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.     

Association between antidepressant drug use and hyponatraemia: a case-control study

AIMS: To estimate the risk of, and risk factors for, hyponatraemia associated with the use of selective serotonin reuptake inhibitors (SSRIs) compared with the use of other antidepressant drugs. METHODS: A case-control study of psychiatric in- and out-patients on antidepressant drugs performed in the mid-southern part of The Netherlands over a 2 year period. Cases (n=29) were all using antidepressant drugs with a serum sodium concentration of < or = 130 mmol l(-1) while controls (n=78) were patients on antidepressants with a normal sodium concentration (136-144 mmol l(-1)). Information on blood sodium concentrations was obtained from clinical chemistry data while information on drug use was obtained from community and hospital pharmacy databases. Medical records were used to ascertain possible risk and confounding factors. Unconditional multivariate logistic regression was used to estimate odds ratios for hyponatraemia in patients on SSRIs compared with patients on other antidepressant drugs. RESULTS: SSRIs were associated with an increased risk of hyponatraemia (OR 3.3; 95% CI 1.3, 8.6) compared with other classes of antidepressant drugs. Stratified and interaction analyses revealed that elderly patients using diuretics concomitantly with SSRIs were at the highest risk of experiencing hyponatraemia (OR 13.5; 95% CI 1.8, 101). CONCLUSIONS: SSRIs are more frequently associated with hyponatraemia than other classes of antidepressant drugs. This adverse drug reaction was more common in older patients (> or = 65 years) and in those using diuretics.     

Citalopram-induced severe hyponatraemia with coma and seizure. Case report with literature and spontaneous reports review

Numerous case reports of hyponatraemia followed increasing use of selective serotonin re-uptake inhibitors (SSRIs) but this adverse effect was only rarely observed in relation to citalopram. We report a case of severe hyponatraemia associated with deep coma, seizure, atrial fibrillation and muscle damage in a 92-year-old woman after only two doses of citalopram, and review 14 cases previously published in the literature and 28 cases spontaneously reported to Australian Drug Reaction Advisory Committee (ADRAC). The data presented suggest that citalopram, as well as SSRIs may cause hyponatraemia secondary to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The majority of symptomatic cases occurred in elderly patients (79% were older than 70 years) and in women (74%). Polymedication and concomitant use of another psychotropic drug or thiazide diuretic may precipitate and/or augment the development of hyponatraemia/SIADH. In 84% of cases, the hyponatraemia associated with citalopram was detected during the first month of treatment. High level of suspicion, close and careful monitoring of serum sodium concentration particularly in elderly patients and especially in the first month of therapy with citalopram may reduce the incidence of this serious and likely not rare adverse effect.     

The erythrocyte sodium and potassium in patients treated with digoxin.

1 Four healthy persons and ten patients with heart failure were studied for 5 to 20 days after they started taking digoxin. The sodium content of their erythrocytes increased and there was an equimolar decrease in potassium content. 2 The increase in erythrocyte sodium for a given increase in plasma digoxin during this acute digitalization was less on average and varied more in the patients than in the healthy persons, that is the patients' erythrocytes were less responsive to digoxin. 3 The average erythrocyte sodium was greater in 183 patients who had been taking digoxin for at least 2 months than in 100 healthy persons not taking digoxin but there was no significant correlation between the plasma digoxin concentrations and erythrocyte sodium concentration in the patients. Indeed, there was no apparent change in the erythrocyte sodium in many of the patients taking digoxin. 4 If the erythrocyte sodium concentration is a reliable guide to the tissue effects of digoxin then the results suggest that there is a wide variation in the response to digoxin between patients both during acute digitalization and during chronic treatment with digoxin.     

A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation?

AIMS

Hyponatraemia is one of the major adverse effects of thiazide and thiazide-like diuretics and the leading cause of drug-induced hyponatraemia requiring hospital admission. We sought to review and analyze all published cases of this important condition.

METHODS

Ovid Medline, Embase, Web of Science and PubMed electronic databases were searched to identify all relevant articles published before October 2013. A proportions meta-analysis was undertaken.

RESULTS

One hundred and two articles were identified of which 49 were single patient case reports. Meta-analysis showed that mean age was 75 (95% CI 73, 77) years, 79% were women (95% CI 74, 82) and mean body mass index was 25 (95% CI 20, 30) kg m⁻². Presentation with thiazide-induced hyponatraemia occurred a mean of 19 (95% CI 8, 30) days after starting treatment, with mean trough serum sodium concentration of 116 (95% CI 113, 120) mm and serum potassium of 3.3 (95% CI 3.0, 3.5) mm. Mean urinary sodium concentration was 64 mm (95% CI 47, 81). The most frequently reported drugs were hydrochlorothiazide, indapamide and bendroflumethiazide.

CONCLUSIONS

Patients with thiazide-induced hyponatraemia were characterized by advanced age, female gender, inappropriate saliuresis and mild hypokalaemia. Low BMI was not found to be a significant risk factor, despite previous suggestions. The time from thiazide initiation to presentation with hyponatraemia suggests that the recommended practice of performing a single investigation of serum biochemistry 7–14 days after thiazide initiation may be insufficient or suboptimal. Further larger and more systematic studies of thiazide-induced hyponatraemia are required.     

Hyponatraemia during psychopharmacological treatment: results of a drug surveillance programme

Hyponatraemia (HN) can be a life-threatening medical condition which may lead to severe neurological and psychiatric symptoms. The AMSP (Arzneimittelsicherheit in der Psychiatrie) is a multicentre drug surveillance programme that assesses severe or new adverse drug reactions during psychopharmacological treatment in psychiatric inpatients. We report on a total of 263 864 psychiatric inpatients monitored from 1993 to 2007 in 80 psychiatric hospitals in Germany, Switzerland and Austria. During this period plasma sodium levels below 130 mmol/l (severe HN according to AMSP) were reported in 93 patients (relative frequency 0.04%). On average, the plasma sodium levels of all cases were 119.7 mmol/l (±5.8 s.d.); median 121 mmol/l (range 104-129 mmol/l). Patients who showed no clinical signs (n=65, 70%) had a mean sodium level of 121.3 mmol/l (±5.0 s.d.); median 122 mmol/l (range 114-129 mmol/l). By contrast, patients with clinical symptoms (n=28, 30%) had a mean sodium level of 116.0 mmol/l (±6.0 s.d.); median 117 mmol/l (range 104-125 mmol/l). HN was mainly observed during treatment with selective serotonin reuptake inhibitors (SSRIs) (0.06%), Serotonin noradrenaline reuptake inhibitors (SNRIs) (0.08%), carbamazepine (0.10%) and oxcarbazepine (1.29%); the highest rate was found for oxcarbazepine. Antipsychotics, mirtazapine and tricyclic antidepressants were only rarely involved in HN (0.003-0.005%). Combinations of several drugs known to induce HN significantly increased the risk of HN, e.g. more than 10-fold for SSRI+diuretics+ACE inhibitors (0.37%) vs. SSRI given alone (0.02%). This is clinically relevant because such combinations, e.g. SSRI+diuretics may occur especially in elderly patients, who are in general at higher risk of developing HN.     

The use of diuretics in modern antihypertensive therapy

Abstract: A review is made to sum up the indications when diuretics may be the drug of choice in the treatment of hypertension. Advantages from the combined treatment of thiazide diuretics and other antihypertensive agents are also emphasized. Adverse effects from diuretic treatment, i. e. hypokalemia, hyperuricemia, impaired glucose tolerance and risks associated with unfavourable serum lipoprotein patterns are discussed. It is concluded that from a hemodynamic point of view thiazide diuretics can be a good therapeutic alternative for most patients, excepting those with hyperkinetic circulation. It is recommended to use lower doses of thiazide diuretics than previously and the monitoring of S-potassium is necessary in all patients.     

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.     

地高辛血浓度监测及其影响因素分析

目的: 通过对190例患者地高辛血药浓度监测,分析影响地高辛血浓度的因素,制订合理给药方案,使地高辛用药安全、有效.方法: 使用荧光偏振免疫法监测地高辛血浓度,并统计分析年龄、疾病、合并用药等因素对地高辛血浓度的影响.结果: 年龄老化及疾病状态中肾功能不全、糖尿病和合并应用胺碘酮、排钾利尿药对地高辛血浓度有显著影响(P<0.05).肝功能及合用ACEI、保钾利尿药、钙离子拮抗药对地高辛血浓度无显著影响(P>0.05);结论: 对地高辛进行血药浓度监测具有非常重要的意义.     

噻嗪类利尿剂及氯沙坦对原发性高血压的血清尿酸水平的影响

目的：观察原发性高血压患者分别服用噻嗪类利尿剂、氯沙坦4周后血清尿酸的变化。方法：对在我院连续诊疗的原发性高血压患者128例随机分为利尿剂组和氯沙坦组,利尿剂组63例,氯沙坦组65例。结果：两组药物均能明显降低患者的血压,且两组降压幅度无明显差异。利尿剂组治疗后尿酸平均升高41．67umol/L（P〈0．01）,氯沙坦组平均下降30．47umol/L（P〈0．01）,两组药物治疗后尿酸之问的差异有显著性。结论：噻嗪类利尿剂会升高原发性高血压病患者尿酸水平,氯沙坦可降低原发性高血压患者的尿酸水平。     

Endogenous digoxin-like immunoreactivity in elderly patients with normal serum creatinine concentrations

The effect of digoxin-like immunoreactive substance (DLIS) on serum digoxin determinations in elderly patients with normal serum creatinine concentrations was studied. Patients in the study group were over 70 years of age; the control population was under 55 years of age. All patients had serum creatinine concentrations of less than or equal to 1.5 mg/dL. Apparent digoxin content of serum samples from patients receiving digoxin and from patients in each age group who were not receiving digoxin was determined in duplicate by each of two radioimmunoassays: RIANEN (New England Nuclear), which detects DLIS, and Immophase (Corning Medical and Scientific), which is far less cross-reactive with DLIS. Results from the patients under 55 years of age were analyzed for inherent bias between the assay methods. In patients over 70 years of age, concentrations of DLIS (differences between serum digoxin concentrations measured by RIANEN and Immophase) were compared with creatinine clearance values. No DLIS was detected in sera of patients who had not received digoxin. For patients who received digoxin, nearly all apparent digoxin concentrations were within the usual therapeutic range. For patients without liver or renal failure who received digoxin, no significant difference in digoxin concentrations was observed between the RIANEN and Immophase assays in either the young (n = 17) or elderly (n = 26) patients. There was no significant increase in the difference between the RIANEN and Immophase results with decreasing creatinine clearance. In the elderly patients with normal serum creatinine concentrations, there was no evidence that measurement of serum digoxin concentration using the RIANEN and Immophase assays was compromised by DLIS.     

Digoxin toxicity in the aged. Characterising and avoiding the problem.

Digoxin is one of the most frequently prescribed drugs, particularly in the elderly population where there is an increased prevalence of atrial fibrillation and cardiac failure. The drug has a narrow therapeutic range and has gained a reputation for producing adverse effects in older patients. The more frail elderly patients with coexistent disease, often taking other treatments, are more at risk from digoxin toxicity due to inappropriate dosing, noncompliance, or increased sensitivity to digoxin resulting from pharmacokinetic or pharmacodynamic interactions. Application of basic pharmacological principles may be helpful in anticipating these problems. Elderly patients more commonly receive digoxin than younger patients, which in part accounts for the higher rates of toxicity in this group. Numerous components contribute to the development of toxicity, and diagnosis of toxicity is difficult in this age group. The measurement of serum concentrations can contribute to the clinical diagnosis. A major problem is the accurate diagnosis of digoxin toxicity which may have numerous nonspecific clinical manifestations, many of which are related to coexisting disease in elderly patients. This diagnostic imprecision is well recognised but has been helped by the introduction of serum digoxin measurement. However, reliance on serum concentrations should not replace clinical judgement, since these do not always correlate with toxicity. The apparently decreasing incidence of toxicity over recent years probably reflects several factors: the improvement in digoxin formulations, awareness of digoxin pharmacology, utilisation of serum concentrations, and the realisation that digoxin withdrawal is a viable proposition in elderly patients. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin overdose, especially in the elderly population.     

Syndrome of inappropriate antidiuretic hormone secretion associated with desvenlafaxine

Objective To report a case of syndrome of inappropriate anti-diuretic hormone (SIADH) secretion associated with desvenlafaxine. Case summary A 57-year-old female with hyponatraemia. Her medications included desvenlafaxine, and symptoms included nausea, anxiety and confusion. The serum sodium at this time was 120 mmol/L, serum osmolality was 263 mosmol/kg, urine osmolality 410 mosmol/kg and urine sodium 63 mmol/L, consistent with a diagnosis of SIADH. Desvenlafaxine was ceased and fluid restriction implemented. After 4 days the sodium increased to 128 mmol/L and fluid restriction was relaxed. During her further 3 weeks inpatient admission the serum sodium ranged from 134 to 137 mmol/L during treatment with mirtazapine. Discussion SIADH has been widely reported with a range of antidepressants. This case report suggests that desvenlafaxine might cause clinically significant hyponatremia. Conclusions Clinicians should be aware of the potential for antidepressants to cause hyponatremia, and take appropriate corrective action where necessary.     

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.     

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.     

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。     

A single-blind, comparative study of hydrochlorothiazide/amiloride ('Moduret' 25) and hydrochlorothiazide/triamterene ('dyazide') in elderly patients with congestive heart failure

The efficacy and biochemical effects of two low-dose thiazide plus potassium-sparing diuretic preparations were compared in the treatment of elderly patients with stable, mild to moderate congestive heart failure. Sixty patients (mean age 80 years) were randomly allocated to treatment with 1 tablet daily of either 25 mg hydrochlorothiazide/2.5 mg amiloride or 25 mg hydrochlorothiazide/50 mg triamterene. The dose was increased to 2 tablets daily if necessary, after 2 weeks, for a further 6 weeks. Patients' response to treatment was assessed at 2, 4 and 8 weeks using a simple clinical scoring system for signs and symptoms of their condition, and routine biochemical analysis was carried out at baseline and the end of treatment. One patient was withdrawn from the study due to a rash which was probably related to hydrochlorothiazide/amiloride treatment. A further 11 patients were excluded from the analysis because of intercurrent illness or inadequate records. Analysis of the results from 48 patients showed that both treatments resulted in an improvement in clinical score and weight reduction, with more than three-quarters of the patients responding to treatment. No serious biochemical disturbances occurred; in particular, no new cases of hyponatraemia (serum sodium less than 130 mmol/l) developed. Both preparations, therefore, were effective and tolerated forms of treatment for mild to moderate congestive heart failure in the elderly and there were no significant differences between them.     

355例次地高辛血清浓度监测结果及影响因素分析

目的：探讨地高辛血清浓度影响因素,为临床合理使用地高辛提供用药参考。方法：回顾性分析皖南医学院弋矶山医院2012年1月~2013年8月355例次地高辛血清浓度监测结果。结果：地高辛血清浓度为（1.85±1.04）ng·mL-1,190例次（53.52%）地高辛血清浓度位于0.8~2.0 ng·mL-1,地高辛血清浓度与地高辛剂量成正相关（r=0.281,P〈0.001）,与血清肌酐清除率（Ccr）成负相关（r=-0.261,P〈0.001）,且地高辛血清浓度超出治疗窗比例亦随着Ccr降低而增加（P〈0.001）。35例次（9.86%）出现地高辛中毒,且地高辛大剂量组（〉0.125 mg·d-1）及地高辛血清浓度〉2.0 ng·mL-1更容易发生地高辛中毒（P〈0.001）。结论：地高辛血清浓度影响因素较多,应密切监测地高辛血清浓度并加强监护,保证患者用药安全、有效。     

Decreased renal clearance of digoxin in chronic congestive heart failure

Summary Renal digoxin clearance was compared in patients suffering from atrial fibrillation with well preserved cardiac function (n=9; salt intake ±170 mmol daily) and patients with chronic congestive heart failure (n=10; salt intake 50 mmol daily and maintenance treatment with diuretics). There was no difference between the groups concering digoxin dosage, creatinine clearance, diuresis or sodium excretion in the urine. Digoxin clearance in chronic heart failure proved to be significantly lower than in atrial fibrillation (48±21 vs 71±36 ml·min^–1, p<0.05), and Cdig/Ccreat was similarly reduced at 0.73±0.15 compared to 1.09±0.27 (p<0.005). Steady state serum digoxin concentration was significantly higher in patients with congestive heart failure (1.44±0.47 vs 0.87±0.33 µg·l^–1, p<0.01). Chronic congestive heart failure is a state with reduced digoxin clearance by the kidney, which could lead to digoxin intoxication not explicable by overdose, reduced renal function or the effect of interacting drugs.