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.     

Poor correlation between predicted ideal and prescribed digoxin dose: a community‐based pharmacokinetic study in the elderly

□ This study assessed if population‐based pharmacokinetics predicted measured plasma digoxin concentrations in elderly community‐managed patients □ Twenty‐seven per cent of the sample showed plasma concentrations consistent with a therapeutic level over an entire 24‐hour dosing schedule; 36 per cent showed therapeutic levels for at least some of the dosing schedule; the remainder showed digoxin concentrations not consistent with achieving a therapeutic plasma concentration for any part of the dosing schedule □ The mean daily prescribed dose of digoxin was significantly lower than that predicted from population kinetics.     

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.     

The pharmacokinetics of beta-methyl digoxin compared with digoxin tablets and capsules

Summary The intestinal absorption and urinary elimination rate of total cardioactive material was compared following digoxin and beta-methyldigoxin (BMD) administration to twelve healthy volunteers. Significantly more injected digoxin was recovered in urine. Urinary clearance was more rapid for digoxin, mean half-lives of elimination being 35 hours for digoxin and 40 hours for BMD. Calculated percentage intestinal absorption was lowest for digoxin tablets with a dissolution rate of 77% in one hour, intermediate for BMD tablets, and maximal for an experimental soft gelatin formulation of digoxin in solution. Respective mean values were 75%, 87% and 97%. Similar steady state plasma concentrations followed twice daily ingestion of the 0.25 mg digoxin tablets and 0.20 mg BMD tablets. Mean peak plasma concentration and percentage urinary recovery of ingested dose were higher during continued BMD administration. Between-subject variation in absorption was higher for the digoxin tablets. The comparative intestinal absorption of BMD and digoxin depends upon the formulation. Digoxin is virtually completely absorbed from a solution encapsulated in soft gelatin. Relatively more BMD is eliminated by nonrenal routes.     

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.     

Serum digoxin levels in patients of a general practice in Germany

Summary Serum digoxin levels were determined in 33 outpatients of a general practice in the countryside, on three occasions at intervals of 8 weeks. All the patients were on long term digoxin treatment, about 2 years on average. About 14 days after the first and the second visits the results of the measurements were sent to the patients, with a comment about their reliability in taking treatment according to the serum digoxin level. At the first visit half of the serum digoxin level were lower than 0.5 ng/ml; the mean serum concentration was 0.52 ng/ml. There was no correlation between serum concentration and age, dose or creatinine level; but there was with replies to the question about regularity of drug intake. The mean serum level at the second and the third visits was 0.88 ng/ml and 0.89 ng/ml, respectively. A correlation was found between the dose and the serum digoxin level. From these results it seems that compliance by the patient plays a major role in producing steady state levels of drugs.Dedicated to Professor Dr. R. Aschenbrenner on the occasion of his 70th birthday     

Interaction between digoxin and indomethacin or ibuprofen.

To study a potential interaction between digoxin and two non-steroid anti-inflammatory drugs, indomethacin (50 mg three times daily) and ibuprofen (600 mg three times daily) were given for 10 days to 10 and 8 patients, respectively, on chronic digoxin treatment. Serum digoxin measured by fluorescence polarisation immunoassay increased significantly (P less than 0.05) during treatment with indomethacin from pre-treatment values of 0.73 +/- 0.34 nmol l-1 (mean +/- s.d.) to a mean value of 1.02 +/- 0.43 nmol l-1, while administration of ibuprofen did not change the steady state serum concentration of digoxin. The result demonstrates that some non-steroidal anti-inflammatory drugs such as indomethacin increase serum digoxin to levels high in the therapeutic range. This should be taken into consideration when co-administering other drugs known to increase the serum concentration of digoxin such as several antiarrhythmics.     

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.     

Comparison of medigoxin and digoxin in the control of atrial fibrillation.

1 Medigoxin (Lanitop) 300 microgram/day and digoxin (Lanoxin) 500 microgram/day were compared in cross-over studies on healthy volunteers and on patients with uncontrolled atrial fibrillation. Serum glycoside concentrations were measured by radioimmunoassay and ventricular rates by ECG. The two regimens appeared to be therapeutically equivalent. 2 The mean serum glycoside concentration in the steady state and the rate at which this state was attained were similar with both drug regimens in the healthy volunteer group. The between-subject variation in serum glycoside concentration was not significantly less during medigoxin administration. 3 The renal clearance of serum glycoside was much lower during medigoxin administration both in healthy volunteers and in patients. This was not due to a difference in serum protein binding. The relatively small dosage requirement for medigoxin was attributed partly to a lower clearance rate and partly to more nearly complete absorption. 4 During the first 2 weeks of the patient study there was a substantial rise in mean serum glycoside concentration and a corresponding fall in ventricular rate. This was attributed to more consistent self-administration of digoxin. The subsequent change to medigoxin had no further effect on mean glycoside concentration, ventricular rate or frequency of ventricular ectopic beats. 5. An attempt to compare the onset of the ventricular rate response to a single oral dose of medigoxin with that to digoxin gave inconclusive results.     

Effect of physical exercise on the pharmacokinetics of digoxin during maintenance treatment

Blood samples were taken repeatedly and urine was collected for digoxin assays on two occasions from 12 healthy male volunteers after an oral maintenance dose of digoxin. On one occasion the subjects exercised intermittently on a bicycle ergometer for 8 h after the dose. On the other occasion they rested in the supine position during the study period. Thirty and 45 min after the intake of digoxin, the serum digoxin concentration was significantly higher during exercise compared with rest, indicating increased absorption rate during exercise. Two and 4 h after the intake of digoxin, the serum digoxin concentration was significantly lower during exercise than during rest. Furthermore, the intermittent bicycle exercise decreased the renal excretion of digoxin during the study period. It also increased the steady state digoxin concentration measured after a terminating standardized period of rest. The most probable reason for these changes in the pharmacokinetics is a previously described increased binding of digoxin to exercising muscles. According to the results, there is reason to believe that the daily physical activity performed by digoxin-treated patients will determine to some extent the body content of digoxin. Changes in activity from day to day may therefore cause variations in the effect of the drug.     

Prognostic Utility of Serum Potassium in Chronic Digoxin Toxicity

Objective

In contrast to patients with acute digoxin overdose, the prognostic utility of the serum potassium concentration for patients with chronic digoxin toxicity is unclear. In such patients, we aimed to evaluate the relationship between pre-treatment serum potassium and survival.

Methods

This was a case-control study at an urban Poison Control Center affiliated with a large urban medical center. We compared the serum potassium concentration between patients with chronic digoxin toxicity resulting in fatality (cases) over a 7-year period (2000–2006) versus survivors (controls) over a 1-year period (2007–2008).

Results

During the study period, there were 13 fatalities (cases) and 13 survivors (controls), of whom seven cases and five controls received appropriately dosed digoxin-specific antibody Fab fragments (Fab). There were no statistically significant differences between cases and controls with respect to serum digoxin concentration, creatinine, age, or sex. Serum potassium elevation pre-Fab was significantly associated with fatality both in mean difference (p<0.03) and using a dichotomous cutoff of 5.0mEq/L (p<0.001), which performed with 92% sensitivity (95% CI 67, 99). In 86% of deaths despite appropriate Fab administration, the clinical presentation included the combination of bradycardia plus hyperkalemia.

Conclusion

In these patients with chronic digoxin toxicity, elevated serum potassium was associated with fatality. The combination of bradycardia and hyperkalemia strongly predicted fatality even in cases with appropriate Fab administration.     

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%.     

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.     

Skeletal muscle digoxin concentration and its relation to serum digoxin concentration and cardiac effect in healthy man

Summary Blood samples and skeletal muscle biopsies (m. quadriceps femoris, vastus lateralis) were taken from seven healthy subjects for analysis of serum and skeletal muscle digoxin concentrations by radioimmunoassay using a percutaneous needle biopsy technique for muscle sampling. The subjects were investigated on two digoxin dose levels and on the third day after withdrawal of digoxin. It was found that the skeletal muscle/serum digoxin ratio was significantly higher than the corresponding ratio obtained in a previous study with muscle sampling (m. rectus abdominis) from patients during open heart surgery. The present study indicates a significant correlation between the digoxin concentrations in serum and skeletal muscle as well as between cardiac effect, measured by changes in QS₂I, and skeletal muscle digoxin concentration. A doubling of the digoxin dose gave a proportional increase in skeletal muscle digoxin concentration. The magnitude of the estimated half-life of skeletal muscle digoxin was the same as previously reported for serum or plasma digoxin.     

地高辛血清浓度影响因素及我院合理应用情况分析

目的:探讨影响地高辛血清浓度(SDC)的因素及我院应用现状,为临床提高地高辛的合理应用比例提出建议。方法:收集2008～2009年我院445名住院患者581例/次服用地高辛并测定血清浓度的临床资料。分析我院目前地高辛应用的现状,应用多元逐步回归法分析年龄(Age)、性别(Gen)、科室(Dept)、合并用药(Drug)、血清肌酐浓度(Scr)、服药剂量(Dose)与SDC的关系。结果:Age、Gen、Dept、Drug、Scr、Dose与SDC有相关性。结论:SDC个体差异较大,影响因素较多。调查中16.2%服用地高辛患者出现不良反应,胃肠道反应最常见,对于其引起的心律失常不良反应应该引起足够的重视。我院外科住院患者SDC相对内科患者高(P<0.05)。对于大多数患者而言,每日用药剂量不宜>0.125mg。老年女性患者应用地高辛尤应注意用药剂量,及时监测。药师在地高辛的合理用药中应发挥更多的作用。     

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.     

Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients

Digoxin, a drug of narrow therapeutic index, is a substrate for common transmembrane transporter, P-glycoprotein, encoded by ABCB1 ( MDR1 ) gene. It has been suggested that ABCB1 polymorphism, as well as co-administration of P-glycoprotein inhibitors, may influence digoxin bioavailability. The aim of the present study was to evaluate the effects of ABCB1 gene polymorphism and P-gp inhibitor co-administration on steady-state digoxin serum concentration in congestive heart failure patients. Digoxin concentrations as well as 3435C > T and 2677G > A,T ABCB1 single nucleotide polymorphisms, were determined in 77 patients administered digoxin (0.25 mg daily) and methyldigoxin (0.50 mg daily), some of them co-medicated with known P-glycoprotein (Pgp) inhibitors. Significant differences were noted in digoxin serum concentrations (C(min,ss)) between patients co-administered and not co-administered P-gp inhibitors: 0.868 +/- 0.348 and 0.524 +/- 0.281 for digoxin (p < 0.002), as well as 1.280 +/- 0.524 and 0.908 +/- 0.358 for methyldigoxin (p < 0.02), respectively. No influence of ABCB1 2677G > A,T and C3435C > T polymorphisms on digoxin concentration was noted. Although some of the previous studies have shown that digoxin pharmacokinetics might be affected by ABCB1 genetic polymorphism, those modest changes are probably clinically irrelevant, and digoxin dose adjustment should include P-gp inhibitor co-administration rather than ABCB1 genotyping.     

地高辛治疗窗浓度的再探讨

目的:探讨地高辛治疗慢性心力衰竭的血清治疗窗浓度范围。方法:将心力衰竭患者随机分成小剂量组和常规剂量组,分别给予小剂量和常规剂量地高辛治疗,采用荧光偏振免疫法测定地高辛血药浓度。结果:小剂量组有效率、无效率、中毒率分别为71.9%、21.9%、6.3%,常规剂量组分别为64.7%、19.1%、16.2%,2组有效率、无效率均无显著性差异(P>0.05),中毒率小剂量组显著低于常规剂量组(P<0.05);小剂量组地高辛有效、无效、中毒浓度分别为(0.87±0.41)、(0.67±0.34)、(1.70±0.48)μg/L,常规剂量组分别为(1.11±0.48)、(0.71±0.39)、(1.69±0.63)μg/L,2组地高辛无效浓度、中毒浓度均无显著性差异(P>0.05),地高辛有效浓度小剂量组显著低于常规剂量组(P<0.01)。结论:地高辛治疗慢性心力衰竭的血清治疗窗浓度范围以0.50～1.50μg/L为宜。     

Relationship between dose and plasma level of digoxin and patient characteristics

Summary The correlation between the daily dose of digoxin, its plasma level and clinical characteristics of 213 patients receiving -acetyldigoxin treatment has been evaluated. After logarithmic transformation of lognormally distributed variables multiple linear regression analysis was performed. Eight predictor variables were chosen: sex, age, height, weight, glycoside dose, creatinine and potassium level in serum and dose of spironolactone. The resulting correlation coefficient was 0.46, i. e. only 100×r²=21.4% of the variance of the steady state digoxin plasma level could be interpreted with the aid of these variables. For only 4 of the 8 variables (age, glycoside dose, serum level of creatinine, and spironolactone dose) were partial coefficients of regression and of correlation significantly different from zero. Almost 80% of the variance could not be accounted for. This finding is in accordance with conclusions in the literature.