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PubMed2003

Pharmacokinetic study of the digoxin-acenocoumarol interaction in rabbits.

A study was carried out to evaluate the potential pharmacokinetic interaction between digoxin and acenocoumarol. The binding of digoxin to rabbit cardiac tissue homogenates was assessed in vitro, using the equilibrium dialysis technique. An increase in the first-order constant (p<0.05) and a reduction in the partition coefficient in the equilibrium situation (p<0.001) of digoxin were observed when the cardiac homogenates were previously treated with acenocoumarol. In the in vivo study, the kinetics of digoxin administered in single and multiple dosage regimens were compared in control rabbits and in rabbits treated simultaneously with acenocoumarol. Kinetic analysis of the results was performed using Non-linear Mixed Effects Modeling (NONMEM). In the presence of acenocoumarol, the population distribution volume (Vd) of digoxin was increased by 40-60%, no differences being found as regards the elimination clearance. Also, joint administration of both drugs led to a reduction in digoxin concentrations in the heart (p<0.01) at the end of the dosage regimen. Both sets of results point to the hypothesis of a hitherto unreported possible pharmacokinetic interaction between the two drugs affecting the distribution process. This interaction could lead to lower plasma digoxin levels, in view of the increased Vd, and a possible reduction in the therapeutic effect, owing to the decrease in affinity and in concentration in heart tissue.

Acenocoumarol↗
PubMed1981

Enhanced bioavailability of digoxin by gamma-cyclodextrin complexation.

Inclusion complex of digoxin with gamma-cyclodextrin (gamma-CyD) in 1:4 molar ratio was prepared, and its dissolution and absorption behaviors were compared with those of digoxin alone. The dissolution rate of digoxin in water was found to be markedly increased by gamma-CyD complexation. Bioavailability of digoxin following the oral administration of gamma-CyD complex to dogs was 5.4 times as much as that of digoxin alone. The present data did indicate improvement of dissolution and absorption characteristics of digoxin by inclusion complexation, suggesting the decrease in dose in oral digoxin therapy.

Animals↗
PubMed2002

Double-blind placebo-controlled trial of aprindine and digoxin for the prevention of symptomatic atrial fibrillation.

A multicenter, placebo-controlled, randomized, double-blind trial compared the preventive effect of aprindine and digoxin on the recurrence of atrial fibrillation (AF) with placebo, and also compare the effectiveness of these 2 drugs in the prevention of AF. Patients with symptomatic paroxysmal or persistent AF who had converted to sinus rhythm (SR) were randomly assigned aprindine (40 mg/day), digoxin (0.25 mg/day) or placebo and followed up on an outpatient basis every 2 weeks for 6 months. Of the 141 patients from 36 participating centers, 47 were given aprindine, 47 digoxin, and 47 were on placebo. After the 6-month follow-up, the Kaplan-Meier estimates of the percentage of patients remaining free of recurrent symptomatic AF on aprindine, digoxin and placebo were 33.3%, 29.2% and 21.5%, respectively. In patients remaining in SR for 15 days after from the start of follow-up, freedom from recurrence was significantly more prevalent in the aprindine group than in the placebo group (p=0.0414), but there was no significant difference between the digoxin and placebo groups. The rate of adverse events was similar in the 3 groups. In conclusion, neither aprindine nor digoxin had a significant effect on preventing relapse of symptomatic AF; however, recurrence of AF occurred later with aprindine than with placebo or digoxin.

Aged↗
PubMed1983

Superiority of oral verapamil therapy to digoxin in treatment of chronic atrial fibrillation.

The efficacy and safety of oral verapamil, 240 mg, with or without digoxin were studied in 52 patients with chronic atrial fibrillation at rest, and during mild and maximal exercise. Twenty-four patients were studied during the following therapeutic modalities: no therapy; digoxin, 0.25 mg and 0.5 mg daily; digoxin, 0.25 mg and verapamil; and verapamil alone. Heart rate at rest and during all levels of exercise was decreased significantly (p less than 0.005), either by combining digoxin with verapamil or by verapamil therapy alone. In contrast, the excessive heart rate response to exercise was not prevented by digoxin even with good serum concentrations. The improved control of heart rate with verapamil was associated with a significantly improved exercise capacity. Verapamil is an important and safe modality of treatment, with or without digoxin, in the long-term control of heart rate in chronic atrial fibrillation. It is superior to digoxin in controlling the ventricular rate and in improving exercise capacity.

Administration, Oral↗
PubMed1989

Reasons for intraindividual inconstancy of the digoxin saliva to serum concentration ratio.

When a constant dose of digoxin was administered orally over several days, the digoxin concentration in saliva and erythrocytes rose faster than in serum. Thus, the saliva/serum concentration ratio was below 1.0 after a single dose and above 1.0 in the steady state. The digoxin concentration was relatively high in "unstimulated" (more or less spontaneous) saliva and decreased with stimulation of the salivary flow rate. It therefore appeared that the actual salivary digoxin concentration depended on 2 components: the digoxin concentration in "stimulated" saliva depended only on the rapid diffusion from the blood into saliva, and the concentration in the "unstimulated" saliva depended on the rapid diffusion and on a slower exchange with the intracellular compartment. It is suggested that unstimulated saliva reflects the intracellular digoxin concentration and stimulated saliva reflects the free digoxin concentration of the serum. Both effects must be taken in account when interpreting the saliva/serum ratio, and they may explain conflicting results in the literature.

Digoxin↗
PubMed1990

Transplacental passage of digoxin in severe Rhesus immunization.

Maternal and umbilical vein digoxin concentrations were determined in 16 mothers and fetuses with severe Rhesus-D disease, eight with, and eight without prior digitalization of the mother, when umbilical cord puncture was performed for diagnosis and intrauterine blood transfusion. In the eight patients without digoxin treatment, the digoxin concentrations in both the mother and the umbilical vein were below the limit of detection (less than 0.3 nmol/l). In the other eight patients digitalization of the mother was started 24-48 hours before the first umbilical cord puncture. The maternal and umbilical vein digoxin concentrations were determined on 26 occasions. Except for two instances, digoxin concentrations in the umbilical vein were always below 1 nmol/l. The mean ratio of maternal to fetal digoxin concentrations before initial transfusion was 2.51 ( +/- ISD = 1.47) and before later transfusions 1.67 ( +/- ISD = 0.61). The differences in mean ratios between initial and later transfusions are not significant (p = 0.16). The mean ratio for the total group was 1.93 ( +/- ISD = 1.01). There was no correlation between the maternal to umbilical vein digoxin ratio and either gestational age or umbilical venous hematocrit. The results of our study indicate that the therapeutic effect of transplacental digitalization in severe Rhesus disease is questionable and that a multicentre randomized trial would be necessary to evaluate whether this treatment is of benefit.

Blood Transfusion, Intrauterine↗
PubMed1980

Reversal of digoxin-induced changes in erythrocyte electrolyte concentrations by penicillamine in children.

Previous reports from this laboratory have shown that penicillamine effectively reduces serum digoxin levels and is a clinically useful drug in correcting digoxin intoxication. To elucidate further the antidigitalis effects of penicillamine a prospective study was undertaken in 10 children aged 4--14 years with congestive heart failure. Plasma and intracellular erythrocyte concentrations of sodium, potassium, calcium as well as Na+/K+ and Na+/Ca++ ratios were measured before digitalization, 6 days after full digitalization while the patients were on maintenance doses of digoxin (0.02 mg/Kg/day, po, maximum 0.25 mg/day) and 6 hours after 1 Gm of oral penicillamine. After digitalization RBC Na+, Ca++, Na+/K+, and Na+/Ca++ increased, whereas RBC K+ levels decreased significantly. Administration of penicillamline not only reduced serum digoxin levels, but it also caused significant alterations in RBC electrolyte concentrations, toward pre-digoxin values. All values were significantly changed after penicillamine. Plasma and RBC magnesium levels were not altered significantly, neither after digitalization nor after penicillamine. It is concluded that in addition to RBC Na+ and K+ levels, intra-erythrocyte levels of calcium are sensitive indicators of digoxin effect; and that penicillamine reverses digoxin-induced RBC electrolyte alterations towards pre-digitalization values.

Adolescent↗
PubMed2006

Telithromycin-induced digoxin toxicity and electrocardiographic changes.

A 58-year-old woman who had been taking digoxin 0.25 mg/day for more than 35 years for heart palpitations after mitral valve repair was prescribed a 5-day course of telithromycin for acute bronchitis. On the sixth day of therapy, she came to the emergency department complaining of general malaise and having experienced three episodes of syncope over the previous 2 days. Laboratory analysis revealed elevated digoxin plasma levels, and electrocardiography showed several nonspecific repolarization anomalies. Telithromycin is known to increase digoxin plasma levels; however, the clinical significance of this interaction is not known. To our knowledge, this is the first report of elevated plasma digoxin levels associated with signs and symptoms of toxicity. This drug interaction-determined as probable according to the Naranjo adverse drug reaction probability scale-may be mediated by P-glycoprotein. By inhibiting the transport of digoxin by P-glycoprotein, telithromycin may have decreased digoxin elimination in the intestinal lumen and its renal tubular excretion, resulting in elevated plasma levels and drug toxicity. Clinicians should be aware of possible digoxin toxicity after concomitant administration with telithromycin, especially in patients who are at risk, such as those with electrolyte abnormalities and decreased renal function.

Acute Disease↗
PubMed2001

Population pharmacokinetics of digoxin in Japanese patients: a 2-compartment pharmacokinetic model.

OBJECTIVE: To clarify the observed variability of digoxin disposition by performing a population pharmacokinetic analysis in a Japanese population. DESIGN: Retrospective analysis of clinical pharmacokinetic data. PATIENTS AND PARTICIPANTS: Data were obtained from 106 patients with heart failure and atrial fibrillation (43 males and 63 females). METHODS: Digoxin concentrations in serum were measured by fluorescence polarisation immunoassay. Population pharmacokinetic analysis was performed using a 2-compartment open pharmacokinetic model with the computer program NONMEM. RESULTS: 246 serum concentrations were obtained. Final pharmacokinetic parameters were: CL (L/h) = (0.036 x TBW + 0.112 x CL(CR)) x 0.77SPI x 0.784CCB, V1 = 1.83 L/kg, V2 = 22.6 L/kg and Q = 0.629 L/h/kg, where CL is total body clearance, V1 and V2 are the apparent volumes of distribution in the central and peripheral compartments, Q is intercompartmental clearance, TBW is total bodyweight (in kg), CL(CR) is creatinine clearance (in ml/min), SPI = 1 for concomitant administration of spironolactone (and zero otherwise) and CCB = 1 for concomitant administration of calcium antagonists (and zero otherwise). Concomitant administration of digoxin and spironolactone resulted in a 23% decrease in digoxin clearance. Concomitant administration of digoxin and calcium antagonists (diltiazem, nicardipine, nifedipine or verapamil) resulted in a 21.6% decrease in digoxin clearance. CONCLUSIONS: The estimated population parameter values may assist clinicians in the individualisation of digoxin dosage regimens.

Cardiotonic Agents↗
PubMed1978

Current considerations in digoxin usage.

Basic considerations in biotransformation and pharmacodynamics are presented as a basis for understanding clinical usage. The role of polarity in determining a given glycoside's duration of action and extent of biotransformation is emphasized. The pharmacokinetics are summarized emphasizing the fact that digoxin is not completely absorbed by oral administration. The important relationship of serum digoxin levels to myocardial content and apparently to myocardial response is reviewed. This relationship and the development of precise methods for measurement of digoxin in serum provide the clinician with accurate means to assess myocardial tolerance for digoxin under diverse clinical circumstances. This review includes discussion of methods of digitalization, appropriate use of serum levels, apparent and real resistance to digoxin, and apparent and real sensitivity to digoxin. The limitations of serum levels as a precise guide to toxicity are analyzed. Finally, new developments in use of immunologic therapy for digoxin intoxication are presented.

Arrhythmias, Cardiac↗
PubMed1997

Digoxin and its related endogenous factors.

The digitalis drugs are plant-derived cardenolide compounds used medicinally for several hundred years. These drugs elicit inotropic and chronotropic effects on the heart, but they also affect many other tissues. The mechanism of action involves inhibition of the ion-transport activity of a membrane-associated protein called Na, K-ATPase (sodium pump). Present theory holds that the sodium pump is the principal molecular receptor for the digitalis drugs. Recent evidence indicates the presence of naturally occurring digitalis-like compounds in mammals. It is believed these compounds, collectively known as either digitalis-like (DLF) or ouabain-like (OLF) factors, may be endogenous hormones regulating the biological activity of the sodium pump and its isoforms. The presence of deglycosylated and other congeners of one specific DLF, the digoxin-like immunoreactive factor (DLIF), has very recently been described in humans. Digoxin as a drug is the most widely prescribed digitalis in the U.S., and its measurement in serum has established a model for present-day therapeutic drug monitoring (TDM). Historically, the accurate measurement of digoxin in blood has been difficult. This article focuses on the present understanding of the clinical use of digoxin, factors that affect the accuracy of measuring digoxin, the principle of measuring metabolically active species of digoxin, and the effects of DLIF and other interfering substances in digoxin immunoassay.

Biological Transport↗
PubMed1979

Digoxin acute intoxication: evaluation of the efficiency of charcoal hemoperfusion.

Since there is no widely used method of reducing the severity of massive digoxin intoxication, the capacity of hemoperfusion with coated, activated charcoal to remove digoxin was evaluated in a case of suicidal digoxin ingestion (25 mg). Seven hours after ingestion the digoxin plasma level was equal to 8.9 ng/ml. This was decreased to 4.5 ng/ml after 6 hr hemoperfusion. The amount of digoxin adsorbed by the column represents 4.8% of the absorbed dose. At a blood flow rate of 170 ml/min, the mean digoxin clearance by hemoperfusion was 44.5 +/- 26.9 ml/min. From these results we conclude that charcoal hemoperfusion in acute digoxin intoxication is of little value.

Adult↗
PubMed1992

Influence of assay methods on serum concentrations of digoxin during FAB fragment treatment.

The treatment of digoxin intoxication has been revolutionized by digoxin specific antibody fragments (Fab). Serum digoxin concentrations may be inaccurate after this treatment. We report a case of digoxin intoxication where the results of serum concentration determinations were strikingly disparate depending on the assay used. To investigate this discrepancy we compared serum samples spiked with digoxin from 0-50 ng/mL in the presence of increasing concentrations of digoxin specific Fab-fragments. Samples were measured using the Abbott TDx assay with and without ultrafiltration of the sample and the Dade-Stratus radial partition assay. The TDx assay was statistically reduced by the Fab-fragments although the magnitude of the effect was small. The radial partition assay was dramatically affected by the addition of Fab-fragments. The predicted non-Fab bound concentration correlated highly with the measured concentration. When samples were ultrafiltered prior to TDx assay, the measured concentration was dramatically depressed but the regression of predicted non-Fab bound concentration versus observed had a significantly lower slope than for the radial partition assay. We hypothesize that this difference is due to serum protein binding in addition to Fab-fragment binding. We conclude that the radial partition assay gives the best approximation of digoxin concentration remaining unbound to Fab-fragments. Ultrafiltration followed by TDx assay gives an acceptable approximation.

Antigen-Antibody Reactions↗
PubMed2002

Appropriateness of digoxin level monitoring.

AIM: To evaluate the proportion of inappropriate digoxin level determinations. METHODS: We performed a retrospective analysis of 210 randomly selected digoxin plasma level determinations in inpatients. Appropriateness criteria were defined combining existing criteria from the literature. The main outcome measure was the proportion of digoxin levels assessed as inappropriate using a priori defined criteria. RESULTS: Of the 210 digoxin levels assessed, 125 (59%; 95% confidence interval [CI] 52-66%) were considered inappropriate, 81 (39%; 95% CI: 32-45%) were appropriate, and 4 (2%) determinations could not be evaluated. Of the 125 levels assessed as inappropriate, the majority (79%) was performed as routine monitoring. Extrapolating the results to all digoxin level determinations in inpatients at our institution resulted in estimated yearly costs of CHF 28,025 (approximately B 18,995) for inappropriate digoxin level determinations. CONCLUSIONS: The majority of digoxin plasma levels determinations were assessed as inappropriate. This was mainly due to the lack of an adequate indication and due to incorrect timing of drawing the blood samples. With regard to indication, routine monitoring was the reason for the majority of levels assessed as inappropriate.

Aged↗
PubMed2003

Digoxin in heart failure and cardiac arrhythmias.

HEART FAILURE: Digoxin therapy has no effect on mortality in heart failure. Digoxin may be useful for maintaining clinical stability and exercise capacity in patients with symptomatic heart failure. Digoxin appears to be of most benefit in patients with severe heart failure, cardiomegaly and a third heart sound. Digoxin should be used as a second-line drug after diuretics, angiotensin-converting enzyme inhibitors and beta-blockers in patients with congestive heart failure who are in sinus rhythm. Digoxin should be used as a first-line drug in patients with congestive heart failure who are in atrial fibrillation. ARRHYTHMIAS: Digoxin has a limited, but useful, role, either alone or in combination with other agents such as beta-blockers, diltiazem or verapamil, in achieving satisfactory resting ventricular rate control in patients with chronic atrial fibrillation. In patients who lead a predominantly sedentary lifestyle (perhaps particularly in those who are elderly), digoxin alone may be the agent of choice.

Anti-Arrhythmia Agents↗
PubMed1998

The level of plasma neuroendocrine activity and the concentration of digoxin in the serum of patients with mild chronic heart failure.

The concentrations of adrenaline, noradrenaline, dopamine, aldosterone, the atrial natriuretic hormone, and plasma renin activity were investigated in 50 patients with mild chronic heart failure. The patients received oral digoxin chronically in a daily dose of 0.125 mg. On the basis of the estimate of the dosing of digoxin these patients were divided into two groups: the first with therapeutic and the second with subtherapeutic concentrations of digoxin in serum. The therapeutic concentration of digoxin in serum was found in 23 patients (46%), while subtherapeutic levels were found in 27 patients (54%). The concentrations of noradrenaline, dopamine, the renin activity of plasma, aldosterone and the atrial natriuretic hormone in the blood serum in the group of patients in whom the presence of subtherapeutic concentrations of digoxin was found, did not differ essentially from the concentration that was observed in the group with therapeutic concentrations. Only the concentration of adrenaline was higher (p < 0.05) in the group of patients with therapeutic concentrations of digoxin. The above results reveal that the neuroendocrine activity of plasma (except for the concentration of adrenaline) is alike in both ranges of digoxin concentrations in serum.

Aged↗
PubMed1999

Clopidogrel, a novel antiplatelet agent, and digoxin: absence of pharmacodynamic and pharmacokinetic interaction.

The safety, and the pharmacodynamic and pharmacokinetic compatibility of clopidogrel, 75 mg daily, with the cardiac glycoside digoxin, were assessed in 12 healthy male subjects who took digoxin 0.25 mg once daily for 20 days and, in addition, clopidogrel 75 mg once daily from day 11 to day 20, so as to achieve steady-state conditions with both drugs. The drugs were taken after an overnight fast, and a standardized breakfast was served 30 minutes later. Blood samples for digoxin determination were drawn pre-dose on days 1, 8, 9, 10, 18, 19, and 20 of the schedule, and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, and 24 hours post-dose on days 10 and 20. Urine samples were collected pre-dose and from 0-4, 4-8, 8-12, and 12-24 hours post-dose on days 10 and 20. Platelet aggregation studies were carried out using ADP at 5 micromol/L final concentration as an agonist. Establishment of steady-state plasma concentrations of digoxin on days 8-11 and 18-21 was confirmed by application of Dunnett's test on the trough plasma concentrations. The plasma pharmacokinetics and urinary excretions of digoxin for day 10 and day 20 were very similar: the day 20/day 10 ratios (90% Cl) were 1.1 (0.99; 1.24) for Cmax, 1.0 (0.92; 1.08) for Cmin, 1.02 (0.96; 1.07) for AUC(0-24), and 0.99 (0.94; 104) for urinary excretion. Mean inhibition of ADP-induced platelet aggregation at the end of the clopidogrel treatment period was 34%. The clinical, cardiac, and biological evidence from the study indicated that clopidogrel administration does not enhance digoxin's cardiac effects. Overall, the data indicated that there is no reason to anticipate an interaction when clopidogrel is added to digoxin for long-term management of patients with cardiac disease.

Adolescent↗
PubMed1978

[Electrophysiological effects of the combined administration of digoxin and propranolol in man].

The electrophysiological effects of the combined administration of digoxin and propranolol were studied in 40 patients, compared with the effects of digoxin alone and considered in relation to anomalies of the conduction pathways. The cycle of the sinus node was only lengthened by digoxin in patients who had an anomaly of sinus node function. In contrast the addition of propranolol always increased it (from 1 109 +/- 53 ms to 1 232 +/- 58 ms). Sinus node recovery time was only increased by combined administration (from 1 331 +/- 101 ms to 1 450 +/- 68 ms). Changes in sino-atrial conduction intervals were not very marked. The AH interval was increased by digoxin (from 97 +/- 4 ms to 109 +/- 6 ms), with propranolol exerting a synergistic effect (119 +/- 6 ms). When there was pre-existing supra-His block only combined administration increased the conduction defect. The HV interval and QRS duration were not altered. The effective atrial refractory period was increased by combined administration (from 264 +/- 10 ms to 304 +/- 14 ms) except in subjects who had supra-His block. The effective refractory period of the AV node (385 +/- 26 ms) was increased by digoxin (450 +/- 37 ms). This effect was potentiated by propranolol (478 +/- 34 ms) except in those subjects who had supra-His block. In three cases in which there were two conduction pathways at A V node level the refractory periods of the rapid and slow pathways were increased by digoxin, with a synergistic effect from propranolol. The ventriculo-atrial conduction time changed from 151 +/- 24 ms to 172 +/- 22 ms following digoxin, then to 193 +/- 34 ms after the addition of propranolol.

Adolescent↗