Elimination Half-life Of Digoxin Research Articles

Modification of the inotropic effect of digoxin by diazepam in rat left atria.

There is a pharmacokinetic interaction between digoxin and diazepam that increases the elimination half-life of digoxin. It may be due to a reduction of digoxin tissue concentrations and to an enhanced effect of diazepam on digoxin binding to plasma albumin. Diazepam (10(-5) M) also induces a positive inotropic effect in guinea-pig isolated atria. In a study of a possible pharmacodynamic interaction between both drugs, the inotropic response to digoxin has been examined in rat isolated atria in the presence of diazepam. The atria were kept in Tyrode at 37 degrees C, bubbled with 95% O2 and 5% CO2 and electrically stimulated at twice the threshold voltage. The results indicate that diazepam induces an inotropic effect at 10(-5) M (P less than 0.05) and reduces (P less than 0.05) at 10(-9), 10(-7) and 10(-5) M the inotropic response to digoxin (10(-5) M).

Activated charcoal increases digoxin elimination in patients

Digoxin continues to be an important cause of drug toxicity. On the basis of a healthy volunteer study, activated charcoal has been proposed as a treatment for digoxin chronic intoxication. In order to evaluate the effect of activated charcoal on digoxin elimination in intoxicated patients during routine practice, we reviewed all Serum Digoxin Level Requests for adult in-patients from 1991 to 1993, with digoxin levels >2.5 ng/ml. Of a total of 39 cases, 23 had been treated with activated charcoal while 16 had not. Digoxin elimination half-life during activated charcoal therapy was 36 h (S.D. 14 h; 95% C.I. 30–42 h) while in the non-treated group it was 68 h (S.D. 19 h, 95% C.I. 57–78). Calculated total body clearance of digoxin was 55 ml/min (S.D. 17 ml/min; 95% C.I. 45–64 ml/min) for the non-treated group versus 98 ml/min (S.D. 34 ml/min; 95% C.I. 83–113 ml/min) for the group receiving charcoal, representing an 78% increase in digoxin elimination.

Clinical and Pharmacokinetic Profiles of Digoxin Immune Fab in Four Patients with Renal Impairment

Minimal pharmacokinetic data on digoxin immune Fab are currently available, especially in patients with impaired renal function. The serum concentration-time profiles of total digoxin, free digoxin, and digoxin immune Fab in four patients with moderate to severe renal impairment who received digoxin immune Fab are presented. The calculated elimination half-life of digoxin immune Fab was 25-73 hours. The calculated elimination half-life of total digoxin was 24-72 hours. Free digoxin concentrations rebounded to a peak of 1-2.9 ng/mL 44-97 hours after the administration of digoxin immune Fab. The areas under the curve for digoxin immune Fab were 213-1026 micrograms.h/mL, and total body clearances were 2.3-7.1 mL/min. The total digoxin concentrations peaked at 14-33 times the pre-Fab digoxin concentrations 5-30 hours after digoxin immune Fab administration. In comparing these data with data available from patients with normal renal function, the half-life of digoxin immune Fab and total digoxin was longer, the peak total digoxin concentration occurred later, the ratio of the peak total digoxin concentration to pre-Fab digoxin concentration was larger, and the rebound in free digoxin occurred later in patients with renal impairment. The Fab dose should not be reduced in patients with renal impairment; however, post-Fab monitoring should be extended to compensate for the prolonged half-life of Fab and later rebound of free digoxin.

Clinical and pharmacokinetic profiles of digoxin immune Fab in four patients with renal impairment

Minimal pharmacokinetic data on digoxin immune Fab are currently available, especially in patients with impaired renal function. The serum concentration-time profiles of total digoxin, free digoxin, and digoxin immune Fab in four patients with moderate to severe renal impairment who received digoxin immune Fab are presented. The calculated elimination half-life of digoxin immune Fab was 25-73 hours. The calculated elimination half-life of total digoxin was 24-72 hours. Free digoxin concentrations rebounded to a peak of 1-2.9 ng/mL 44-97 hours after the administration of digoxin immune Fab. The areas under the curve for digoxin immune Fab were 213-1026 micrograms.h/mL, and total body clearances were 2.3-7.1 mL/min. The total digoxin concentrations peaked at 14-33 times the pre-Fab digoxin concentrations 5-30 hours after digoxin immune Fab administration. In comparing these data with data available from patients with normal renal function, the half-life of digoxin immune Fab and total digoxin was longer, the peak total digoxin concentration occurred later, the ratio of the peak total digoxin concentration to pre-Fab digoxin concentration was larger, and the rebound in free digoxin occurred later in patients with renal impairment. The Fab dose should not be reduced in patients with renal impairment; however, post-Fab monitoring should be extended to compensate for the prolonged half-life of Fab and later rebound of free digoxin.

Effects of coadministration of propafenone on the pharmacokinetics of digoxin in healthy volunteer subjects.

Previous reports have suggested an interaction between propafenone and digoxin. We investigated the pharmacokinetics of IV digoxin when given alone (Phase I), after pretreatment with propafenone 150 mg every 8 hours for seven days (Phase II), and after propafenone 300 mg every 8 hours for 7 days (Phase III). The total body clearance of digoxin during Phase I was 2.45 ml/min/kg and was 2.17 ml/min/kg during Phase II (NS) and decreased to 1.92 ml/min/kg during Phase III (P less than 0.05). The renal clearance and half-life of digoxin were not significantly altered by propafenone. There was a trend towards a decrease in the volume of distribution of digoxin from 9.43 L/kg in Phase I, to 9.33 L/kg in Phase II, and 8.02 L/kg in Phase III. Similarly there was a trend towards a decreased nonrenal clearance of digoxin from 1.21 ml/min/kg during Phase I to 1.01 ml/min/kg during Phase II and to 0.75 ml/min/kg during Phase III. The changes in volume of distribution and nonrenal clearance parallel each other resulting in no change in the elimination half-life of digoxin. It is postulated that the mechanism of this interaction is due to decreases in the volume of distribution and nonrenal elimination of digoxin by propafenone. The degree of this interaction was related to the dose of propafenone. The magnitude of this interaction may be greater in patients and, thus, may require a reduction in the digoxin dose.

Chronic Treatment with Fluvoxamine, Clovoxamine, and Placebo: Interaction with Digoxin and Effects on Sleep and Alertness

The influence of 17 days of administration of fluvoxamine or clovoxamine, two new antidepressant agents, on the kinetics of a single intravenous dose of digoxin, and on self-rated parameters of sedation, mood, and sleep, was evaluated in a series of healthy volunteers. In the fluvoxamine study, subjects received fluvoxamine, 100 mg daily, or matching placebo for 17 consecutive days in a crossover design. For the clovoxamine study, subjects received clovoxamine, 150 mg daily, or placebo for 17 days. All treatments were double blind. At the end of each treatment, digoxin kinetics were evaluated following a single 1.25 mg intravenous dose. Compared to the placebo condition, fluvoxamine had no significant influence on digoxin elimination half-life (57 vs 47 hours), volume of distribution (10.5 vs 10.3 liters/kg), total clearance (2.4 vs 3.0 ml/min/kg), or 72 hour urinary excretion (33 vs 37 percent of the dose). Likewise clovoxamine did not alter digoxin elimination half-life (39 vs 40 hours), volume of distribution (10.7 vs 10.2 liters/kg), or total clearance 3.4 vs 3.4 ml/min/kg). 72 hour urinary excretion of digoxin was slightly increased by clovoxamine (41 vs 50 percent of the dose, P less than .05). Self-ratings indicated a sedating effect of fluvoxamine, with reports of difficulty attaining morning alertness. These effects were not reported with clovoxamine. Thus clovoxamine and fluvoxamine appear to have differential effects on sleep and alertness in healthy volunteers. However, neither have an important influence on the kinetics of digoxin.

Digitalis. An update of clinical pharmacokinetics, therapeutic monitoring techniques and treatment recommendations.

The intestinal absorption of digoxin is essentially a passive non-saturable diffusion process, although a saturable carrier-mediated component also plays an important role. The bioavailability varies between 40 and 100%: the presence of food may reduce the peak serum concentration, but does not reduce the amount of digoxin absorbed. Recent development of a capsule containing a hydroalcoholic vehicle may reduce interindividual variations in absorption. Pharmacokinetic analysis of the distribution of digoxin suggests 3 compartments, the slow distribution phase accounting for the lag time between the inotropic effects and the plasma concentration profile. Digoxin is extensively bound to tissues such as myocardium, renal, skeletal muscle as well as red blood cells, but not to adipose tissue. Plasma protein binding varies between 20 and 30%: displacement of digoxin from protein binding sites does not cause significant clinical effects. As expected, haemodialysis or exchange transfusions do not significantly alter the body load of digoxin. The apparent volume of distribution of digoxin varies between 5 and 7.3 L/kg; this may be reduced by, for example, electrolyte abnormalities which reduce digoxin binding to the myocardium. The elimination half-life of digoxin is 36 hours, with 60 to 80% being excreted unchanged, by passive glomerular filtration and active tubular secretion. The remainder is excreted non-renally. Clearance is therefore dependent on renal function and declines in renal disease and in elderly patients. Digoxin interacts with other drugs at any stage of absorption (e.g. cholestyramine), distribution (e.g. quinidine), metabolism (e.g. phenytoin) or elimination (e.g. diltiazem). Patients should, therefore, be carefully monitored when changing a therapeutic regimen which includes any drugs known to interact with digoxin. Clinical monitoring is more important than therapeutic drug monitoring which should be reserved for suspected toxicity, doubts about efficacy, or in cases of poor compliance. With the advent of newer treatment modalities, digoxin is no longer the treatment of first choice in supraventricular arrhythmias and congestive heart failure. However, with careful monitoring, digoxin remains an important therapeutic option.

Direct treatment of fetal supraventricular tachycardia after failed transplacental therapy

Digitalization by direct intramuscular injection of the fetus successfully controlled supraventricular tachycardia at 24 weeks' gestation after more traditional intensive trials of transplacental therapy with digoxin, verapamil, and procainamide, either separately or in combination, had failed. The fetal pharmacokinetics were calculated from fetal blood samples obtained by cordocentesis. No clear evidence of placental transfer of digoxin administered to the mother could be found despite a digoxin concentration in the mother that ranged from 1.8 to 2.6 ng/ml for 4 days. After direct fetal digitalization we calculated that the coefficient of elimination for digoxin from the fetus was 0.0463 hr−1, and digoxin elimination half-life was 15.9 hours. The latter time span is substantially less than the 50-hour half-life previously reported in newborn infants with low birth weight. The fetal/maternal concentration ratio of procainamide was 0.914. However, maternal clearance of procainamide (9.7 ml/kg−1/min−1) was twice as long as the clearance reported for nonpregnant patients undergoing fast acetylation. We conclude first, that at least in the dose of this ill fetus, little digoxin administered to the mother crossed the placentae; and second, that while direct fetal therapy with digoxin is effective, the necessary frequent number of injections render this therapy impractical. Direct fetal digitalization should probably be reserved for the preterm fetus who has evidence of heart failure and has not responded to maternally administered therapy other than digoxin.

Amiodarone-digoxin interaction: Clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications

Administration of amiodarone (600 to 1,600 mg/day) to 28 patients during long-term digoxin therapy (0.25 +/- 0.05 mg/day) increased serum digoxin level from 0.97 +/- 0.45 to 1.98 +/- 0.84 ng/ml (p less than 0.001). Gastrointestinal side effects occurred in nine patients, central nervous system reactions occurred in five and cardiovascular reactions occurred in four. Pharmacokinetic studies in six patients with a 1 mg intravenous digoxin dose before and during amiodarone therapy increased serum digoxin level at 30 minutes from 8.59 +/- 1.68 to 10.07 +/- 1.70 ng/ml (p less than 0.05). Amiodarone caused a 31% prolongation of digoxin elimination half-life from 49.5 +/- 8.8 to 65.0 +/- 28.8 hours, but the increase in half-life was not statistically significant. Total body clearance was reduced significantly (29%, p less than 0.05) from 2.05 +/- 0.76 to 1.46 +/- 0.64 ml/min per kg. Nonrenal clearance also showed a significant decrease (33%, p less than 0.05) from 1.20 +/- 0.46 to 0.80 +/- 0.30 ml/min per kg. The renal clearance decreased by 22% and the volume of distribution decreased by 11% after amiodarone therapy, but these changes were not significant. The data show that the mechanism of digoxin-amiodarone interaction is multifactorial and emphasize the need for close monitoring of serum digoxin levels and clinical features during concurrent digoxin-amiodarone therapy.

Digoxin kinetics in the elderly.

Digoxin elimination phase kinetics have been studied in 24 hospital in-patients (mean age 79 years), six of whom showed no evidence of digoxin toxicity. The others, with suspected toxicity, have been grouped according to the nature of the drug effects observed. Renal function, digoxin elimination half-life, apparent volume of digoxin distribution, and notional body content of digoxin have been compared between the groups. Apart from two hyperthyroid patients, the volumes of distribution averaged 6.1 1/kg. Toxic patients tended to have lower creatinine clearances, longer digoxin half-lives, and higher body contents of digoxin than the nontoxic, but the highest body contents were found in those with systemic toxicity. Thyrotoxicosis increases the apparent volume of digoxin distribution in the elderly.

Digoxin-quinidine interaction in unanesthetized guinea pigs.

The clinically relevant interaction between quinidine (3 mg/kg) and digoxin (0.6 mg/kg plus 20 microCi 3H-digoxin) was investigated using unanesthetized and unrestrained guinea pigs for in vivo pharmacokinetic and tissue disposition studies. Quinidine caused a significant elevation of plasma levels of digoxin as early as 5 min after injection, and the increase persisted for at least 8 h. A significant decrease in the volume of distribution for digoxin from 3.6 to 2.7 liters/kg (20%) was observed in quinidine-treated animals. No change was noted in the dominant elimination half-life of digoxin in quinidine-treated animals. The decreased volume of distribution appeared to be due to displacement of digoxin from tissue stores by quinidine as evidenced by decreased tissue to plasma ratios for kidney (41%), intestine (41%), fat (33%), lung (31%), left ventricle (27%), liver (24%), left atrium (22%), right ventricle (21%), right atrium (18%), pancreas (12%), and bladder (-4%) samples.

Pharmacokinetics of digoxin in patients subjected to the quinidine-digoxin interaction.

1 This study was designed to evaluate pharmacokinetically the digoxin-quinidine interaction in patients with atrial fibrillation. 2 Five patients on maintenance digoxin therapy were given [3H]-digoxin as a single i.v. dose before and during quinidine therapy and the elimination of [3H]-digoxin from plasma and excretion in urine were determined. 3 The mean steady state plasma concentration of digoxin increased from 0.7 to 1.3 nmol/l after quinidine administration. 4 The apparent volume of distribution of digoxin decreased on the average 38%. Renal clearance and the total body clearance of digoxin decreased 51 and 56% respectively (mean values). Also non renal clearance was reduced. The fraction of digoxin excreted unmetabolised in urine did not change during quinidine treatment. The mean elimination half life of digoxin increased from 49 to 72 h during quinidine. 5 In two patients the DC-shock did not cause a conversion to sinus rhythm. However, the quinidine induced changes in the pharmacokinetics of digoxin in these patients did not differ from the others. 6 Quinidine appears to decrease the amount of digoxin distributed to body tissue(s). In addition, the reduction of renal clearance of digoxin and the observed unchanged clearance of creatinine suggests an inhibition of the renal secretion of digoxin.

Effect of quinine on digoxin kinetics.

Six subjects were evaluated for the effect of quinine, the l-isomer of quinidine, on digoxin pharmokinetics. A 1.0-mg intravenous digoxin dose was given before and during quinine administration, followed by the measurement of digoxin serum and urine concentrations for 96 hr after each dose. Quinine reduced digoxin total body clearance by 26% from 2.98 to 2.22 ml/min/kg (p < 0.03). Digoxin elimination half-life (t 1/2) was lengthened from 34.2 to 51.8 hr, reflecting a 32% decrease in digoxin elimination rate constant (p < 0.003). Quinine did not reduce digoxin renal clearance or any volumes of distribution. The amount of digoxin excreted into the urine increased from x = 628. 29 micrograms to x = 772.52 micrograms (p < 0.02). Digoxin nonrenal clearance decreased an average of 55% from 1.2 to 0.55 ml/min/kg (p < 0.05). These results suggest that quinine alters digoxin metabolism or biliary secretion, reducing digoxin total body clearance by a mechanism that is qualitatively similar, but quamtitatively different, from quinidine.

The effects of acute focal cerebral ischemia on digoxin toxicity and pharmacokinetics.

24 h after ligation of the left middle cerebral artery in cats (sham operation in the control group), a constant intravenous infusion of digoxin was begun and continued to toxicity (ventricular rhythm) and death. We found that the lethal dose of digoxin was significantly less in the stroke group than in the control group, but the lethal plasma digoxin concentration was significantly greater in the stroke group than in the control group. In a subsequent study, we demonstrated that ischemic stroke caused a significant prolongation in the elimination half-life of digoxin and an increase in the volume of distribution. The mean plasma clearance of the stroke group was approximately three fourths of that of the control group. We concluded that the decreased tolerance to digoxin after ischemic stroke was due to the prolonged half-life and decreased clearance of digoxin.

Digoxin-Quinidine Interaction

Several recent reports have shown that plasma concentrations of digoxin increase when quinidine is administered along with digoxin; the present study was designed to explore the pharmacokinetics of this digoxin-quinidine interaction in six subjects. The elimination half-life of digoxin, although variable, did not change appreciably (42 vs. 44 hours) when quinidine was administered. Other pharmacokinetic values were substantially reduced in the presence of quinidine: total body clearance (from 3.08 to 1.96 ml per minute per kilogram), renal clearance (from 1.64 to 1.09 ml per minute per kilogram) and volume of distribution (from 10.87 to 7.35 liters per kilogram). The results may be explained by the displacement of digoxin from binding sites in tissue by quinidine, causing a rise in the plasma concentration of digoxin. The reduction in renal clearance of digoxin may result also from inhibition of renal secretion of digoxin by quinidine. (N Engl J Med 300:1238–1241, 1979)