Influence of everyday physical activity on the serum digoxin concentration in digoxin-treated patients

Summary. Thirteen patients admitted to hospital because of known or suspected cardiac disease who had been treated with digoxin within, at least, the previous month were investigated. Blood samples for serum digoxin analysis by radioimmunoassay were taken before and after 40 min rest in supine in the ward and later in the outpatient clinic, all samples taken about 24 h after the last dose of digoxin. The serum digoxin concentration measured before rest in the outpatient clinic was significantly lower than those measured in the ward before and after rest. This is possibly related to physical activity prior to blood sampling since after 40 min rest in the outpatient clinic the serum digoxin concentration had increased and the concentration after rest was not significantly different from the concentrations measured in the ward. In analogy with a previous finding of a decrease in serum digoxin concentration during exercise in healthy subjects ingesting digoxin, the present results suggest that everyday physical activity affects the serum digoxin concentration. This must be taken into account when interpreting the results of serum digoxin measurements.     

EFFECTS OF ORAL PRAZOSIN ON TOTAL PLASMA DIGOXIN LEVELS

Prazosin and digoxin are frequently coadministered in clinical practice. To determine the effects of oral prazosin treatment on steady-state digoxin levels, 20 patients receiving a constant maintenance dose of digoxin, who had normal renal and liver functions and were not receiving any other treatment, were given 5 mg of prazosin for 3 days. Plasma digoxin levels were measured before, on days 1 and 3 of prazosin treatment, and after prazosin had been discontinued. It was found that prazosin significantly increased plasma digoxin levels. On discontinuation of prazosin digoxin levels returned to their previous values.     

Digoxin pharmacokinetics: role of renal failure in dosage regimen design.

Radioimmunoassayed serum concentration and urinary excretion data for digoxin from azotemic patients were characterized using a 2-compartment open model. Urinary excretion rates of digoxin as well as serum concentration data are needed to accurately characterize the disposition of the drug. Seven patients with renal failure showed highly variable steady-state volumes of distribution (V-ss-D equals 195 to 489 liters/1.73 m-minus2) and t1/2beta values (1.5 to 5.2 days). This variability is a major limiting factor in the use of dosage regimen nomograms that assume a constant V-ss-D and a rigorous relationship between t1/2beta and creatinine clearance (Cl-CR). Body clearance (Cl-B) is a parameter that is affected by both elimination and distribution of drugs. A linear relationship between Cl-B and renal clearance of digoxin or Cl-CR was found and was used to develop a model-independent approach to calculation of maintenance doses of digoxin. Several methods for calculating steady-state serum concentrations of digoxin (C-ss-p) were compared with actual measurements obtained in 16 chronically medicated patients. Optimum computation of C-ss-p is obtained by use of digoxin renal and body clearances. Variability in the digoxin:creatinine renal clearance ratio is the major limiting factor in prediction of digoxin dosage regimens.     

Spironolactone-induced changes in digoxin kinetics

Plasma clearance, volumes of distribution, and renal and extrarenal clearances of digoxin were calculated from plasma digoxin concentrations and urinary excretion of digoxin after intravenous injection of digoxin in 8 subjects. The investigation was repeated in the same subjects during long-term treatment with spironolactone. Increased plasma concentration of digoxin was detected during spironolactone treatment. Calculated plasma and renal clearances of digoxin and the volumes of distribution decreased statistically significant. Near maximal capacity for the tubular secretion of digoxin was found when normal digoxin dosage was used. It is suggested that unless spironolactone decreases the myocardial sensitivity for digoxin, the loading dose as well as the maintenance dose of digoxin should be reduced during treatment with spironolactone.     

Predictive performance of serum digoxin concentration in patients with congestive heart failure by a hyperbolic model based on creatinine clearance

OBJECTIVES: To formulate a simple equation for determining the daily dose requirements of digoxin by inclusion of creatinine clearance (Ccr) values as an explanatory variable. METHODS: We included 235 routine monitoring and clinical laboratory test data (steady-state serum digoxin concentration and Ccr values), obtained from hospitalized patients receiving digoxin for treatment of congestive heart failure. The 107 data sets were fitted to a hyperbolic model to account for the relation between the ratio of serum digoxin level to the daily dose (L/D) and the Ccr values determined by six methods. Their correlation coefficients (r) were computed by non-linear regression analysis. To evaluate the validity of the best-fitting model, the predictive performance of the L/D ratios was compared with those given by seven reference models previously published, using another 128 data sets. RESULTS: The hyperbolic model involving the Ccr values estimated by Cockcroft and Gault's equation showed the closest correlation (r = 0.81) between the actual and estimated Ccr values. Mean prediction error (ME), a measure of bias, of the L/D ratio (0.018 ng/mL) was almost negligible when other data were fitted to the proposed model, and this ME value proved to be much smaller than those calculated from the previously published prediction models. Mean absolute prediction error, a measure of precision, by the proposed model was also satisfactory for prediction. CONCLUSION: The newly developed model provided good predictive performance of serum digoxin level. Taking simplicity in practical use into account, the clinical application of the proposed model will allow for accurate and rapid determination of the initial maintenance dosing regimen of digoxin based on the individual Ccr value, without actual measurement of its serum concentration.     

Population pharmacokinetic investigation of digoxin in Japanese neonates

OBJECTIVE: To establish the role of patient characteristics in estimating doses of digoxin for neonates using routine therapeutic drug monitoring data. METHOD: The steady-state blood level data (n = 129) after repetitive oral administration in 71 hospitalized neonates were analysed using Nonlinear Mixed Effects Modelling (nonmem), a computer program designed for analysing drug pharmacokinetics in study populations through pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a one-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on digoxin disposition was investigated. RESULTS: Estimates generated by nonmem indicated that the clearance of digoxin (CL/F; L/h) was influenced by the demographic variables: total body weight (TBW), gestational age (GA) and neonate clearance factor (trough serum concentration of digoxin; Conc). These influences could be modelled by the equation CL/F = 0.0261 x TBW (kg)0.645 x Conc (ng/mL)(-0.724) x GA (weeks)0.8. The interindividual variability in digoxin clearance was modelled with proportional errors. The estimated coefficient of variation was 7.0%, and the residual variability was 13.1%. CONCLUSION: Clinical application of the model to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve the desired therapeutic effect. However, the digoxin dosage regimen for the individual patient should be based on a careful appraisal of their clinical need for the drug.     

Digoxin concentration in saliva and plasma in infants, children, and adolescents with heart disease

Background

Because of its narrow therapeutic index, therapeutic monitoring of digoxin is important in the management of infants and children receiving the drug for cardiac failure or arrhythmias, or following accidental ingestion. Whether saliva can replace plasma in the therapeutic monitoring of digoxin therapy in children is unclear.

Objective

This study assessed the value of determining saliva digoxin concentration in infants, children, and adolescents.

Methods

Infants, children, and adolescents receiving digoxin for various indications, whose digoxin dosage had remained unchanged for ≥10 days, and whose compliance was good according to the parents were enrolled. Digoxin concentration was measured in paired specimens of citric acid-stimulated mixed saliva and plasma obtained simultaneously.

Results

Eighteen children (10 boys, 8 girls; mean [SD] age, 42.3 [53.1] months [range, 2 months-14 years]) were included in the study. Digoxin therapy was administered for cardiac failure due to dilated cardiomyopathy in 9 patients (50.0%), ventricular septal defect in 4 (22.2%), supraventricular tachycardia in 3 (16.7%), and after cardiac surgery in 2 (11.1%). Digoxin concentration in the 20 paired specimens obtained varied from 0.0 to 0.92 ng/mL (mean [SD], 0.25 [0.26] ng/mL) in saliva and from 0.27 to 1.54 ng/mL (mean [SD], 0.77 [0.40] ng/mL) in plasma. The mean plasma/saliva digoxin concentration ratio was 2.8.

Conclusions

This study of infants, children, and adolescents receiving digoxin for a variety of indications and whose dose was unchanged for ≥10 days showed that marked individual variability in the saliva/plasma concentration ratio precludes the use of saliva in predicting the plasma digoxin concentration. The value of saliva digoxin (as opposed to plasma digoxin) measurements in the assessment of the cardiac effects of the drug in children remains to be determined.     

The effect of carbohydrates on ammonium and ketoacid excretion during starvation

The metabolic effects of oral ingestion of minute quantities of carbohydrate during prolonged starvation were studied in nine obese subjects. Measurements were made during a control period of total starvation, during the ingestion of 7.5 g carbohydrate daily, and finally during the ingestion of 15.0 g carbohydrate daily. Daily ketoacid excretion fell after carbohydrate ingestion and was significantly correlated (r = 0.62, P < 0.01) with the amount of carbohydrate administered. Despite this fall in ketoacids, the concentration of blood ketoacids, plasma free fatty acids, and serum insulin remained constant throughout the study. Urinary ammonium excretion, closely correlated with ketoacid output (r = 0.95, P < 0.001), also fell significantly after carbohydrate ingestion. No significant changes were present in extracellular or urinary pH. Urea nitrogen excretion did not change when urinary ammonium output fell. These results indicate that: the excretion of ketoacids and ammonium in starving man is exquisitely sensitive to minute amounts of ingested carbohydrate; the change in ketonuria appears to be due to increased renal ketoacid reabsorption after carbohydrate ingestion; and the nitrogen-sparing effect of reducing renal ammonium output in starvation can be dissociated from nitrogen sparing occurring because of changes in urine urea excretion.     

Effects of verapamil, diltiazem, and nifedipine on plasma levels and renal excretion of digitoxin

To determine whether verapamil, diltiazem, or nifedipine affect digitoxin kinetics, glycoside plasma concentrations and renal excretion were measured before and during steady-state dosing in 30 patients with cardiac insufficiency. The mean (+/- SD) digitoxin plasma concentration was 14.27 +/- 3.66 ng/ml before and 18.15 +/- 5.33 ng/ml during verapamil dosing in 10 patients over a period of 4 to 6 weeks. Renal digitoxin clearance was not influenced by verapamil, but total body clearance and extrarenal clearance of digitoxin were reduced by 27% and 29%, respectively. Diltiazem resulted in a 6% to 31% (mean = 21%) increase in plasma digitoxin concentrations in five of 10 patients because of reduced extrarenal clearance of digitoxin. In contrast to verapamil, the concomitant dosing of nifedipine over 4 to 6 weeks did not alter digitoxin plasma levels or daily renal excretion. Based on these observations, the risk of digitalis intoxication after combined dosing with verapamil and digitoxin is much less pronounced than that after digoxin, and thus this glycoside is a valuable alternative.     

Increase in serum digoxin concentration produced by quinidine does not increase the potential for digoxin-induced ventricular arrhythmias in dogs

Chronic treatment of dogs with digoxin alone, quinidine alone and digoxin in combination with quinidine was initiated in dogs to assess changes in arrhythmogenic potential associated with the quinidine-induced increase in serum digoxin concentration observed during combined digoxin and quinidine treatment. The arrhythmogenic potential of digoxin was evaluated through the use of the acetylstrophanthidin (AcS) tolerance test. AcS was infused at a rate of 5 micrograms/kg/min until ventricular arrhythmias occurred during a drug-free period and during chronic treatment with digoxin, quinidine and digoxin plus quinidine. The dose of AcS required to initiate ventricular arrhythmias is inversely related to the arrhythmogenic potential of digoxin present at the time of AcS infusion. Administration of quinidine alone in two different dosage regimens produced serum quinidine concentrations of 5.99 +/- 1.18 and 2.99 +/- 0.43 micrograms/ml and significantly increased AcS tolerance, whereas digoxin alone, over a wide range of serum digoxin concentrations, significantly decreased AcS tolerance. This decrease in AcS tolerance was linearly related to the serum digoxin concentration. The addition of quinidine treatment to animals receiving digoxin resulted in a significant elevation in the steady-state serum digoxin concentration. However, the AcS tolerance determined during the elevated serum digoxin concentration induced by quinidine was greater than that determined during treatment with the same dose of digoxin alone. Thus, quinidine administration to animals receiving digoxin resulted in a significant increase in the steady-state serum digoxin concentration but did not increase the arrhythmogenic potential of digoxin over that observed during treatment with the same dose of digoxin alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of digoxin in healthy subjects receiving taranabant,a novel cannabinoid-1 receptor inverse agonist

Introduction

Interaction studies with digoxin (Lanoxin®; GlaxoSmithKline, Research Triangle Park, NC, USA), a commonly prescribed cardiac glycoside with a narrow therapeutic index and a long half-life, are typically required during the development of a new drug, particularly when it is likely that digoxin may be given to patients also treated with the new agent, taranabant—a cannabinoid-1 receptor inverse agonist—for weight loss. This study was designed to establish if this combination of therapy has the potential of a significant pharmacokinetic interaction.

Methods

This open-label, fixed-sequence, two-period study investigated whether taranabant, administered to steady state, affects the well-described single-dose pharmacokinetics of digoxin. During the first period, 12 healthy men and women ranging in age from 21 to 35 years received a single oral dose of digoxin 0.5 mg. Following a 10-day wash out, they started a 19-day taranabant dosing regimen (6 mg once daily from day ?14 to day 5) designed to establish and maintain steady-state levels of taranabant. On study day 1, subjects received a single oral dose of digoxin 0.5 mg. The plasma levels of digoxin were followed for an additional 4 days while the dosing of taranabant continued.

Results

The geometric mean ratio and 90% confidence intervals for digoxin AUC_0-∞ were 0.91 (0.83, 0.99), falling within the prespecified comparability intervals (CI) of (0.8, 1.25), which is within the usually allowed interval for bioequivalence. The geometric mean ratio and 90% CI for digoxin maximum plasma concentration (C_max) were 1.23 (1.09, 1.40). The median time to C_max was the same for both treatments.

Conclusion

Multiple doses of 6 mg taranabant do not have a clinically meaningful effect on the pharmacokinetics of a single oral dose of digoxin.

     

阿奇霉素对地高辛血药浓度的影响

目的 探讨阿奇霉素对地高辛血药浓度的影响.方法长期口服地高辛且血药浓度稳定在0.5～2.0 ng/mL的心力衰竭患者316例,其中158例纳入试验组(口服或静脉滴注阿奇霉素),余下158例纳入对照组(未接受阿奇霉素治疗);酶放大免疫法测定试验组使用阿奇霉素前后的外周血地高辛浓度,并与对照组进行比较.结果 试验组患者在使用阿奇霉素5 d后地高辛血药浓度由(1.1±0.5)ng/mL升高至(1.5±0.5)ng/mL(P<0.05),大于2.0 ng/mL者13例(占8.2%);老年(≥60岁)患者地高辛浓度增高尤其明显(P<0.01).试验组地高辛浓度为(1.5±0.5)ng/mL,高于对照组的(1.1±0.3)ng/mL(P<0.05).结论 阿奇霉素可导致地高辛血药浓度升高,尤其是老年患者;应避免同时使用阿奇霉素和地高辛,减少毒性反应.     

Beta-blockade and binding of digoxin to skeletal muscle

Summary. The effect of beta-blockade and a 1-h bicycle exercise test on the digoxin concentration in skeletal muscle (thigh) and serum was studied in 10 healthy men, who had ingested 0·5 mg digoxin daily for 2 weeks. Each subject performed two exercise tests at 100–140 W during maintenance digoxin treatment and 24 h after the latest dose. They rested in the supine position for 2·5 h before the exercise. Sixty minutes before the start of the exercise 0·25 mg/kg b.w. propranolol or saline (control) were injected (single-blind). At the end of the exercise the mean heart rate was 30% lower with beta-blockade (P < 0·001). During exercise the mean skeletal muscle digoxin concentration increased by 29% (P<0·01) in the control situation and by 12% (NS) with beta-blockade. The results indicate that propranolol partly inhibits the exercise-induced increase in skeletal muscle digoxin binding. This might be due to inhibition of a catecholamine-induced stimulation of Na⁺-K⁺ATPase during exercise.     

CORRELATION BETWEEN PREDICTED AND MEASURED DIGOXIN SERUM CONCENTRATIONS

Measurement of digoxin serum concentration can be useful as a direct guide to the dose appropriate to individual patients. Therefore, we have attempted to predict digoxin serum concentration in 62 patients with a wide range of body weight, age and renal function, using creatinine clearance and individual digoxin dose. Creatinine clearance in each patient was determined by the Cockroft and Gault method (1). Digoxin clearance was determined by Scheiner's method (2). Once digoxin clearance was determined, the predicted steady-state serum concentration was calculated using general pharmacokinetic principles. Each patient was on digoxin therapy for at least 1 month. Digoxin serum concentration was measured by the newly developed fluorescence polarization immunoassay (FPIA). A linear regression analysis was performed on the data from the predicted and measured serum level which yielded a slope of 0.9463, intercept of 0.0950 and a correlation coefficient (r) of 0.9600. The method was found to be very useful to predict digoxin serum levels in overdosed and underdosed patients.     

Digoxin biotransformation

Serum digoxin and metabolites were assayed in plasma and urine by HPLC in 10 dialysis-dependent patients with end-stage renal failure (group I) and in five patients with comparatively normal renal function (group II) after ingestion of 150 muCi 3H-digoxin-12 alpha. Thirteen patients were on maintenance digoxin therapy and were at steady state. Metabolites found regularly but usually in small amounts, were 3 beta-digoxigenin and its mono- and bis-digitoxosides, and 3-keto and 3 alpha(epi)-digoxigenin. Quantitatively the most abundant metabolites were polar and averaged 26% (7 to 76) of the radioactivity in plasma 6 hr after drug, and 60% (11 to 88) for digoxin for all 15 patients. Neither values between group I and II for the polar metabolites nor digoxin differed significantly. The metabolites reacted with antibody to digoxin to varying degrees and may make up an important component of the serum digoxin concentration when determined by standard radioimmunoassay. In some patients, digoxin undergoes extensive biotransformation, mainly, we suggest by hydrolysis, oxidation, epimerization, and conjugation to polar end-metabolites.     

Quinidine reduces biliary clearance of digoxin in man

Quinidine is known to reduce the renal clearance of digoxin, but this effect does not completely explain the influence of quinidine on the total clearance of digoxin. We therefore studied the effect of quinidine administration on biliary clearance of digoxin in five patients with atrial fibrillation. Biliary clearance of digoxin under steady state conditions before and during treatment with quinidine was investigated using a duodenal-marker-perfusion technique. Quinidine caused an average 42% (range 21-65%, P less than 0.02) reduction of the measured biliary clearance of digoxin. We conclude that the biliary effect adds to the previously demonstrated inhibitory effect of quinidine on the renal clearance of digoxin and helps to explain the decrease in total clearance of the drug. This is the first demonstration in man of a pharmacokinetic drug interaction at the level of biliary excretion.     

Pharmacokinetics of cefoperazone in patients with neoplastic disease.

The pharmacokinetics of cefoperazone, a new semisynthetic cephalosporin, were studied in 34 patients with neoplastic disease. This compound was administered in a variety of doses and schedules without observable toxicity in any patient. The mean peak serum concentration after a 15-min intravenous infusion of 2 g was 264 microgram/ml after the first dose; the serum half-life was 2.1 h. There was no significant change in half-life or serum concentrations after 4 or 7 days of therapy. The mean peak serum concentration after infusion of 1 g over 15 min was 133 microgram/ml, with a mean of 10.7 microgram/ml at 6 h. The serum half-life was 2 h. The mean peak serum concentration after infusion of 1 g over 0.5 h was 101 microgram/ml. When 8 g was subsequently administered daily by a continuous infusion schedule, levels were maintained at 80 microgram/ml. When the dose was increased to 16 g daily, serum concentrations were maintained at an average of 153 microgram/ml. Only 37% of cefoperazone was recovered in the urine in a 12-h period after the initial dose, suggesting the importance of other mechanisms of excretion; however, serum concentrations in one patient with renal insufficiency were significantly higher than serum concentrations in patients with normal renal function.     

Assessing the accuracy of a computerized decision support system for digoxin dosing in primary care: an observational study

BACKGROUND: This study was carried out as part of a European Union funded project (PharmDIS-e+), to develop and evaluate software aimed at assisting physicians with drug dosing. A drug that causes particular problems with drug dosing in primary care is digoxin because of its narrow therapeutic range and low therapeutic index. OBJECTIVES: To determine (i) accuracy of the PharmDIS-e+ software for predicting serum digoxin levels in patients who are taking this drug regularly; (ii) whether there are statistically significant differences between predicted digoxin levels and those measured by a laboratory and (iii) whether there are differences between doses prescribed by general practitioners and those suggested by the program. METHODS: We needed 45 patients to have 95% Power to reject the null hypothesis that the mean serum digoxin concentration was within 10% of the mean predicted digoxin concentration. Patients were recruited from two general practices and had been taking digoxin for at least 4 months. Exclusion criteria were dementia, low adherence to digoxin and use of other medications known to interact to a clinically important extent with digoxin. RESULTS: Forty-five patients were recruited. There was a correlation of 0.65 between measured and predicted digoxin concentrations (P < 0.001). The mean difference was 0.12 microg/L (SD 0.26; 95% CI 0.04, 0.19, P = 0.005). Forty-seven per cent of the patients were prescribed the same dose as recommended by the software, 44% were prescribed a higher dose and 9% a lower dose than recommended. CONCLUSION: PharmDIS-e+ software was able to predict serum digoxin levels with acceptable accuracy in most patients.     

Digoxin intoxication: the relationship of clinical presentation to serum digoxin concentration

A radioimmunoassay for serum digoxin concentration has been used to study the interrelationships of circulating levels of the drug and various factors in the clinical setting in 48 hospitalized patients with cardiac rhythm disturbances due to digoxin intoxication. 131 patients on maintenance doses of digoxin without toxicity and 48 patients with equivocal evidence of digoxin excess were also studied and compared with the toxic group.Patients with cardiac rhythm disturbances due to digoxin intoxication tended to be older and to have diminished renal function compared with the nontoxic group; body weight, serum potassium concentration, underlying cardiac rhythm, and nature of cardiac disease were not significantly different for the groups as a whole. Despite comparable mean daily digoxin dosages, digoxin intoxicated patients had a mean serum digoxin concentration of 3.7 +/-1.0 (SD) ng/ml, while nontoxic patients had a mean level of 1.4 +/-0.7 ng/ml (P < 0.001), 90% of patients without evidence of toxicity had serum digoxin concentrations of 2.0 ng/ml or less, while 87% of the toxic group had levels above 2.0; the range of overlap between the two groups extended from 1.6 to 3.0 ng/ml. Patients with atrioventricular block as their principal toxic manifestation had a significantly lower mean serum digoxin concentration than those in whom ectopic impulse formation was the chief rhythm disturbance.Patients with equivocal evidence of digoxin excess had received comparable daily maintenance doses of digoxin but had a mean serum concentration of 1.9 +/-0.8 ng/ml, intermediate between those of the nontoxic (P < 0.005) and toxic (P < 0.001) groups. Renal function as judged by mean blood urea nitrogen concentration was also intermediate.The data indicate that knowledge of the serum digoxin concentration, weighed in the clinical context, is useful in the management of patients receiving this drug.     

Digitalis therapy in practice: correlation between clinical evaluation and plasma digoxin concentration (author's transl)]

In a prospective study 73 patients on maintenance digitalis treatment at the Paracelsus Institute, Bad Hall, were clinically examined and the dosage of the drug was adjusted according to cardiac symptoms. The clinical effects were correlated to digoxin concentrations measured on the day following admission to hospital and on the 21st day of treatment. The following practical conclusions were reached: 1. More than 50% of the patients were underdigitalized. 2. There is often no indication for digitalis therapy in patients with a low daily maintenance digoxin dosage and normal renal funciton. 3. The usual recommended maintenance dosage of digoxin provides serum digoxin levels in the lower region of the therapeutic range. 4. Patients with symptoms of decompensation taking an average dosage of digoxin need more digitalis. There is generally no danger of toxicity when the dosage is increased. 5. The serum digoxin concentration in patients with slightly reduced renal function lies in the upper region of the therapeutic range with usual doses of digoxin.