Increase In Serum Digoxin Concentration Research Articles

Digoxin Immune Fab Administration following an Unexplained Increase in Serum Digoxin Concentration

Objective: To report a case of digoxin immune Fab (DIF) administration following an unexplained increase in serum digoxin concentration in an asymptomatic patient with chronic renal failure. Case Summary: A 70-year-old man presented to the hospital with congestive heart failure, atrial fibrillation, chronic renal failure, and suspected digoxin toxicity. By day 3, he developed a more stable cardiac rhythm with nodal beats. His last known digoxin dose was 12 hours prior to admission. No explanation for an elevated serum digoxin concentration 48 hours after admission could be found. Despite absence of other signs of digoxin toxicity, DIF 80 mg iv was administered, and was immediately followed by 40 mg. Discussion: This case illustrates that elevated digoxin concentrations may be observed in patients with renal failure. These may not be true high concentrations because of the following potential factors: (1) the presence of digoxin-like factors, (2) increased biotransformation of digoxin, and (3) accumulation of metabolites that interfere with the assay. Digoxin metabolites are known to cross-react with the antibodies in commonly used digoxin immunoassays, and may be inappropriately interpreted to signal digoxin toxicity. Both the accuracy and reliability of digoxin immunoassay techniques have been questioned or challenged over the years. It is difficult to determine whether a reported toxic serum digoxin concentration represents the true concentration or cross-reactivity between digoxin metabolites and antibodies used in most digoxin immunoassays. Data Sources: Data collection sources included retrospective review of patient medical records, personal contact with one of the physicians involved in rendering patient care for interpretation of the electrocardiogram changes, clinical symptoms and rationale for DIF administration, and contact with the immunoassay technologist, who indicated that the fluorescence polarization immunoassay technique was used for analysis of digoxin concentrations. The medical literature then was reviewed. Conclusions: DIF should be reserved for use in symptomatic patients. Elevated digoxin concentrations must be evaluated for various factors that can cause falsely elevated values. Clinical signs and symptoms are critical in making the decision to use Fab. Antidotal measures should be based on correlation of patient symptoms with serum digoxin concentrations.

Pharmacokinetics of digoxin administered to horses with congestive heart failure

Summary Nine horses with (naturally acquired) congestive heart failure were treated with 2.2 μg of digoxin/kg of body weight by the Iv route, followed by 11 μg/kg administered orally every 12 hours thereafter. Furosemide was administered IV concurrently with IV administered digoxin every 12 hours. Serum concentration of digoxin was measured after the first (Iv) and seventh (orally administered) dose. After Iv administration, digoxin disposition was described by a 2-compartment model, with a rapid distribution phase (t1/2α = 0.17 hour), followed by a slower elimination phase (β = 0.096 ± 0.055 h−1, t1/2β = 7.2 hours, where β is the exponential term from the elimination phase of the concentration vs time curve). Bioavailability after oral administration was 21.2 ± 10.8%. After the seventh orally administered dose, serum concentration of digoxin peaked 1 to 2 hours later, and was 1.9 ± 0.7 ng/ml (mean ± sd). In 4 horses, a second increase in serum digoxin concentration was observed 4 to 8 hours after the initial peak, which possibly was evidence of enterohepatic recycling of the drug. Response to treatment included reduction in heart rate, peripheral edema, and pulmonary edema, but these could not be attributed to the digoxin alone because the horses were treated concurrently with furosemide.

Antiarrhythmic effect of lorcainide in patients taking digoxin.

To assess the antiarrhythmic effect of lorcainide and determine whether there is a pharmacokinetic interaction between lorcainide and digoxin, 12 patients with frequent premature ventricular depolarizations (PVDs) who were taking digoxin were treated with lorcainide. During a placebo period, serum digoxin concentration was measured for three days; plasma lorcainide concentration, a 12-lead electrocardiogram (ECG), and a 24-hour continuous ECG were measured on the day before the patients began lorcainide and repeated on days 3, 7, and 14 of treatment. Lorcainide was given 100 mg bid or 100 mg tid. Lorcainide did not suppress group mean PVDs per hour, pairs, or ventricular tachycardia. Only four patients (33%) responded with greater than or equal to 80% suppression of PVDs. Mean ejection fraction for responders was 46 +/- 6%, and for nonresponders it was 28 +/- 9% (P less than .01). There was no significant pharmacokinetic interaction between lorcainide and digoxin. Mean digoxin concentration did not change after lorcainide administration; two patients had greater than or equal to 50% increase in serum digoxin concentration. Patients with heart failure or reduced ejection fraction define a subset who have unpredictable effects from lorcainide, including a reduced antiarrhythmic effect.

Pharmacokinetic interaction study with ramipril and digoxin in healthy volunteers

Coadministration of captopril has been shown to increase serum digoxin concentration. The effects of ramipril, a new angiotensin converting enzyme inhibitor, on serum digoxin concentration after multiple dosing were studied in 12 healthy volunteers. All subjects were receiving steady-state digoxin medication (0.5 mg daily), and ramipril (5 mg daily) was coadministered for 14 days. Serum digoxin concentration was measured repeatedly before, during and up to 1 week after ramipril coadministration at 8 a.m. (trough values) and on selected trial days at 11 a.m., 3 hours after the morning medication. Simultaneously, blood levels of ramipril and its active metabolite diacid were determined. Volunteers were followed closely for side effects and for changes in blood pressure, heart rate and electrocardiogram. Safety pharmacology included serial determination of sodium, potassium, serum glutamic oxaloacetic transaminase, creatinine and a full blood count. Mean serum digoxin concentration was not significantly influenced by ramipril coadministration with trough levels of 0.90 ± 0.24 before, 0.93 ± 0.38 during and 0.82 ± 0.33 ng/ml after ramipril medication. The increase in serum digoxin concentration 3 hours after the morning dose was also not significantly affected by ramipril. Serum levels of ramipril and its diacid showed a wide range of variation. Mean serum potassium increased by 0.3 mmol/liter during ramipril coadministration with development of symptomless hyperkalemia (6.0 mmol/liter) in 1 subject. The only other side effect possibly related to ramipril was a dry cough in 1 subject. Both drugs were well tolerated. Ramipril showed no significant influence on serum digoxin levels in healthy volunteers.

No increase in serum digoxin concentration with high-dose diltiazem

The effect of incremental diltiazem dosing during concomitant digoxin administration over a four-week period in eight healthy adult volunteers (mean age, 28 ± 4 years) was studied. The study group received 0.25 mg of digoxin twice daily for two days, after which they received 0.25 mg daily for the duration of the study. Following baseline electrocardiographic evaluation and measurement of trough digoxin levels, all subjects received 120 mg of diltiazem daily for one week, then 240 mg daily for one week, followed by 360 mg daily for one week. Resting electrocardiographic parameters (heart rate, P-R interval), renal function, electrolyte values, and digoxin and diltiazem concentrations were measured weekly. Daily administration of 360 mg of diltiazem plus 0.25 mg of digoxin resulted in a significant decrease in heart rate (from 68 ± 9 beats per minute to 61 ± 10 beats per minute; p <0.05), a marginal increase in P-R interval (from 169 ± 22 msec to 179 ± 21 msec; p = 0.08), and no significant change in trough serum digoxin concentration (from 0.85 ± 0.08 ng/ml to 0.90 ± 0.08 ng/ml; p = NS). The administration of up to 360 mg of diltiazem per day with 0.25 mg of digoxin per day was not associated with significant increases in serum digoxin concentrations in healthy subjects.

Lack of effects of diltiazem on digoxin pharmacokinetics.

Diltiazem is a member of a class of pharmacologic agents that block the passage of calcium ions across cell membranes, the calcium‐channel blockers. Several investigators have reported a clinically important pharmacokinetic and pharmacologic interaction between digoxin and verapamil.1–4 Despite earlier suggestions of such an interaction with nifedipine, recent works have convincingly shown that no pharmacokinetic changes occur.5–7 Thus, it appears that nifedipine has no clinically significant interaction with digoxin. Similar work has been limited with diltiazem. A recent investigation by Yoshida and associates,8 suggested no increase in digoxin serum concentration and a slight decrease in renal digoxin clearance after diltiazem had been added versus a control period. Rameis and co‐workers9 recently reported a 22.4% increase in serum digoxin concentration when diltiazem was added. The purpose of this study was to further evaluate this potential interaction.

Digoxin and nifedipine

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 digoxin 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-nifedipine interaction, several subsequent studies have shown no significant 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.

Myocardial monovalent cation transport during the quinidine-digoxin interaction in dogs.

To study the relationship of the serum digoxin concentration to the digoxin effect on monovalent cation transport during the quinidine-digoxin interaction, we used radiolabeled rubidium to measure monovalent cation active transport in myocardial biopsy samples from dogs. In a preliminary study, we showed that quinidine did not affect rubidium uptake by myocardial samples from intact dogs. Then, we studied four groups, each consisting of 13 dogs, which received either saline, low dose digoxin, high dose digoxin, or low dose digoxin plus quinidine treatment. In these groups of dogs, the following steady state serum digoxin concentrations were achieved: saline-treated, 0 ng/ml; low dose digoxin, 1.2 +/- 0.2 ng/ml (mean +/- SD); high dose digoxin, 2.4 +/- 0.4 ng/ml; and low-dose digoxin plus quinidine treated, 2.3 +/- 1.1 ng/ml. Compared to control values, rubidium uptake was decreased by 17% in dogs treated with low dose digoxin (P less than 0.05) and by 38% in dogs treated with high dose digoxin (P less than 0.01 vs. saline-treated, P less than 0.01 vs. low dose digoxin). Although low dose digoxin plus quinidine-treated dogs had the same mean serum digoxin concentration as the high dose digoxin-treated dogs, rubidium uptake in low dose digoxin plus quinidine-treated dogs was decreased by only 17% compared to control (P less than 0.05 vs. saline-treated, (P less than 0.01 vs. high dose digoxin). During the quinidine-digoxin interaction in the intact dog, the reduction in myocardial rubidium uptake is less than expected from the increase in serum digoxin concentration.

Digoxin-Verapamil Interaction

Recent studies have shown a significant increase in plasma digoxin concentration during verapamil treatment. This phenomenon has been attributed in part to reduced renal clearance of digoxin owing to inhibition of the digoxin tubular secretory process. We studied the influence of digoxin-verapamil interaction on [125I]digoxin uptake by various rat tissues in vitro, employing the tissue slice technique. Slice/medium digoxin ratios (mean +/- SD) were: kidney, 4.09 +/- 0.60; heart, 3.63 +/- 0.41; liver, 3.93 +/- 0.39; and muscle, 3.55 +/- 0.55. Addition of verapamil to the incubation medium resulted in a 15.6% reduction of digoxin uptake by kidney tissue, to 3.38 +/- 0.49 (p less than 0.0005). Verapamil failed to reduce digoxin uptake in liver, heart, or striated muscle. We conclude that the renal cortical transport mechanism of digoxin may be inhibited by verapamil. In contrast, the unaffected uptake of digoxin in heart or muscle indicates that the increase in serum digoxin concentration in the presence of verapamil is not caused or accompanied by redistribution of digoxin from the heart or striated muscle.

Quinidine and Digoxin An Important Interaction

An increase in serum digoxin concentration occurs in 90% of patients given quinidine. On average, the serum digoxin doubles during treatment with therapeutic doses of quinidine. Almost every patient treated with quinidine will have a decrease in the renal clearance of digoxin and many will have a decrease in the volume of distribution of digoxin. Whether changes in the inotropic effect of digoxin occur during concurrent quinidine administration is an unsettled area. However, gastrointestinal and cardiac toxicity, which closely resemble digitalis toxicity, often occur when quinidine causes the serum digoxin concentration to rise. These effects subside when the digoxin dose is reduced. Therefore it is prudent to monitor serum digoxin concentrations during concomitant quinidine treatment and to adjust the digoxin dose according to the results. When the toxicity is severe or dose adjustment is difficult, another antiarrhythmic drug should be selected.

Quinidine-digoxin interaction: evidence for involvement of an extrarenal mechanism.

The influence of quinidine 750mg per day for one week on serum digoxin concentration (SDC) was evaluated in digitalized anuric patients on chronic haemodialysis. During quinidine administration the SDC increased markedly, from 0.84 +/- 0.37 to 1.58 +/- 0.72 ng/ml (p less than 0.01), a comparable effect ot that reported previously in patients with normal renal function. Neither in vitro nor in vivo did quinidine alter the serum protein binding of digoxin. The increase in SDC in anuric patients indicates a decrease in the extrarenal clearance of digoxin, which means that mechanisms other than of renal origin are also involved in the interaction of quinidine and digoxin. There was great interindividual variability in the extent of the quinidine-induced rise in SDC. Regardless of the state of renal function, careful monitoring of digitalized patients seems mandatory once quinidine treatment is initiated.

Quinidine-digoxin interaction: effect of quinidine on 86Rb-uptake of human erythrocytes.

Co-administration of quinidine results in a marked increase in serum digoxin concentration (SDC). The implication of this increase in SDC in regard to an increased digoxin effect on the heart is controversial. The 86Rb-erythrocyte-assay represents a perfect model to study whether quinidine interferes with digoxin at the Na-K-ATPase (the so called glycoside receptor) and thus presumably with the inotropic effect of the glycoside. The inhibitory effect of digoxin (0-150 ng/ml) on the 86Rb-uptake was measured in the absence and presence of quinidine in therapeutic or higher concentrations (0-60 microgram/ml). Addition of quinidine produced no effect on digoxin-induced inhibition of Na-K-ATPase activity. Together with our clinical observations these results strongly suggest that the increased SDC during concomitant quinidine therapy actually reflects an increased digoxin effect on the heart.

Further insights into digoxin-quinidine interaction: Lack of correlation between serum digoxin concentration and inotropic state of the heart

The digoxin-quinidine interaction was studied in nine healthy human subjects aged 26 to 31 years. A single oral dose (400 mg) of quinidine sulfate administered to subjects taking digoxin resulted in a mean (± standard error of the mean) increase within 1 to 6 hours in the serum digoxin concentration of 0.12 ± 0.01 ng/ ml (p <0.0001), an increase of 21 percent. Continued quinidine administration for 24 hours resulted in a 59 percent increase in the mean serum digoxin concentration from 0.68 ± 0.04 to 1.04 ± 0.06 ng/ ml (alpha = 0.05). At the same time, however, systolic time intervals demonstrated a lengthening of the mean left ventricular ejection time index from 406 ± 4 to 419 ± 2 ms (alpha = 0.05) and the mean Q−S 2 Index from 524 ± 6 to 532 ± 7 ms (difference not significant [NS]). When compared with the shortening of these intervals predicted from the digoxin dose-response curve if digoxin were the only variable, the lengthening actually observed for both intervals was highly significant. The negative inotropic effect of quinidine administration alone was assessed with systolic time intervals in four subjects. The left ventricular ejection time index lengthened from 419 ± 3 to 425 ± 6 ms (NS) and the Q−S 2 index from 541 ± 6 to 550 ± 7 ms (NS). Therefore, the lengthening of these intervals in subjects taking digitalis after the addition of quinidine represents more than just the negative inotropic effect of quinidine, and occurs despite the increase in serum digoxin concentration. The results of this study support the view that quinidine displaces digoxin from tissue-binding sites as a major mechanism of the interaction. Furthermore, it appears that quinidine may specifically displace digoxin from cardiac-binding sites. These results raise important questions concerning the recommendation to reduce the maintenance digoxin dose when concomitant quinidine therapy is initiated.

Effects of selected drugs on serum digoxin concentration in dogs

The effects of quinidine, quinine, aspirin, ibuprofen, indomethacin and acetaminophen on steady state serum digoxin concentrations and total body digoxin clearance were studied in an animal model designed to simulate closely the clinical use of these drugs. When administered concurrently with digoxin, all of these drugs, with the exception of acetaminophen, caused a significant increase in serum digoxin concentration. Serum digoxin concentration was elevated (p <0.05) from 1.0 ± 0.14 to 2.06 ± 0.32 ng/ml with quinidine, from 0.70 ± 0.10 to 1.28 ± 0.20 ng/ml with quinine, from 1.12 ± 0.15 to 2.58 ± 0.24 ng/ml with aspirin, from 0.76 ± 0.08 to 1.1 ± 0.16 ng/ ml with indomethacin and from 0.90 ± 0.16 to 3.5 ± 0.65 ng/ ml with the largest dose of ibuprofen studied. Serum creatinine concentration was not elevated by administration of any of these drugs. The effects of aspirin and ibuprofen on serum digoxin concentration were directly related to the serum concentration of these drugs. The elevation in serum digoxin concentration produced by these drugs was due, at least in part, to a reduction in digoxin clearance. Digoxin clearance in the absence of any other treatment was 531 ± 34 ml/h per kg and was reduced ( p <0.05) to 352 ± 31,348 ± 39,462 ± 52 and 317 ± 56 ml/ h per kg by quinidine, quinine, aspirin and ibuprofen, respectively. Acetaminophen did not significantly alter the clearance of digoxin. These results clearly demonstrate that several commonly used drugs when administered concurrently with digoxin are capable of significantly elevating serum digoxin concentrations and thus may have the potential to increase the toxicity of this widely used cardiac glycoside. A drug-induced reduction in digoxin clearance appears likely to play an important role in increasing the serum digoxin concentration. Although these findings require confirmation in human beings, they suggest that caution should be used in administering large doses of nonsteroidal antiinflammatory drugs in conjunction with cardiac glycosides.

Enhanced Cardiac Effect of Digoxin During Quinidine Treatment

Quinidine causes an increase in the serum digoxin concentration. Three patients were studied to determine if the increase in serum concentration is paralleled by an increase in the cardiac effect of digoxin. Each patient's clinical condition and serum digoxin concentration were stable when quinidine administration was begun. In all three patients, serum digoxin concentrations increased significantly after beginning quinidine, and decreased when quinidine was discontinued. While taking quinidine, all three patients had ECG findings that suggested enhanced digitalis effect and one patient had clinical evidence of an increased hemodynamic effect. These effects paralleled the increases in serum digoxin concentration. Our findings suggest that the increase in serum digoxin concentration, which occurs after beginning quinidine, is associated with an increase in the effect of digoxin on the heart.