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PubMed1999

Inhibition of P-glycoprotein-mediated drug transport: A unifying mechanism to explain the interaction between digoxin and quinidine [seecomments].

BACKGROUND: Although quinidine is known to elevate plasma digoxin concentrations, the mechanism underlying this interaction is not fully understood. Digoxin is not extensively metabolized, but it is known to be transported by the drug efflux pump P-glycoprotein, which is expressed in excretory tissues (kidney, liver, intestine) and at the blood-brain barrier. Accordingly, we tested the hypothesis that inhibition of P-glycoprotein-mediated digoxin transport by quinidine contributes to the digoxin-quinidine interaction. METHODS AND RESULTS: First, we demonstrated active transcellular transport of both digoxin and quinidine in cultured cell lines that express P-glycoprotein in a polarized fashion. In addition, 5 micromol/L quinidine inhibited P-glycoprotein-mediated digoxin transport by 57%. Second, the effect of quinidine on digoxin disposition was studied in wild-type and in mdr1a(-/-) mice, in which the gene expressing the major digoxin-transporting P-glycoprotein has been disrupted. Because the in vitro data showed that quinidine itself is a P-glycoprotein substrate, quinidine doses were reduced in mdr1a(-/-) mice to produce plasma concentrations similar to those in wild-type control animals. Quinidine increased plasma digoxin concentrations by 73.0% (P=0.05) in wild-type animals, compared with 19.5% (P=NS) in mdr1a(-/-) mice. Moreover, quinidine increased digoxin brain concentrations by 73.2% (P=0.05) in wild-type animals; by contrast, quinidine did not increase digoxin brain concentrations in mdr1a(-/-) mice but rather decreased them (-30.7%, P<0.01). CONCLUSIONS: Quinidine and digoxin are both substrates for P-glycoprotein, and quinidine is a potent inhibitor of digoxin transport in vitro. The in vivo data strongly support the hypothesis that inhibition of P-glycoprotein-mediated digoxin elimination plays an important role in the increase of plasma digoxin concentration occurring with quinidine coadministration in wild-type mice and thus support a similar mechanism in humans.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1981

Effect of quinidine on the digoxin receptor in vitro.

To investigate the basis for a clinically important digitalis-quinidine interaction that is characterized by increases in serums digoxin concentrations when quinidine is administered to digoxin-treated patients, we have studied in vitro the interaction of quinidine with the digoxin receptor. Evidence has been obtained that quinidine is capable of decreasing the affinity for digoxin of cardiac glycoside receptor sites on purified Na,K-ATPase and on intact human erythrocyte membranes. As others have shown, quinidine is capable of inhibiting Na,K-ATPase activity, and evidence has been obtained in the current study that, while quinidine can reduce the affinity of the enzyme for digoxin, it is also capable of acting together with digoxin in inhibiting enzyme activity to a degree greater than the inhibitory effect of digoxin alone. The concentrations of digoxin and quinidine used in this study were considerably greater than their therapeutic serum concentrations. Nevertheless, these observations are consistent with the hypothesis that the increases in serum digoxin concentrations and the decreases in volumes of digoxin distribution observed clinically when quinidine is administered to digoxin-treated patients may reflect, at least in part, a decrease in the affinity of tissue receptors for digoxin. The possibility must also be considered that enhanced cardiac effects of digoxin may occur clinically as the result of an augmentation, by quinidine, of digoxin effects, which more than compensates for the modest reduction in digoxin binding.

Biological Transport, Active↗
PubMed2001

The effects of tegaserod (HTF 919) on the pharmacokinetics and pharmacodynamics of digoxin in healthy subjects.

Tegaserod (HTF 919) is a highly specific 5-HT4 receptor partial agonist that exhibits promotile activity throughout the gastrointestinal tract and is under development for the treatment of functional gastrointestinal motility disorders. The present study was designed to assess the effect of multiple doses of tegaserod on the single-dose pharmacokinetics and pharmacodynamics of digoxin, a commonly prescribed agent for congestive heart failure. The study was an open-label, randomized, two-period crossover design of 12 healthy subjects. One treatment included digoxin treatment alone; the other treatment included a combined digoxin and tegaserod treatment. On day 1 of the digoxin treatment period, subjects received a single 1 mg oral dose of digoxin. In the combined tegaserod/digoxin treatment period, subjects received a single oral dose of 1 mg digoxin after 3 days of tegaserod (6 mg bid). After coadministration of tegaserod, systemic exposure to digoxin was decreased; mean AUC decreased by 11.9% (p < 0.05) relative to digoxin alone. Cmax was decreased by about 15% (p < 0.05). The 0.5-hour difference in the median tmax between the two treatments was not statistically significant. Because the steady-state trough concentration of digoxin (C(SS,min)) correlates with pharmacological effects, C(SS,min) for digoxin alone and in combination with tegaserod was simulated based on both parametric compartmental modeling and nonparametric superpositioning approaches. The predicted arithmetic mean C(SS,min) for combination therapy is 86% to 89% of that following digoxin alone. Likewise, the predicted arithmetic mean steady-state peak concentration (C(SS,min)) and AUC at steady state during a dosing interval (AUC(SS,tau)) have a similar decrease. This extent of decrease in systemic exposure of digoxin at steady state is unlikely to be clinically relevant. Administration of tegaserod (6 mg bid) was well tolerated, both alone and in combination with a single dose of digoxin. There were no pharmacodynamic changes in ventricular rate and QT interval following coadministration of tegaserod with digoxin. The 1.5-hour and 2-hour postdose plasma concentrations of tegaserod on days 3 and 4 confirmed adequate exposure. In conclusion, dose adjustment for digoxin is unlikely to be needed when tegaserod is coadministered.

Adolescent↗
PubMed1983

Verapamil and digoxin: interactions in the rat.

Verapamil and digoxin are often used in combination and clinical experience suggests that verapamil may increase digoxin toxicity. We have explored the effects of verapamil upon digoxin induced tachyarrhythmias and have undertaken a preliminary study of the influence of verapamil on digoxin pharmacokinetics in the rat. Anesthetized rats received 20 mg/kg of digoxin intraperitoneally followed by verapamil i.v., 0.3 mg/kg, in repeated doses either immediately after digoxin or only after the onset of digoxin induced arrhythmias. Digoxin alone produced prolonged paroxysmal atrial tachycardia in 88-100% of rats and verapamil converted 75% of rats to sinus rhythm and significantly reduced digoxin induced mortality. In a later study, rats were injected with 10 mg/kg verapamil i.p. twice a day for 7 days or only with saline. On the seventh day all the rats received 0.5 mg/kg of digoxin i.p. Eight hours later the animals were sacrificed and plasma, heart, brain, liver, kidney and muscle (diaphragm) digoxin concentration was measured by radioimmunoassay. Digoxin levels were twice as high in plasma, heart, liver and muscle of verapamil pretreated rats (p less than 0.01). Two types of verapamil - digoxin interactions are demonstrated in the above studies; one in which verapamil modifies digoxin induced arrhythmias and a second pharmacokinetic effect in which pretreatment with verapamil increases digoxin concentration in the plasma and in several tissues.

Animals↗
PubMed1993

[Digoxin poisoning in patients of 2 geriatric departments in London: prevalence and mortality].

Digoxin is a toxic drug with a narrow therapeutic index that is mostly used by the elderly. Although it is accepted that toxicity of digoxin occurs more frequently in elderly than in younger patients, there is dispute about its prevalence and associated mortality. A study was therefore set up to, on the one hand, find the prevalence and associated mortality of digoxin toxicity in patients admitted onto two geriatric wards in London and, on the other hand, to study the relationship between serum digoxin level and age, serum urea, serum potassium and serum calcium in geriatric patients with digoxin toxicity. Over a period of three years 1438 patients (age 75-93) were admitted of whom 452 (31%) were on digoxin. Thirty-five patients (7.7%) were diagnosed as having digoxin toxicity. Eight patients (22.9%) with digoxin toxicity died during admission. Mortality was higher although not statistically significant for the patients with toxicity than for the patients who were on digoxin without toxicity. The fatal outcome was not predicted by age, serum urea, serum potassium or serum calcium. The serum digoxin level of the eight patients who died was lower than the level of those (n = 23) who survived. Four patients (11%) had a normal serum digoxin level and clinical features of digoxin toxicity that disappeared on stopping digoxin. A hypothesis is put foreward to explain the weak association between serum digoxin level and digoxin toxicity in geriatric patients.

Aged↗
PubMedDate not supplied

Homogeneous electrogenerated chemiluminescence immunoassay for the determination of digoxin employing Ru(bpy)(2)(dcbpy)NHS and carrier protein.

A highly sensitive homogeneous electrogenerated chemiluminescence (ECL) immunoassay for the determination of anti-digoxin antibody and digoxin hapten was developed employing Ru(bpy)(2)(dcbpy)NHS (bpy = 2,2'-bipyridyl; dcbpy = 2,2'-bipyridine-4,4'-dicarboxylic acid; NHS = N-hydroxysuccinimide ester) as an electrochemiluminescent label and bovine serum albumin (BSA) as a carrier protein. A digoxin hapten was indirectly heavily labelled with Ru(bpy)(2)(dcbpy)NHS through BSA to form Ru(bpy)(2)(dcbpy)NHS-BSA-digoxin conjugate. The ECL intensity of the immunocomplex of the conjugate with anti-digoxin antibody markedly decreased when the immunoreaction between Ru(bpy)(2)(dcbpy)NHS-BSA-digoxin conjugate and anti-digoxin antibody took place. Two formats, direct homogeneous immunoassay for anti-digoxin antibody and competitive immunoassay for digoxin, were developed to determine anti-digoxin antibody and digoxin, respectively. The anti-digoxin antibody concentration in the range 7.6 x 10(-8)-7.6 x 10(-6) g/mL was determined by direct homogeneous format. Digoxin hapten was determined throughout the range 4.0 x 10(-10)-1.0 x 10(-7) g/mL with a detection limit of 1.0 x 10(-10) g/mL by competitive format. The relative standard derivation for 6.0 x 10(-9) g/mL was 4.3%. The method has been applied to assaying digoxin in control human serum.

2,2'-Dipyridyl↗
PubMed1995

Comparative study of efficacy and safety of low-dose diltiazem or betaxolol in combination with digoxin to control ventricular rate in chronic atrial fibrillation: randomized crossover study.

BACKGROUND: The combination therapy of low-dose diltiazem or bexatolol with digoxin can be a useful adjunct for achieving heart rate control with minimal side effects. But there has not been a study including patients with impaired left ventricular function and evaluating whether the beneficial effects of medication will be maintained during a follow-up period. OBJECTIVES: The purpose of this study was three-fold: (1) to compare the efficacy of digoxin with low-dose diltiazem and digoxin with low-dose betaxolol on randomized crossover study; (2) to evaluate whether the beneficial effects of medication will be maintained after 7 months; (3) to evaluate the safety of the combination therapy in patients with impaired left ventricular function. METHODS: We did a prospective randomized crossover study in 35 patients with chronic atrial fibrillation (AF) including 15 patients with left ventricular dysfunction. After enrollment, each patient was evaluated for heart rate, blood pressure, rate-pressure products, maximal exercise tolerance at rest and during symptom-limited treadmill test before medication, at 4 weeks after medication of digoxin (0.125-0.5 mg daily) with diltiazem (90 mg twice daily), and at 4 weeks after digoxin with betaxolol (20 mg once daily). We performed 24-h ambulatory electrocardiogram (ECG) in 15 patients at the end of each phase of treatment. We repeated symptom-limited treadmill test like above method in 15 patients at 7 months of medication. RESULTS: (1) Ventricular rates were significantly reduced in digoxin with low-dose betaxolol therapy at rest and during exercise (67 +/- 3, 135 +/- 5 (mean +/- S.E.M.) beats/min, respectively) in comparison to digoxin with low-dose diltiazem therapy (80 +/- 7, 154 +/- 5) (P < 0.05). (2) Rate-pressure products were significantly less in digoxin with low-dose betaxolol at rest and during exercise (85 +/- 4, 213 +/- 12 x 10(2) mmHg/min) than in digoxin with low-dose diltiazem therapy (105 +/- 6, 269 +/- 12) (P < 0.05). (3) Exercise capacity was significantly improved in digoxin with low-dose betaxolol (9.3 +/- 0.5 METS) or digoxin with low-dose diltiazem (9.7 +/- 0.5) in comparison to control state (8.3 +/- 0.5) (P < 0.05). (4) At 7 months evaluation, there was no significant difference between at 4 weeks and at 7 months. (5) Results on 24-h ambulatory ECG showed the same findings as on treadmill test. (6) Although side effects occurred more frequently in digoxin with low-dose betaxolol therapy, they were minimal and no patient had to withdraw medication. Worsening of left ventricular dysfunction was not observed. CONCLUSION: Our study suggested that (1) combination therapy of low-dose betaxolol with digoxin was more superior to low-dose diltiazem with digoxin in controlling ventricular rate and reducing rate-pressure products; (2) the effects controlling ventricular rate, reducing rate-pressure products and improving exercise capacity have been well maintained even after 7 months of medication with each combination therapy.

Adrenergic beta-Antagonists↗
PubMed1991

Which cardiac disturbances should be treated with digoxin immune Fab (ovine) antibody?

Digoxin excess can produce characteristic bradyarrhythmias, tachyarrhythmias, and hyperkalemia. The bradyarrhythmias, which consist of disturbances in conduction and block at the level of the atrioventricular and sinus nodes, are mediated by a direct and vagotonic effect. The vagotonic effect of excess digoxin may also result in a marked slowing of the sinus rate in the setting of severe toxicity. Digoxin increases automatic and triggered electrical activity in atrial muscle, His-Purkinje system, and ventricular muscle, which predisposes to tachycardias. Many of the tachyarrhythmias are relatively specific for the toxic effects of digoxin. Atrial tachycardias with variable atrioventricular block, accelerated junctional rhythms (especially in the setting of atrial fibrillation), and fascicular tachycardias are characteristic digoxin toxic rhythms. Digoxin-specific antibody fragments should be considered the treatment of choice for any digoxin toxic arrhythmia associated with hemodynamic compromise or the threat of hemodynamic compromise. Hyperkalemia, when due to acute severe digoxin toxicity, is also an appropriate indication for digoxin-specific Fab fragment therapy. When assessing the risk:benefit ratio for using digoxin-specific Fab fragment therapy, one needs to determine, in addition to the electrocardiographic manifestations and patient's hemodynamic status (1) the severity of toxicity, as indexed by the amount ingested and/or the serum digoxin concentration; (2) the expected time course for reversal of toxicity, which is usually determined by the status of renal function; (3) the need for digoxin to provide ventricular rate control or improved ventricular contractility and therapeutic alternatives to digoxin; (4) the presence of a strong allergy history; (5) the presence of such factors as increased age and severity of heart disease that may predispose to digoxin toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Arrhythmias, Cardiac↗
PubMed1977

The effects of oral propranolol, digoxin and combination therapy on the resting and exercise electrocardiogram.

The effects of propranolol, digoxin and combination therapy (/D) on the resting and exercise ECG were studied in ten normal subjects and 20 patients with coronary artery disease (CAD) given a sequence of oral placebo, propranolol, P/D, digoxin and placebo, for two week periods. Digoxin produced a significant decrease in T-wave amplitude and often resulted in ST segment depression in the resting ECG. Propranolol, digoxin, and P/D tended to decrease the QTc interval and prolong the PR interval. However, CAD patients were more sensitive to PR prolongation than normals while receiving propranolol or digoxin alone. Propranolol therapy did not significantly affect the ST segment of the exercise ECG in the normal subjects or the CAD patients without an ischemic control exercise ECG. By contrast, 50 per cent of the normal subjects developed "false-positive" ischemic ST segment responses to exercise while receiving digoxin of P/D and three of eight CAD patients without ischemic control exercise ST segments had a similar response to digoxin or P/D. In 12 CAD patients with ischemic control exercise ST segments, propranolol did not affect the amount of ST segment depression at the onset of angina or the maximum amount of ST segment depression. Digoxin or P/D both uniformly increased the maximum amount of ST segment depression which was greater with digoxin than P/D. However, the maximum heart rate on P/D was significantly reduced as compared to that on digoxin. It is concluded that (1) CAD patients are more sensitive to propranolol or digoxin-induced AV block than normals, (2) propranolol does not change the magnitude of ischemic exercise ST segment depression, (3) digoxin increases ischemic exercise ST segment depression and results in a high incidence of false-positive exercise tests, and (4) the addition of propranolol to digoxin attenuates the effects of digoxin on the exercise ST segment.

Administration, Oral↗
PubMed1983

Cardiac effects of treatment with quinidine and digoxin, alone and in combination.

Systolic time intervals (QS2-I and LVET-I) and echocardiographically determined ejection fraction and velocity of circumferential fiber shortening were recorded in 10 healthy volunteers as measures of inotropic effect during maintenance treatment with 4 consecutive drug regimens: (1) quinidine, 1,200 mg/day; (2) digoxin, average dose 0.31 mg/day; (3) the combination of (1) and (2); and (4) digoxin alone (average dose 0.65 mg/day) to provide the same steady-state serum concentration of digoxin as during the period with combination of digoxin and quinidine. The steady-state serum concentration of digoxin during the low-dose regimen increased from 0.72 +/- 0.15 (mean +/- standard deviation [SD]) to 1.63 +/- 0.28 nmol/liter when quinidine was added. With the high dose of digoxin alone, the serum digoxin level reached 1.68 +/- 0.50 nmol/liter. Skeletal muscle digoxin concentrations during these periods were 27.7 +/- 8.3, 48.7 +/- 16.2, and 51.6 +/- 23.6 nmol/kg of dry weight, respectively. The skeletal muscle to serum concentration ratio of digoxin decreased significantly during quinidine treatment. Systolic time intervals were significantly prolonged by quinidine alone and shortened by digoxin alone, the latter effect being dose-dependent. Subtracting the effect of quinidine itself, the induced increase in digoxin level caused a significant increase in inotropic effect. When these corrected values were compared with those attained during the period with the same steady-state digoxin concentration but in the absence of quinidine, no significant differences were found. Echocardiographically measured ejection fraction and velocity of circumferential fiber shortening showed trends for similar drug effects, as did the systolic time intervals. This study, performed under steady-state conditions, demonstrates that the quinidine-induced increase in steady-state serum digoxin concentration will, with due consideration to quinidine's own pharmacodynamic properties, be accompanied by increased cardiac effects. This indicates that quinidine is not interfering with active receptor sites in the heart for digoxin.

Adult↗
PubMed2002

The effect of erythromycin and clarithromycin on the pharmacokinetics of intravenous digoxin in healthy volunteers.

Several case reports have suggested an interaction between digoxin and macrolide antibiotics. The authors investigated the effect of erythromycin and clarithromycin on the pharmacokinetics of intravenously administered digoxin (0.5 mg) in healthy subjects. Nine male subjects participated in three studies (digoxin alone, digoxin with erythromycin, and digoxin with clarithromycin). Subjects took erythromycin (800 mg per day) or clarithromycin (400 mg per day) on the day before digoxin dosing and during the kinetic study, Neither of the macrolides affected serum digoxin concentration-time curves. However, more than 1.3-fold increases in urinary digoxin excretions were observed during erythromycin and clarithromycin coadministration compared with digoxin alone. There were significant differences in renal clearance between macrolide coadministration and the control condition (digoxin alone: 98.4 ml/min; digoxin with erythromycin: 137.3 ml/min; digoxin with clarithromycin: 133.6 ml/min). In conclusion, neither erythromycin nor clarithromycin has a significant effect on serum digoxin disposition after an intravenous administration. Renal digoxin excretion is not inhibited but rather enhanced by both macrolides.

Administration, Oral↗
PubMed1997

Economic impact of digoxin toxicity.

The costs of digoxin toxicity to the US healthcare system have not been previously reported. Therefore, the 1994 database of US University Health-System Consortium (UHC) was searched for cases of digoxin toxicity using the International Classification of Diseases (9th edition) [ICD-9] codes. In addition, the medical records of 17 patients admitted to the University of Illinois Hospital from September 1994 to July 1995 with a diagnosis of digoxin toxicity were also reviewed. Of the 17 patients, 14 were admitted with a primary diagnosis of digoxin toxicity. Causes of digoxin toxicity were worsening renal function (6 patients), excessive dosage prescribed (4 patients), excessive dosage self-administered (2 patients), multiple prescriptions (2 patients), accidental ingestion (1 patient), drug-drug interaction (1 patient) and unknown (1 patient). Digoxin toxicity could have been prevented in 9 (53%) of the 17 patients. The mean length of stay in the hospital as a result of digoxin toxicity was 3.3 +/- 1.2 days. The mean laboratory cost associated with digoxin toxicity was $US275.54 +/- $US106.57 and the mean hospital bed cost was $US3781.92 +/- $US2572.22. The mean overall cost associated with digoxin toxicity was $US4087.05 +/- $US2659.76. There was a significant correlation between the total cost associated with digoxin toxicity and the serum digoxin concentration on admission (r = 0.73, p < 0.01). From the UHC database, a total of 836 cases of digoxin toxicity in 56 hospitals were identified. This represented the occurrence of digoxin toxicity in 0.07% of all patients admitted to these US academic hospitals. Digoxin toxicity results in considerable costs to the healthcare system. Most cases can be considered readily preventable with proper patient counselling and education.

Adolescent↗
PubMed1988

Effect of aspirin, furosemide, and commercial low-salt diet on digoxin pharmacokinetic properties in clinically normal cats.

Steady-state serum digoxin concentration ([digoxin]) was measured for 48 hours in 6 healthy cats after they were treated with digoxin tablets (0.01 mg/kg of body weight, q 48 h) for 10 days and again after concurrent treatment of identical duration with orally administered digoxin, aspirin (80 mg, q 48 h), furosemide (2 mg/kg, q 12 h), and a commercial low-salt diet. The concurrent treatment substantially altered digoxin pharmacokinetic properties, with a resultant increase in peak (mean +/- SEM; from 2.1 +/- 0.35 to 3.3 +/- 0.6 ng/ml), 8-hour (from 1.4 +/- 0.35 to 2.5 +/- 0.64 ng/ml), and 48-hour mean (from 1.1 +/- 0.22 to 2.2 +/- 0.57 ng/ml) serum [digoxin]; an increase in the number of hours during which serum [digoxin] was in the toxic range (from 3 +/- 1.7 to 24.7 +/- 9.8 h); and a decrease in oral clearance (from 0.15 +/- 0.04 to 0.08 +/- 0.02 L/h.kg). Of these differences, all but the 8-hour serum [digoxin] were significant at P less than 0.05. Similar sampling procedures were performed in 3 cats after administration of digoxin alone (0.01 mg/kg, q 48 h) until steady-state conditions were reached (10 days) and again after an additional 10 days of treatment. Differences were not noticed in digoxin pharmacokinetic properties. Eight-hour serum [digoxin] was shown to correlate closely with the mean serum [digoxin] at steady-state conditions when digoxin was administered every 48 hours. Variation in digoxin pharmacokinetic properties was noticed between cats.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1980

Alteration of digoxin pharmacokinetics by a single dose of quinidine.

To determine whether a single dose of quinidine sulfate might alter serum digoxin levels, patients receiving maintenance digoxin therapy who required quinidine had their serum digoxin levels measured after oral administration of digoxin, quinidine, or both. In group 1, digoxin and quinidine were administered orally together; in group 2, digoxin was administered orally alone; and in group 3, quinidine was administered orally, 24 hours after the last dose of digoxin. In group 1, serum digoxin level increased by 2.0+/-0.4 ng/mL (from 1.0+/-0.1 ng/mL), but in group 2, serum digoxin level increased by only 1.0+/-0.1 ng/mL (from 1.0+/-0.1 ng/mL). Group 3 showed no change in serum digoxin concentration. Time of maximum digoxin concentration also occurred earlier when digoxin and quinidine were administered together. Thus, a single dose of quinidine will increase the peak digoxin level when administered together with oral digoxin.

Administration, Oral↗
PubMed1978

Hemoperfusion removal of digoxin from dogs.

Removal of digoxin by XAD-4 hemoperfusion columns was tested after four dogs were given 0.06 mg/kg of digoxin i.v. Dogs were perfused for 4 to 5 hr at a flow of 105 ml/min through a 100 gm XAD-4 column 16 hr after the dose. Pharmacokinetic analysis of digoxin levels was performed with a three-compartment model. The apparent postdistribution t1/2 was 16.0 +/- 2.9 (S.D.) hr and decreased to 7.1 +/- 2.1 hr during perfusion. Digoxin perfusion clearance was 46 ml/min. An average of 51 microgram of digoxin was recovered from used columns. CP of digoxin calculated from the total R was 127.5 +/- 13 ml/min or 2.3 times greater than plasma flow. With the use of 3H-digoxin, canine blood was found to contain 2.5 times as much digoxin as did plasma. After perfusion there was an increase in serum digoxin levels in all dogs. Computer analysis showed that the increase in plasma digoxin levels immediately after hemoperfusion occurred because the central compartment, which was depleted of digoxin during hemoperfusion, was refilled from peripheral compartments. This study demonstrated that (1) XAD-4 hemoperfusion doubles the rate of removal of digoxin from dogs, (2) dog whole blood contains more than twice as much digoxin than does plasma, so that hemoperfusion clearance exceeds plasma flow, and (3) a multicompartmental pharmacokinetic model explains the increase in serum digoxin concentrations observed at the completion of hemoperfusion.

Animals↗
PubMed1977

[Serum digoxin concentration: dependence on body weight and age].

In patients of a cardiological practice, 121 digoxin serum concentrations were determined by radioimmunoassay (RIA). Some drugs were suspected of interfering with the RIA or with the pharmacokinetics of digoxin. Patients having such additional drugs or patients with elevated serum creatinine were not included. The daily maintenance dose of digoxin was roughly adjusted to body weight. Patients with 0.5 mg digoxin daily showed unexpectedly low serum digoxin levels not fully explained by the relatively high body weight. This dose group was not included in the following correlations. At a maintenance dose of 0.25 and 0.375 mg digoxin and in the age groups 40-69 years (n = 66) there was an approximately inverse proportionality between serum digoxin concentration (per 0.25 mg digoxin daily) and body weight. When all age classes from 20 to 89 years were included (n = 96), a week positive correlation between serum digoxin concentration (per 0.25 mg digoxin daily and per 69.28 kg body weight) and age was found. A similar positive correlation resulted between serum digoxin concentration (per 0.25 mg digoxin daily) and the reciprocal of the nomographically determined creatinine clearance, always within the normal serum creatinine range. Based on these correlations, two simplified formulas are presented to predict the serum concentration and therapeutic maintenance dose of digoxin. The formulas are valid for the normal serum creatinine range and for digoxin tablets of optimal bioavailability.

Adult↗
PubMed1996

Prevalence of appropriate and inappropriate indications for use of digoxin in older patients at the time of admission to a nursing home.

OBJECTIVE: To investigate the prevalence of digoxin use and appropriate and inappropriate indications for digoxin use in older patients at the time of admission to a nursing home. DESIGN: In a prospective study of 500 consecutive patients aged 60 years of age or older admitted to a nursing home, 96 (19%) patients were receiving digoxin at the time of admission to the nursing home. Appropriate and inappropriate indications for digoxin use were investigated in these 96 patients. SETTING: A large, long-term health care facility where 500 consecutive older patients were studied. PATIENTS: The 500 patients included 344 women and 156 men, mean age 81 +/- 8 years (range 60-100). MEASUREMENTS AND MAIN RESULTS: Ninety-six of the 500 patients (19%) were receiving digoxin at the time of admission to the nursing home. Fifty-one (53%) of the 96 patients receiving digoxin had an appropriate indication for digoxin use, and 45 (47%) had an inappropriate indication for digoxin use. Appropriate indications for digoxin use included atrial fibrillation with or without congestive heart failure (CHF) in 35 patients (36%) and CHF with sinus rhythm and abnormal left ventricular (LV) ejection fraction in 16 patients (17%). Inappropriate indications for digoxin used included CHF with sinus rhythm and normal LV ejection fraction in 18 patients (19%), misdiagnosis of edema or dyspnea as CHF in patients with sinus rhythm and normal LV ejection function in 17 patients (18%), history of possible (undocumented) paroxysmal atrial fibrillation in nine patients (9%), and sinus tachycardia in one patient (1%). Two of the 45 patients (5%) inappropriately treated with digoxin had evidence of digitalis toxicity on their admission electrocardiogram. CONCLUSIONS: The prevalence of digoxin use was 19% in older patients at the time of admission to the nursing home. Almost half of patients (47%) receiving digoxin at the time of admission had an inappropriate indication for digoxin use at that time.

Aged↗
PubMed1985

Prazosin alters free and total plasma digoxin levels in dogs.

Digoxin has been associated with a variety of drug interactions. Studies in our laboratory indicate that single doses of prazosin may alter plasma steady-state digoxin levels. Adult mongrel dogs were given digoxin tablets orally (0.008 mg/kg, twice daily) until steady-state levels of digoxin were reached. Dogs were then tested in a cross-over study with prazosin and saline. Plasma samples were assayed for both free and total plasma digoxin via radioimmunoassay. Free drug was separated from protein bound drug utilizing a micropartition system. Plasma binding of digoxin as well as nonspecific tissue binding was reduced by prazosin and resulted in an increased fraction of free digoxin in plasma. The increase in free digoxin leads to an increase in the pool of digoxin available for pharmacologic activity. Acute experiments demonstrated such an increased pharmacologic effect of digoxin in the presence of prazosin. Prazosin pretreatment prior to a continuous digoxin infusion significantly increased the positive inotropic effect of digoxin compared to dogs receiving only digoxin.

Animals↗