our findings are in agreement with those of Pedersen et a1.14We observed no significant alteration in serum digoxin concentrations when nifedipine was administered to patients with cardiovascular disease in combination with digoxin therapy. Our study, like that of Pedersen et al.,14 supports the hypothesis that verapamil and nifedipine have very different effects on digoxin kinetics in humans. More importantly, our study suggests that nifedipine and verapamil have very differing effects in the cardiac patient receiving digoxin. It therefore appears unlikely that changes in serum digoxin concentrations will occur or that alterations of digoxin dosages will be necessary upon the initiation of nifedipine in cardiac patients. Good clinical judgement dictates, however, that at the initiation of any new medication in the cardiac patient, he or she should be assessed for potential changes in
Nifedipine effects on serum digorin concentrations
physiologic status, drug interactions, drug toxicity, and adverse as well as beneficial effects. The authors thank Judy Cox, and Barbara Bond for secretarial
Ph.D., for statistical assistance.
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