The influence of verapamil on serum digoxin concentration.

Abstract

SUMMARY The -effect of verapamil on the pharmacokinetics of digoxin was studied in 49 patients with chronic atrial fibrillation. A dose of 240 mg/day of verapamil was given to the patients who were receiving a stable dose of digoxin.Serum digoxin levels rose from 0.76 i 0.54 ng/ml (mean ± SD) to 1.31 ± 0.54 ng/ml during verapamil treatment (p < 0.0005). This effect was dose-dependent, as shown in seven subjects who received 160 mg and then, 240 mg of verapamil: There was a stepwise rise in serum digoxin concentration from a control value of 0.60 ± 0.11 ng/ml to 0.84 ± 0.18 ng/ml and 1.24 ± 0.40 ng/ml, respectively (p < 0.01 for both steps). The effect of verapamil developed gradually within the first few days in seven subjects in whom serum digoxin concentration reached, within 7 days, 90% of the increase observed 14 days after onset of verapamil. Renal digoxin clearance decreased significantly (26.1 i 9.7 vs 55.1 ± 12.3 ml/min,p < 0.005) in six patients in whom serum digoxin concentration increased. It did not change in one patient in whom serum digoxin concentration was not influenced by verapamil. Creatinine clearance did not change in any of these seven. The same effects on digoxin clearance were observed in three normal subjects. Among the 49 patients, verapamil resulted in the development of signs and symptoms that suggested digitalis toxicity in seven.Verapamil significantly increases serum digoxin concentration. The process is dose-dependent and gradual, and it is at least partially explained by reduced renal excretion without reduction in glomerular filtration. The dose of digoxin may need readjustment in patients who are concomitantly receiving verapamil.VERAPAMIL, a calcium antagonist, is an effective antiarrhythmic agent.' It also appears to be useful in other clinical settings.", 8I" Many of the patients who receive verapamil are also treated with digitalis. Since various drugs affect the serum digoxin concentration and clearance, 6121 we tested the effect of verapamil on the pharmacokinetics of digoxin in a consecutive series of 49 patients who were taking digoxin as treatment of chronic atrial fibrillation.22 Methods SubjectsThe study included 49 patients (20 men and 29 women), ages 30-78 years (mean ± SD 61 ± 9.6 years), who were taking a daily maintenance dose of 0.25 mg of digoxin (manufactured by Teva Group, Inc.; bioavailability of this brand equals that of Lanoxin23) for chronic atrial fibrillation. The dose of digoxin had remained unchanged for at least 2 months before the study. The diagnosis of the patients and their functional capacity are listed in tables 1 and 2. Main ProtocolThe main protocol of the study is illustrated in figure 1. The patient took the daily digoxin dose between 8 p.m. and 9 p.m. The blood samples for serum digoxin concentration were always drawn during the next morning, 12-14 hours after ingestion of digoxin. When the patients were receiving verapamil, the morning dose of verapamil was taken between 6 a.m. and 7 a.m. All other medications, such as diuretics, vasodil...

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

“…Although the actual molecular details of these interactions are currently unknown, the drug has been shown to inhibit the ATPase activity of a second drug by competitive, non-competitive and allosteric mechanisms in an in vitro study [30]. Verapamil has also been shown to inhibit cardiovascular drug transport by human Pgp in vivo [4,31,32].…”

The drug treatment of atrial fibrillation.

“…Overall heart rate variability (maximum heart rate -minimum heart rate) is thereby reduced by combining digoxin and verapamil treatment. This pharmacodynamic interaction is associated with a pharmacokinetic interaction in that the addition of oral verapamil causes a significant increase in digoxin blood level because of lowered renal clearance (Klein et al, 1982;Schwartz et al, 1982). In most clinical situations this interaction is unimportant and will not produce digoxin toxicity because most patients are taking doses of digoxin which give low serum levels-indeed arbitrarily doubling the dose failed to produce toxic symptoms in two studies (Channer et al, 1987;Lang et al, 1983) although follow up was short.…”

Iii. Digitalis in the Elderly

“…Treatment with quinidine may increase digoxin levels by as much as 1 0 0~o , perhaps by alteration of tissue binding (23). Verapamil decreases renal digoxin clearance and hence increases digoxin plasma levels (24). Antibiotic treatment alters the bacterial flora of the large bowel, and, in a proportion of patients, increases the amount of digoxin absorbed (25).…”