Skeletal muscle digoxin concentration during digitalization and during withdrawal of digoxin treatment

Summary Blood samples and skeletal muscle biopsies (m. quadriceps femoris, vastus lateralis) were taken from 15 patients during digitalization or during withdrawal of digoxin treatment for analysis of serum and skeletal muscle digoxin concentrations. A percutaneous needle biopsy technique was used for muscle sampling and digoxin was analysed by radio-immunoassay. During slow digitalization with 0.25 mg digoxin daily the skeletal muscle digoxin concentrations after 2 and 4 days were 45% (range 19%–62%; n=3) and 78% (range 56%–92%; n=3) respectively, of the steady state concentration (defined as the digoxin concentration after 25–40 days of treatment). After 9 and 11 days of treatment the skeletal muscle digoxin concentrations were 106% (range 84%–133%; n=5) and 116% (range 72%–164%; n=3) respectively, of the steady state concentration. A doubling of the digoxin dose gave a proportional increase in skeletal muscle digoxin concentration (three patients). The magnitude of the estimated half-life of skeletal muscle digoxin was the same as previously reported in healthy subjects. No significant correlations were found between changes in systolic time intervals and steady state serum or skeletal muscle digoxin concentrations.     

Quinidine-induced changes in serum and skeletal muscle digoxin concentration; evidence of saturable binding of digoxin to skeletal muscle

Summary Eleven patients with atrial fibrillation on maintenance digoxin therapy were investigated by analysis of serum (SDC) and skeletal muscle (SMDC) digoxin concentrations before and 24 h and 2 weeks after starting quinidine treatment. After cardioversion the maintenance dose of digoxin was reduced in order to obtain the same steady-state SDC after 2 weeks, as before quinidine. SDC was increased by quinidine therapy from 1.56 to 2.40 nmol/1 after 24 h. With the reduced digoxin dose SDC was 1.68 nmol/1 after 2 weeks. The ratio SMDC/SDC decreased after 24 h of quinidine treatment from 35.4 to 29.0 (p<0.01). After 2 weeks of quinidine treatment with the reduced digoxin dose, the ratio had risen to 38.1, which did not differ significantly from the initial ratio. The present data suggest that the reduced skeletal muscle binding of digoxin during quinidine therapy is due to saturation of digoxin binding sites secondary to the increase in the total body load of digoxin at steady-state, and not to direct interference by quinidine with digoxin binding sites.     

Skeletal muscle binding and renal excretion of digoxin in man

Summary Ten healthy subjects were treated with three or four different doses of digoxin, 0.25 to 0.88 mg daily, in random order. Digoxin concentrations in serum (SDC) and skeletal muscle (SMDC) were determined as well as its renal clearance after 2 weeks of treatment with each dose. The mean ratio SMDC/SDC decreased non-significantly by about 20% from 33±15 at the lowest SDC interval (0.5–0.9 nmol/l) to 28±7 at the highest concentration interval (2.0–2.4 nmol/l). This is in accordance with findings from previous studies. No significant change was observed in the renal clearance of digoxin with increasing digoxin concentration, supporting the concept of first-order renal elimination of digoxin.     

Physical exercise and binding of digoxin to skeletal muscle — Effect of muscle activation frequency

Summary Ten healthy subjects who had ingested 0.5 mg digoxin daily for at least 10 days, performed a 1-hour bicycle exercise test on two occasions, 24 h after the latest dose, with the same work load but at two different pedalling rates, 40 and 80 rpm. During exercise the mean digoxin concentration in the thigh muscle increased by 8% at 40 rpm (n.s.) and by 29% at 80 rpm (p<0.01). The serum digoxin concentration decreased by 39% at both pedalling rates (p<0.001). The results suggest that the increase in skeletal muscle digoxin concentration during exercise is related to the neuromuscular activation frequency. The digoxin concentration in erythrocytes was measured in 16 healthy subjects before and 1 minute after a 1-hour bicycle exercise test. The erythrocyte digoxin concentration decreased by 12% (p<0.01) during the exercise indicating that the increased uptake of digoxin in skeletal muscle during exercise influences the digoxin concentration in other tissues.     

Effect of salbutamol on digoxin pharmacokinetics

Summary A single dose of the ₂-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a ₂-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man.Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 g·kg^–1·h^–1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i. v. injection of digoxin 15 g·kg^–1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0–6 h was 15% lower during salbutamol infusion than during saline infusion. Salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. Salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium. The results support the hypothesis that the salbutamol-induced decrease in serum digoxin is caused by increased distribution of digoxin to skeletal muscle (and possibly other tissues), and that this may be secondary to a ₂-adrenoceptor-mediated increase in Na-K-ATPase activity.     

Pharmacokinetics of various single intravenous and oral doses of omeprazole

Summary The effect of a therapeutic dose of oral salbutamol on serum and skeletal muscle digoxin concentrations has been studied in volunteers digitalised with digoxin. On one occasion a biopsy was taken from the quadriceps after 2 h of supine rest and then 3–4 mg salbutamol was given orally. Blood samples were taken before and after that dose and another muscle biopsy specimen was taken from the same thigh 180 min after the medication. On another occasion control blood sampling, ECG and blood pressure recordings were made but without muscle biopsies or salbutamol administration.Compared to the control measurements, salbutamol decreased the serum digoxin concentration (0.30 nmol·1^–1). It also reduced the serum potassium concentration (0.58 mmol·1^–1).The digoxin concentration in skeletal muscle did not change significantly after the intake of salbutamol. Thus, even a therapeutic oral dose of salbutamol reduces the serum digoxin concentration in man.     

The effect of everyday exercise on steady state digoxin concentrations

The purpose of this study was to evaluate the effect of 1 hour of everyday exercise (walking at patient's own pace) on serum digoxin concentrations. Nine white male subjects (ages 58-74) who had been taking the same digoxin dose for greater than 1 month participated. There were three continuous phases: 1 hour of rest, 1 hour of exercise, and a final hour of rest. Serum digoxin concentrations were drawn every 20 minutes. During the first rest period, serum digoxin concentrations rose 30% from the first concentration drawn in the study. After 1 hour of exercise, serum digoxin concentrations fell 26.8% from the last concentration of the first rest period. At the end of the second hour of rest, serum digoxin concentrations increased by 36.6% from the last concentration. Repeated measures analysis of variance demonstrated a significant (P less than .01) change in serum digoxin concentrations. Significant (P less than .01) differences were found between sampling times 0 and 60, 60 and 80, 60 and 100, 60 and 120 and 180 minutes using a paired t-test with Bonferroni correction. A weak correlation (r = 0.74, r2 = 0.55) between percent change in concentrations and age during the exercise phase was found, but there was no correlation between the percent change in concentrations and age during the two immobilization phases. Because significant changes in concentrations occurred during each phase of the study, we conclude that the influence of everyday exercise should be taken into account when interpreting serum digoxin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Digoxin toxicity compared with myocardial digoxin and potassium concentration

1 Twenty-nine dogs were given digoxin (0.25 mg) by mouth twice daily for eight days. Some of them (group 1) also received diuretics and others (group 2) a mineralocorticoid. The dogs were then given an intravenous bolus injection of digoxin and plasma and cardiac muscle were analysed for digoxin and potassium. 2 In the digitalized dogs, myocardial potassium concentration decreased following the intravenous injection of either 0.05 or 0.15 mg/kg digoxin; in contrast, in those dogs given diuretics or mineralocorticoid the potassium concentration increased. 3 Ventricular arrhythmias occurred after digoxin injection (0.05 mg/kg) in the hypokalemic dogs, in those given a mineralocortocoid and in those dogs which received a toxic digoxin dose (0.15 mg/kg). No arrhythmias where seen in the control (digitalized) group. 4 Myocardial digoxin concentrations were similar in the control digitalized group and in the mineralocorticoid-treated dogs after the intravenous administration of the lower digoxin dose (0.05 mg/kg). The myocardial digoxin concentration was significantly higher in the hypokalemic group and in the group receiving the higher digoxin dose (0.15 mg/kg). 5 There was no obvious relationship between the occurrence of arrhythmias and the myocardial concentration of digoxin or potassium.     

Digoxin concentration in right atrial myocardium,skeletal muscle and serum in man: Influence of atrial rhythm

Summary Serum, right atrial myocardium and skeletal muscle collected from 32 adult patients undergoing open heart surgery were analyzed for digoxin by radioimmunoassay. Preoperatively 20 patients were in sinus rhythm and 12 were in atrial fibrillation. In patients with sinus rhythm, but not in patients with atrial fibrillation, there was a highly significant correlation between digoxin concentration in serum and right atrial myocardium, in skeletal muscle and right atrial myocardium, and in serum and skeletal muscle. The means and variances of the ratios right atrial myocardium/serum and right atrial myocardium/skeletal muscle were significantly higher in patients with atrial fibrillation than in those with sinus rhythm. This, plus the lack of difference in ratios skeletal muscle/serum between these groups of patients, indicate increased right atrial digoxin binding in atrial fibrillation in man. This conclusion is further supported by the finding of similar or higher digoxin concentration in right atrial myocardium than in left ventricular myocardium in atrial fibrillation (6 patients), and a lower digoxin concentration in right atrial myocardium than in left ventricular myocardium in sinus rhythm (3 patients).     

Effects of adrenaline and mental stress on serum digoxin concentration.

Physical activity and pharmacological stimulation of beta 2-adrenoceptors by salbutamol increase skeletal muscle digoxin binding with a secondary decrease in serum digoxin, possibly due to increased Na-K-ATPase activity. The present study was undertaken to examine if adrenaline (ADR) infusion and sympathoadrenal stimulation by mental stress affect the serum concentrations of digoxin and potassium. After 10 days on 0.50 mg digoxin orally, 35 healthy volunteers were investigated following 2 h of supine rest. They were divided into four groups: intravenous saline (placebo, n = 10). ADR infusion at the rates of 0.1 nmol kg-1 min-1 (ADR-L, n = 8), 0.4 nmol kg-1 min-1 (ADR-H, n = 7), or subjected to a mental stress [a color-word conflict test (CWT), n = 10]. Arterial blood samples were taken before and during the active period (50 min) and during the following 60 min (at rest) to analyze serum digoxin and potassium and plasma ADR and noradrenaline (NA). All variables were stable during placebo infusion. ADR infusions caused significant and dose-dependent decreases in serum digoxin (p less than 0.05 during ADR-L and p less than 0.001 during ADR-H) and serum potassium (p less than 0.05 and p less than 0.001, respectively). CWT, on the other hand, did not reduce serum digoxin and caused a slight decrease in serum potassium only in the poststress period. Thus, ADR caused dose-dependent shifts of digoxin and potassium, whereas mental stress failed to do so, possibly due to a modest ADR response and small increases in sympathetic nerve activity in skeletal muscle.     

Monoamine uptake inhibition by plasma from healthy volunteers after single oral doses of the antidepressant milnacipran

Summary Beta₂-receptor stimulation has been reported to increase the concentration of³H-ouabain in rat skeletal muscle. The present study was undertaken to see if beta₂-adrenoceptor stimulation by i.v. injection of salbutamol had any influence on the pharmacokinetics of digoxin in man. Ten volunteers were digitalized with digoxin and were investigated on two occasions. On each occasion a muscle biopsy was taken from the quadriceps after 2 h of supine rest. An injection of salbutamol 4 µg·kg^–1 b.wt. or saline was then given intravenously. Blood samples were taken before and after the injection and further muscle biopsy was taken from the same thigh 120 min after the injection.Compared to the injection of saline, salbutamol caused a decrease in the serum digoxin and potassium concentrations. The change in serum potassium was significantly correlated with that in digoxin. The digoxin concentration in skeletal muscle was not significantly changed by either the salbutamol or saline injections.     

心力衰竭患者地高辛血药浓度监测及分析

目的 探讨对应用地高辛的心力衰竭患者进行血药浓度监测的必要性.方法 选择2010年3月至2013年3月于解放军第一一三医院收治的300例心力衰竭患者,均给予地高辛进行治疗,服药时间均超过5个半衰期.将所有患者根据地高辛剂量分为A组（0.125 mg/d地高辛,193例）和B组（0.250 mg/d地高辛,107例）.采用荧光偏振免疫法对患者的地高辛血药浓度进行测定,对地高辛不同给药剂量的血药浓度监测结果、不同地高辛口服剂量与临床疗效的关系、不同地高辛血药浓度与临床疗效的关系进行分析和比较.结果 A组血药浓度＜ 0.8 μg/L和0.8～1.4 μg/L的患者比例均明显多于B组[13.0％ 25例）比1.9％（2例）,24.4％（47例）比7.5％（8例）],差异均有统计学意义（Х^2=10.33、13.09,P＜0.05）;而A组血药浓度＞ 2.0μg/L的患者比例明显少于B组[4.1％（8例）比37.4％（40例）],差异有统计学意义（Х^2=45.74,P＜0.05）.A组有效率为80.3％（155/193）,明显高于B组（65.4％,70/107）,差异有统计学意义（Х^2=8.14,P＜0.05）;A组中毒发生率为7.8％（15/193）,明显低于B组（16.8％,18/107）,差异有统计学意义（Х^2 =5.76,P＜0.05）.地高辛血药浓度＜0.8 μg/L组患者的无效率明显高于地高辛血药浓度0.8 ～1.4、1.5 ～2.0、＞2.0 μg/L组[81.5％（22/27）比36.4％（20/27）、0、0],差异有统计学意义（Х^2=42.03、137.60、137.60,P＜0.05）;地高辛血药浓度1.5 ～2.0 μg/L组有效率明显高于地高辛血药浓度＜0.8、0.8～1.4、＞2.0μg/L组[94.1％（160/170）比18.5％（5/27）、63.6％（35/55）、52.1％（25/48）],差异有统计学意义（Х^2=116.20、27.89、44.85,P＜0.05）;地高辛浓度＞2.0μg/L组的中毒发生率明显高于地高辛血药浓度＜0.8、0.8 ～1.4、1.5～2.0μg/L组[47.9％ （23/48）比0、0、5.9％ （10/170）],差异有统计学意义（Х^2=62.98、62.98、44.85,P＜0.05）.结论 对心力衰竭患者使用地高辛进行治疗时,对患者的血药浓度进行监测是非常必要的,根据监测结果实时调节给药剂量,以保证患者的治疗效果,同时预防药物过量导致中毒.     

地高辛血药浓度监测及个体化给药

目的 测 定患 者 地 高 辛血 药 浓 度 ，为 临 床 合理 用 药 提 供参 考 。 方 法 采 用 荧光 偏 振 免 疫 法测 定８３例 地 高 辛 血 药 浓 度 ，分 析 血 药 浓 度 与 疗 效 的 关 系 及 其 影 响 因 素 以 及 不 同 给 药 方 案 对 测 定 结 果 的 影 响 。 结果 有 效浓 度 范围 （０．８～２．０ 滋ｇ／Ｌ）与临 床 表现 并不 完 全一 致，影响 因 素较 多，不同 给药 方 案监 测结 果 差异 较 大。结论 地 高辛 血 药浓 度监 测 必须 密切 结 合临 床，综合 考 虑各 方面 的 因素 ，实 现个 体化 给 药。     

地高辛血药浓度监测在临床中的应用

目的：探讨地高辛血药浓度监测的临床意义,为临床合理用药提供参考。方法：采用EMIT法测定地高辛血药浓度,对50例患者的79例次m药浓度监测结果进行回顾性分析。结果：79例次地高辛血药浓度测定值在治疗浓度0．8～2．2ng·ml^-1内的共40例次,占50．63％;低于治疗浓度范围下限（〈0．8ng·ml^-1）的18例次,占22．79％;高于治疗浓度上限（〉2．2ng·ml^-1的21例次,占26．58％。性别对地高辛血药浓度兀显著影响。随年龄增大,地高辛血药浓度呈增高的趋势。结论：通过监测地高辛血药浓度说明本院应用地高辛基本合理。对高龄患者应适当减少地高辛剂量。     

Effect of urapidil on steady-state serum digoxin concentration in healthy subjects

Summary In an open, randomized, two-period change-over study the effect of urapidil, an antihypertensive agent, on steady-state serum digoxin levels was investgated in 12 healthy male volunteers. The subjects were given digoxin 0.25 mg once daily for 4 days to produce a steady-state digoxin level in serum. At the end of that time the subjects received either digoxin monotherapy or digoxin and concomitant treatment with urapidil 60 mg b.d. for a further 4 days. Subsequently the treatments were changed over.The absorption characteristics C_max and t_max of digoxin were not altered by concomitant urapidil treatment. The geometric mean and nonparametric 95% confidence limits of digoxin relative bioavailability were 97% (93%–103%).Therefore, concomitant administration of urapidil with digoxin treatments did not appear to alter the rate and extent of absorption of the glycoside.     

我院地高辛血药浓度监测7年回顾性分析

目的　通过对我院 1995～ 2 0 0 1年地高辛血药浓度监测结果进行回顾性的统计分析 ,进一步提高我院临床用药水平。方法　采用荧光偏振免疫法 (FPIA)测定地高辛血药浓度 ,使用spss10 .0版统计软件包对数据进行统计。 结果　性别对地高辛血药浓度无显著性影响 (P >0 .0 5 ) ;年龄对地高辛血药浓度有显著性影响 (P <0 .0 5 )。结论　地高辛血药浓度监测能为临床实行最佳个体化给药提供可靠的依据     

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.     

Plasma digoxin concentration fluctuations associated with timing of plasma sampling and amiodarone administration

A 31-year-old man with dilated cardiomyopathy was hospitalized for new-onset atrial fibrillation. Oral amiodarone 600 mg/day was started to control his arrhythmia, and the patient continued to receive digoxin 0.125 mg/day, which was prescribed 4 days earlier at a heart failure clinic. The patient's digoxin plasma concentration peaked early on hospital day 3 at 2.93 ng/ml; digoxin was withheld. Over the next 3 days, the patient's digoxin plasma concentrations rose and fell daily. These fluctuations correlated with the timing of blood sampling in relation to oral amiodarone administration. The patient's renal function remained stable, and he developed no signs or symptoms of digoxin toxicity. To our knowledge, no case reports have associated significant fluctuations of digoxin plasma concentrations that correspond to the timing of oral amiodarone administration. Tissue-to-plasma redistribution appears to be a possible mechanism for this interaction, with the most significant effect occurring 8-10 hours after amiodarone administration. Clinicians should be aware that digoxin plasma concentrations may not correlate with digoxin tissue concentrations in this setting. When a loading dose of oral amiodarone is required in a patient receiving digoxin, the digoxin dosage should first be reduced, and digoxin therapy should be adjusted based on signs and symptoms of digoxin toxicity.     

The level of plasma neuroendocrine activity and the concentration of digoxin in the serum of patients with mild chronic heart failure

The concentrations of adrenaline, noradrenaline, dopamine, aldosterone, the atrial natriuretic hormone, and plasma renin activity were investigated in 50 patients with mild chronic heart failure. The patients received oral digoxin chronically in a daily dose of 0.125 mg. On the basis of the estimate of the dosing of digoxin these patients were divided into two groups: the first with therapeutic and the second with subtherapeutic concentrations of digoxin in serum. The therapeutic concentration of digoxin in serum was found in 23 patients (46%), while subtherapeutic levels were found in 27 patients (54%). The concentrations of noradrenaline, dopamine, the renin activity of plasma, aldosterone and the atrial natriuretic hormone in the blood serum in the group of patients in whom the presence of subtherapeutic concentrations of digoxin was found, did not differ essentially from the concentration that was observed in the group with therapeutic concentrations. Only the concentration of adrenaline was higher (p < 0.05) in the group of patients with therapeutic concentrations of digoxin. The above results reveal that the neuroendocrine activity of plasma (except for the concentration of adrenaline) is alike in both ranges of digoxin concentrations in serum.     

Common ATP-binding cassette B1 variants are associated with increased digoxin serum concentration

BACKGROUND AND OBJECTIVE: Digoxin is a known substrate of ATP-binding cassette B1 (ABCB1/MDR1). The results of studies on the association between ABCB1 polymorphisms and digoxin kinetics, however, remain contradictory. Almost all studies were small and involved only single dose kinetics. The goal of this study was to establish ABCB1 genotype effect on digoxin blood concentrations in a large cohort of chronic digoxin users in a general Dutch European population. METHODS: Digoxin users were identified in the Rotterdam Study, a prospective population-based cohort study of individuals aged 55 years and above. Digoxin blood levels were gathered from regional hospitals and laboratories. ABCB1 single nucleotide polymorphisms (SNPs) 1236C-->T, 2677G-->T/A, and 3435C-->T were assessed on peripheral blood DNA using Taqman assays. We studied the association between the ABCB1 genotypes and haplotypes, and digoxin blood levels using linear regression models adjusting for potential confounders. RESULTS: Digoxin serum levels and DNA were available for 195 participants (56.4% women, mean age 79.4 years). All three ABCB1 variants were significantly associated with serum digoxin concentration (0.18-0.21 microg/l per additional T allele). The association was even stronger for the 1236-2677-3435 TTT haplotype allele [0.26 mug/l (95% CI 0.14-0.38)], but absent for other haplotypes (CGC allele considered referent), suggesting an interaction of SNPs in a causal haplotype instead of individual SNP effects. CONCLUSION: We found that the common ABCB1 1236C-->T, 2677G-->T, and 3435C-->T variants and the associated TTT haplotype were associated with higher digoxin serum concentrations in a cohort of elderly European digoxin users in the general population.