Serum digoxin concentrations in a representative digoxin — Consuming adult population

Summary As part of health examination of a representative sample of an adult population (n=8000) serum digoxin concentration was measured in 661 patients on continuous digoxin therapy. The prescribed mean daily dose of digoxin was significantly higher in men (223 µg) than in women (201 µg); the dose significantly decreased with increasing age. The mean serum digoxin concentration was the same in men and women and it differed insignificantly between age groups, although older persons tended to have a higher concentration. The age — adjusted mean steady state digoxin concentration was 1.02 ng/ml in men and 0.98 ng/ml in women; in about 60% the concentration was within the therapeutic range (0.80–2.00 ng/ml). The concentrations were clearly related to daily dose of digoxin. At equal dose levels old persons tended to have higher concentrations than younger persons. The interindividual variation in serum digoxin concentrations was very wide. However, when digoxin measurements in the same subjects were repeated about three months later, a good correlation between the two measurements was found. The interval between the last dose of digoxin and the collection of blood (up to 41 h) had relatively little effect on individual serum digoxin concentrations. Patients on concomitant thiazide or loop diuretic therapy had the same mean serum digoxin concentration as those not-receiving a diuretic. The mean concentration was significantly higher in patients taking a thiazide or loop diuretic combined with triamterene. The difference may have been due to an interaction between triamterene and digoxin.     

Clinical study on digoxin tablets with high bioavailability (author's transl)

The relationship between different maintenance doses and the steady-state digoxin blood concentration was studied in 160 patients with heart failure. All patients received digoxin tablets of the same brand (Digacin). The bioavailability of this brand is 82% compared with an i.v. standard. During the treatment with daily doses of 0.2 mg and 0.3 mg average serum digoxin levels of 1.09 +/- 0.45 ng/ml and 1.33 +/- 0.53 ng/ml were measured in patients with normal renal function. The daily dose of 0.4 mg digoxin was in correlation to an average serum level of 1.75 +/- 0.81 ng/ml. 81% and 86% of all patients with normal renal function taking 0.2 or 0.3 mg digoxin every day were found to have levels in the range of 0.7 to 2.0 ng/ml. The influence of sex, age, height, body weight, maintenance dose, serum creatinine and serum potassium on the variance of the digoxin plasma levels was computed by multiple linear regression. The multiple correlation coefficient was r = 0.666, the coefficient of determination (100 r2) being 44.4%. Therefore 44.4% of the total variance could be explained by these variables. Individual variables accounted for the following percentages of the total variance: serum creatinine 29.1%; maintenance dose 14.5%; age 4.3%; and reciprocal of body weight 3.9%.     

Serum digoxin levels related to plasma propafenone levels during concomitant treatment

Nine patients with supraventricular rhythm disorders were treated during 5-day periods with different oral doses (300, 450, 600, and 900 mg daily) of propafenone concomitantly to long-term digoxin treatment. A poor correlation (r = .398; P less than .05) was obtained when the difference between the mean digoxin serum level (calculated with the Cmin data determined each of the 5 days) observed during a given propafenone dose and the mean digoxin serum level observed before propafenone treatment, was correlated with the dose of propafenone; but an evident correlation (r = .778; P less than .01) was found when the difference in digoxin level was correlated with the plasma propafenone concentration. The propafenone effect of increasing digoxin blood levels was thus concluded to be poorly dose dependent but strongly concentration dependent. The association of propafenone to a long-term digoxin treatment can be considered with a low risk of toxicity when plasma propafenone concentration does not exceed about 1000 ng/mL. Propafenone plasma levels are unpredictable in view of their wide interindividual variation for a given dose, so their measurement is advised to detect high levels and consequently to prevent a rise in digoxin serum concentrations with the possibility of toxicity. In clinical practice, when propafenone concentration determinations are not readily available, digoxin serum levels at least have to be carefully monitored.     

Passage of digoxin into cerebrospinal fluid in man

The passage of digoxin into the cerebrospinal fluid (CSF) was studied in 8 infants on maintenance therapy with digoxin, 11 adult patients on long-term digoxin therapy, and 15 patients, previously non-digitalized, who were given 0.5 mg digoxin orally 1 hr to 12 hrs prior to lumbar puncture. Digoxin in the serum and CSF was determined by radioimmunoassay. In the infants a mean serum concentration of 1.5 ng/ml (range 0.7-2.3 ng/ml) was found, and a simultaneous mean CSF concentration of 0.5 ng/ml (range 0.3-1.1 ng/ml). In the adults on long-term therapy, the corresponding figures were 1.1 ng/ml (range 0.5-2.2 ng/ml) and 0.3 ng/ml (range 0-0.6 ng/ml). Among the 15 patients given a single oral dose of digoxin, detectable CSF concentrations (0.2-0.3 ng/ml) were found in five, 1-12 hrs after the administration of the drug. In three paediatric patients with hydrocephalus (3 months-5 years) digoxin therapy was started as an attempt to decrease CSF production. In these patients, the production of CSF was reduced by 17, 25 and 30%, respectively.     

Loading dose of digoxin in renal failure.

1 Twenty-two dialysis dependent patients received an intravenous loading dose of digoxin of 10 microgram/kg and the mean +/- s.d. serum digoxin concentration 24 h later was 1.5 ng/ml +/- 0.4 (range 0.8--2.1 ng/ml). No evidence of toxicity was observed. 2 The average apparent volume of distribution of digoxin in dialysis dependent patients was found to be reduced by about one third compared with that reported for individuals with normal renal function, but there was great variation. 3 An appropriate intravenous loading dose of digoxin in most patients with advanced renal failure is 10 microgram/kg.     

Serum digoxin and beta-methyldigoxin in elderly patients on hospital admission: correlation with home compliance and clinical variables

Summary Serum digoxin and beta-methyldigoxin (BMD) were measured in 165 elderly patients (age >60 years) admitted to hospital, of whom 109 had been treated at home with digoxin and 56 with BMD.The mean BMD level was significantly lower than that of digoxin (1.1 vs. 1.4 ng/ml). Creatinine clearance and daily dose were the variables most strongly associated with digoxin level, and the prescribed dose and serum albumin were the best predictors of the BMD concentration. Compliance was assessed by a compliance index (CI), namely the ratio of the measured glycoside concentration, corrected for creatinine clearance, over the expected steady-state dose, calculated from a hospitalized reference group. Compliant individuals in both treatment groups, i.e. those with a CI > the median value, were characterized by a lower daily dose and dosage frequency.Toxicity, whether clinical or electrocardiographic, was present in 9% of the patients and was associated only with a significantly higher mean serum level of the drug.     

Absorption of digoxin in infants

Summary The bioavailability of digoxin in solution was studied in 4 newborn infants with heart failure. Serum digoxin concentrations were determined by radioimmunoassay using¹²⁵I. Bioavailability was estimated by comparison of the areas under the 8-h serum concentration curves (8-h AUC) after intravenous and oral administration of the glycoside. After oral administration of digoxin (1/4 of the digitalizing dose, 0.05 mg/kg bw), peak serum values of 2.3 – 4.4 ng/ml were reached within 30–90 min. After intravenous administration of the same amount of the glycoside, there was a rapid decrease in serum concentration during the first 2 h, and after about 4 h the serum concentration curves paralled those obtained after oral dosing. Based on within subject comparison of intravenous and oral 8-h AUC's, the mean bioavailability of digoxin was estimated to be 72 per cent (range 52 – 79 per cent). It was concluded that digoxin in solution, given to infants with mild to moderate heart failure, is well absorbed and biologically available to the same extent as in adults.     

Digoxin-desethylamiodarone interaction in the rat: comparison with the effects of amiodarone

We have shown that there is a pharmacokinetic interaction between amiodarone and digoxin that results in an increase in steady-state serum and tissue concentrations of digoxin in rats. There is a linear correlation between serum levels of amiodarone, as well as desethylamiodarone, and steady-state serum digoxin levels in rats treated with amiodarone. Since desethylamiodarone is formed in amounts equal to that of the parent compound during chronic amiodarone therapy, we investigated the possibility of desethylamiodarone directly interacting with digoxin in rats. Rats that received digoxin alone showed a serum level of 0.32 +/- 0.08 ng/ml, whereas those that received combination therapies showed a serum level of 3.25 +/- 1.06 ng/ml (p less than 0.001) with desethylamiodarone administration, and 3.00 +/- 0.87 ng/ml with amiodarone administration. Concomitant administration of desethylamiodarone and digoxin increased digoxin concentration in the myocardium by 110% (p less than 0.001), in the skeletal muscle by 208% (p less than 0.001) and in the brain by 110% (p less than 0.001). The corresponding figures for amiodarone-digoxin administration were 94% (p less than 0.001), 172% (p less than 0.001) and 80% (p less than 0.001). The tissue/serum ratios of digoxin concentrations in the myocardium, skeletal muscle, and brain were decreased in the rats that received combination therapies, indicating reduced tissue binding of digoxin. The data indicate that desethylamiodarone interacts with digoxin in a manner similar to that of the parent compound.     

Comparison of two different loading doses of digoxin in severe renal impairment

Summary The correct loading dose of digoxin in patients with advanced renal failure is still a matter of discussion. The effect has been studied of loading doses of digoxin 0.625 mg or 1.25 mg given over 48 h according to randomized crossover design to healthy volunteers and to two different groups of patients with renal impairment and the same mean endogenous creatinine clearance of about 15 ml/min. The subsequent maintenance dose for 4 days was digoxin 0.25 mg in the volunteers and 0.125 mg in both groups of patients. The minimum plasma digoxin concentrations before each dose was measured by radioimmunoassay and the plasma levels in the different groups have been compared. In the healthy volunteers no significant difference was found during the study, despite wide variation in the plasma digoxin concentration. In contrast, in patients with renal failure, the group with the higher loading dose showed significantly higher plasma concentrations 24, 36 and 48 h after drug administration, reaching the highest mean value of 2.2 ng/ml at 48 h. However, after 120 h of maintenance therapy a mean digoxin concentration of 1.3 mg/ml was found in both groups. Thus, despite different loading doses identical plasma concentrations were reached during administration of the same maintenance therapy. The higher plasma digoxin concentration obtained during administration of a higher loading dose might be the cause of arrythmias in individual patients.     

The Foeto–Maternal Distribution of Digoxin in Early Human Pregnancy

Abstract The concentrations of digoxin in maternal and foetal serum and in foetal tissues were measured after two oral doses in 12–16 weeks pregnancies. In maternal serum a digoxin level of 1.3 ng/ml was found, while the foetal serum level was 0.7 ng/ml. The placenta had a concentration of 5.8 ng/g, but no measurable amounts of digoxin were found in amniotic fluid, foetal heart, kidney, liver or muscle.     

Use of digoxin in a low density population area in Sweden

Summary Plasma digoxin was measured in all patients receiving digoxin (Lanacrist, Draco) in a well-defined low density population area in Sweden. The number of treated patients (n=75) corresponded to 3 % of the population. The average prescribed daily dose of digoxin was 0.25 mg, and the mean plasma concentration (n=74) was 0.85 (S.D. 0.52) ng/ml. Of the concentrations found 3 % were above and 62 % were below the apparent therapeutic range, 1 – 2 ng/ml. The findings were compared with analyses performed in a hospital laboratory (n=300), the majority being inpatients receiving a similar daily dose. In the latter, 22 % had a plasma level above and about 33 % below the apparent therapeutic range. In the former group no difference in plasma digoxin concentration could be demonstrated between patients treated with digoxin (n=34) and those treated with both digoxin and diuretics (n=40). In a group of eight patients plasma digoxin rose significantly after they were informed of the importance of taking their medicine regularly. Poor compliance with prescribed therapy was even documented in patients in cardiac failure.     

Comparative study of the absolute bioavailability of four oral digoxin preparations (author's transl)

In a randomized cross over study on 19 normal subjects the absolute bioavailability of four oral digoxin preparations (Digacin containing a silica gel matrix as preparation A and three other commercial digoxin tablet preparations, B, C and D) were investigated applying digoxin in a daily dose of 0.25 mg for 10 consecutive days. On day 8, 9 and 10, the serum digoxin concentration and the amount of digoxin excreted with 24-h urine were measured radioimmunologically. After i.v. administration the mean serum digoxin concentration amounted to 0.58 ng/ml. With oral administration preparation A achieved the highest concentration (0.51 ng/ml) and preparation C the lowest (0.42 ng/ml). Accordingly, after i.v. administration 118 microgram digoxin were excreted with the 24-h urine and 95 microgram after the oral preparation A and 73 microgram after preparation C, respectively. From the serum concentrations and the amount excreted with the urine the absolute bioavailability was calculated: 88.0 and 80.4%, respectively, for preparation A, 82.5 and 67.2% for preparation B, 72.7 and 61.8% for preparation C, 76.2 and 67.3% for preparation D.     

Evaluation of a sex-based difference in the pharmacokinetics of digoxin

STUDY OBJECTIVE: To determine whether a sex-based difference in digoxin pharmacokinetics exists in patients receiving long-term digoxin therapy for chronic heart failure or atrial fibrillation. DESIGN: Single-center, retrospective review of medical records. SETTING: University-based teaching hospital and outpatient clinic. PATIENTS: Sixty-seven adults (32 men, 35 women) with chronic heart failure or atrial fibrillation who were receiving digoxin therapy. MEASUREMENTS AND MAIN RESULTS: Serum digoxin concentrations and daily digoxin doses were obtained from patients' medical records. Daily doses were adjusted for patients' actual and ideal body weight and body mass index (BMI). The ratio between the serum digoxin concentration and each of the adjusted daily doses of digoxin was compared between men and women. The mean +/- SD serum digoxin concentration was 0.85 +/- 0.51 ng/ml for men compared with 1.02 +/- 0.51 ng/ml for women. Mean +/- SD unadjusted doses of digoxin were 0.180 +/- 0.063 and 0.164 +/- 0.059 mg/day for men and women, respectively; the difference was not statistically significant. Ratios of serum digoxin concentration to daily digoxin doses did not differ by sex when doses were estimated with actual or ideal weight. Only the ratio of the digoxin concentration to the BMI-adjusted dose was significantly different between men and women (0.14 +/- 0.09 and 0.19 +/- 0.11, respectively, p<0.05). CONCLUSION: Sex-based differences in digoxin pharmacokinetics were absent when actual or ideal body weight was used. However, the ratio of serum digoxin concentration to daily digoxin dose adjusted for BMI differed by sex. Because digoxin is distributed to lean body mass, use of the BMI could have overadjusted body weight, leading to inaccurate pharmacokinetic assumptions and calculations. The pharmacokinetics of digoxin do not appear to differ by sex.     

我院 127 例地高辛血药浓度监测与结果分析

目的探讨地高辛血药浓度的监测,促进地高辛科学合理用药。方法回顾性分析127例患者地高辛血药浓度的监测结果,观察其疗效。结果地高辛血药浓度〈0．5ng／ml者10例（7．87％）,0．5~2．0ng／ml者108例（85．04％）,〉2．0ng／ml者9例（7．09％）。结论合理控制地高辛的血药浓度,制订个体化的给药方案,可达到最佳临床治疗效果,有效降低地高辛中毒率,减少药物不良反应的发生。     

Effect of coadministration of verapamil and quinidine on serum digoxin concentration

Both quinidine and verapamil are known to increase the serum digoxin concentration (SDC), and other calcium channel blockers may have a similar effect. Since an increasing number of patients is likely to be treated concurrently with digoxin, quinidine and a calcium channel blocker, a study was done to show whether coadministered quinidine and verapamil would cooperate to elevate the SDC. Nine healthy volunteers on basic digoxin treatment (Leanoxin 0.125 mg t.i.d.) were treated with placebo, verapamil 80 mg t.i.d. and the combination (verapamil 80 mg plus quinidine base 160 mg t.i.d.), for 2 weeks in a randomized sequence. Drug concentration and various cardiovascular parameters were measured each week and/or at the end of each treatment period. Steady state concentrations were always obtained within 1 week and drug levels at the end of the first and second weeks of treatment were almost identical. The plasma verapamil concentration (PVC) was 25.8 +/- 9.9 ng/ml during coadministration of verapamil and digoxin, and 15.7 +/- 6.9 ng/ml during combined verapamil-quinidine coadministration, when the serum quinidine concentration (SQC) was 1.26 +/- 0.50 micrograms/ml. Compared to placebo SDC rose by 53% from 0.62 +/- 0.16 to 0.95 +/- 0.29 ng/ml (p less than 0.001) during verapamil treatment and further to 1.58 +/- 0.38 ng/ml (155% rise; p less than 0.001) during combined verapamil-quinidine coadministration. Thus each drug maintained its own effect on SDC in the presence of the other, and their actions became combined in increasing the SDC.(ABSTRACT TRUNCATED AT 250 WORDS)     

Decrease of intracranial pressure and weight with digoxin in obesity

Fourteen obese patients (body mass index = 34-47 kg/m2; mean = 40 kg/m2) with lumbar cerebrospinal fluid pressure (Pcsf) above 20 cm water in 10 of the 14 patients were treated with digoxin with a serum concentration of at least 1.0 nmol/L (0.8 ng/ml) for 6 months. Pcsf decreased significantly during digoxin medication (p < 0.005). Although there were no diet restrictions, all patients decreased in weight (range: 3-25 kg; mean = 10.6 kg) during the 6 months (p < 0.001). When digoxin medication was stopped in 3 patients, prompt weight increase occurred. Most patients needed progressively increased digoxin doses to attain stabilized serum concentrations at the stipulated level, in 5 patients more than 0.5 mg a day. Five of 13 patients developed diabetes mellitus during the digoxin medication. The larger the dose of digoxin, the greater the risk for diabetes mellitus to occur.     

Nadolol in human serum and breast milk

1 Simultaneous serum and milk samples were collected over a 10-day period from twelve normotensive, lactating subjects who ingested 80 mg nadolol once daily for a period of 5 days. For comparative purposes, serum samples were also collected from seven patients with a history of mild essential hypertension who ingested the same dose of nadolol for a period of 13 days. 2 In lactating subjects, steady-state serum concentrations of nadolol were attained in 3 days. Milk concentrations of nadolol were much higher than serum concentrations starting on Day 3 and throughout the remainder of the study. The mean (+/- s.e. mean) steady-state levels of nadolol in milk (356.9 +/- 40.4 ng/ml) were 4.6 times higher than the mean steady-state levels in serum (77.3 +/- 6.9 ng/ml). 3 In hypertensive patients, the mean serum concentration of nadolol 24 h after the twelfth dose was 40.3 +/- 8.2 ng/ml as compared to a mean serum concentration in lactating subjects of 40.7 +/- 3.4 ng/ml, 24 h after the fifth dose. Mean serum concentrations in hypertensive patients at 1 and 4 h after the final daily dose were not significantly different from those in lactating subjects. 4 It can be estimated that a 5 kg nursing infant would consume about 2-7% of the daily adult therapeutic dose of nadolol. The data suggest that caution should be exercised in the use of nadolol in lactating patients.     

Interaction between digoxin and propafenone

The pharmacokinetic and pharmacodynamic interactions between digoxin and propafenone were investigated in 10 hospitalized patients with heart disease and cardiac arrhythmias. During steady state (0.25 mg/day) the glycoside was combined with 600 mg of propafenone daily for 1 week. The mean +/- SD serum digoxin concentration (SDC) was 0.97 +/- 0.29 ng/ml before and 1.54 +/- 0.65 ng/ml (p less than 0.003) during propafenone administration. Propafenone induced a mean decrease in 31.1 and 31.7% in total and renal digoxin clearances, respectively. The increase in SDCs was accompanied by a decrease in heart rate (HR) and shortening of QTC (QT interval corrected for HR). In patients receiving digoxin and propafenone simultaneously, the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity.     

The effects of captopril on serum digoxin levels in patients with severe congestive heart failure

The effects of captopril on serum digoxin concentrations were studied in 8 patients with severe (NYHA Class IV) congestive heart failure. Serum digoxin concentrations were determined before and after the administration of captopril for 1 week in patients on chronic digoxin therapy. Each patient who was taking 0.25 mg of digoxin PO q.d., was administered 12.5 mg of captopril PO t.i.d. for 7 days. The peak serum concentration of digoxin (Cmax) before and after (on Days 0 and 7) captopril administration was 1.7+/-0.2 ng/ml and 2.7+/-0.2 ng/ml, the time to peak (tmax) was 2.4+/-0.5 h and 1.3+/-0.2 h, and the area under the 24-hour digoxin concentration-time curve (AUC0-24h) was 30.0+/-1.5 ng x h/ml and 41.7+/-3.4 ng x h/ml, respectively. While captopril caused a significant increase in peak serum concentration and the area under the digoxin concentration-time curve, it decreased the time to digoxin peak (p = 0.01, p = 0.04, p = 0.01, respectively). No patient developed evidence of digoxin toxicity. Concomitant administration of captopril with digoxin increases serum digoxin concentration in patients with severe congestive heart failure.