Distribution of amiodarone and desethylamiodarone in a patient with acute myocardial infarction after intravenous administration

The autopsy tissues concentration of amiodarone and desethylamiodarone of a man with acute myocardial infarction treated acutely with intravenous amiodarone is reported. Our data indicate that amiodarone is quickly distributed into all highly perfused tissues after intravenous administration with a high amiodarone/desethylamiodarone ratio. We also report here the autopsy case of a woman who died after 30 days of oral therapy with amiodarone. The increase in heart/plasma ratio of amiodarone and desethylamiodarone concentrations and the decrease in amiodarone/desethylamiodarone ratio after one month of therapy could explain the latency in the antiarrhythmic action of the drug.     

Pharmacokinetic evaluation of the digoxin-amiodarone interaction

Amiodarone is known to raise serum digoxin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction in 10 normal subjects. The pharmacokinetic variables for digoxin were determined after a 1.0 mg intravenous dose of digoxin in each subject, before and after oral amiodarone, 400 mg daily for 3 weeks. During amiodarone administration, systemic clearance of digoxin was reduced from 234 +/- 72 ml/min (mean +/- standard deviation) to 172 +/- 33 ml/min (p less than 0.01). This was due to reductions in both renal clearance (from 105 +/- 39 to 84 +/- 15 ml/min) (p less than 0.05) and nonrenal clearance (from 130 +/- 38 to 88 +/- 20 ml/min) (p less than 0.01). Digoxin half-life of elimination was prolonged from 34 +/- 13 to 40 +/- 16 hours (p less than 0.05). Digoxin volume of distribution was not significantly changed. Amiodarone caused a three- to fivefold increase in serum reverse triiodothyronine levels, but changes in thyroid function were not quantitatively related to the changes in digoxin pharmacokinetics. These alterations in digoxin pharmacokinetics produced by amiodarone explain the increase in serum digoxin level that has been observed when this drug combination has been used clinically.     

A previously unrecognized drug interaction between quinidine and digoxin.

Following the development of digoxin radioimmunoassay, we noted that serum digoxin concentrations appeared to rise in patients given quinidine. To further evaluate this important possible interaction between digoxin and quinidine, charts from 863 cardiology patients were reviewed. Ninety two patients received both drugs after having been on digoxin alone; 38 were ineligible for the study because of insufficient data and 27 were excluded because of changing renal function and/or concomitant antiarrhythmic drug therapy, leaving 27. Serum digoxin increased in 25 of the 27 study patients (93%) during quinidine therapy; mean serum digoxin rose from 1.4 ng/ml before quinidine to 3.2 ng/ml during quinidine. Anorexia, nausea and/or vomiting developed in 16 patients (59%) during quinidine therapy, but disappeared in all 10 patients in whom digoxin alone was reduced in dose, suggesting that digoxin had a causative role in the appearance of these symptoms although they developed only after quinidine had begun. Three of thirteen patients with only atrial arrhythmias on digoxin prior to quinidine developed new ventricular premature depolarizations (VPD) after starting quinidine; two of these three as well as four patients with prior VPDs developed new ventricular tachycardia, ventricular fibrillation, asystole, or sudden death. When starting quinidine in patients who are taking digoxin, the clinical course, ECG and serum digoxin should be followed closely.     

The Day-to-Day Variation in Serum Digoxin Concentration

ABSTRACT. Serum digoxin concentration was measured in 70 medical patients 7 and 8 days after admission to hospital. The digoxin treatment taken at home was continued in hospital. There was no statistically significant difference between mean digoxin concentrations in samples taken at day 7 (1.52 nmol/l) and day 8 (1.48 nmol/l). The variation in serum digoxin concentration from day to day expressed as SD was 0.25 nmol/l; 95% confidence limits were +0.51 nmol/1, and 99% confidence limits +0.67 nmol/1. Variations in serum digoxin concentration were not correlated to age, sex, body weight, serum creatinine and the oral dose of digoxin.     

The Diagnostic Value of Determination of Intraerythrocytic Sodium and Potassium Concentrations versus Plasma Digoxin Concentration in Digoxin Intoxication

ABSTRACT Plasma digoxin measurements have proved unserviceable as a means of differentiating between toxic and non-toxic patients. In order to assess the value of a biological effect of digoxin in this discrimination, intraerythrocytic sodium and potassium concentrations were determined in 55 chronically digitalized patients of whom 10 were digoxin-intoxicated according to ECG criteria. Digitoxicity was associated with elevated intraerythrocytic sodium concentration (mean ± SEM 19.3±1.2 versus 11.3±0.3 mmol/1, p<0.001) and reduced intraerythrocytic potassium concentration (94.6±2.3 versus 100.0±0.6 mmol/1, p<0.001) compared to non-toxic patients. Mean (± SEM) plasma digoxin concentrations in the two groups were 3.14±0.41 and 1.57±0.09 nmol/1, respectively (p<0.001). When diagnosing toxicity in chronically digitalized patients, plasma digoxin and intraerythrocytic sodium determinations showed sensitivities of 60 and 100%, respectively. The predictive values of a positive test were 75% for plasma digoxin and 83% for intraerythrocytic sodium.     

The impact of serum concentration-guided digoxin therapy on mortality of heart failure patients: A long-term follow-up,propensity-matched cohort study

BackgroundRecently published studies suggested that digoxin may increase mortality in heart failure with reduced ejection fraction (HFrEF). However, in the vast majority of former trials serum digoxin concentration (SDC) was not measured and therapy was not SDC‐guided.AimTo assess the impact of SDC‐guided digoxin therapy on mortality in HFrEF patients.MethodsData of 580 HFrEF patients were retrospectively analyzed. In patients on digoxin, SDC was measured every 3 months and digoxin dosage was SDC‐guided (target SDC: 0.5‐0.9 ng/mL). All‐cause mortality of digoxin users and nonusers was compared after propensity score matching (PSM).ResultsAfter 7.1 ± 4.7 years follow‐up period (FUP) all‐cause mortality of digoxin users (n = 180) was significantly higher than nonusers (n = 297) (propensity‐adjusted HR = 1.430; 95% CI = 1.134‐1.804; P = .003). Patients having SDC of 0.9 to 1.1 ng/mL (n = 60) or > 1.1 ng/mL (n = 44) at any time during the FUP had an increased risk of all‐cause mortality (HR = 1.750; 95% CI = 1.257‐2.436, P = .001 and HR = 1.687; 95% CI = 1.153‐2.466, P = .007), while patients having a maximal SDC < 0.9 ng/mL (n = 76) had similar mortality risk (HR = 1.139; 95% CI = 0.827‐1.570, P = .426), compared to digoxin nonusers.ConclusionsAccording to our propensity‐matched analysis, SDC‐guided digoxin therapy was associated with increased all‐cause mortality in optimally treated HFrEF patients, especially with SDC ≥0.9 ng/mL. These results reinforce the expert opinion that digoxin in HFrEF can only be used among carefully selected patients with close SDC monitoring.     

胺碘酮在心房颤动治疗中的研究进展

近年来,对心房颤动治疗方法的探讨已成为医学界研究的焦点问题并取得了很大进展,同时胺碘酮在心房颤动治疗中的地位也有所改变。目前胺碘酮在心房颤动中的地位如何,怎样合理地应用胺碘酮?现就这些问题作一综述。     

The meddling microbes midst our medicines

It is not surprising that the complex metabolic machinery of the gut microbiome has accidental, or directed, ability to alter our medicines and influence their efficacy. What is not known is the extent to which this has contributed to drug failures or contraindications, or to the derailment of clinical trials. Some studies are unraveling the mechanisms by which the microbiota alter specific drugs, such as digoxin, and contribute to variations in efficacies between patient populations. Microbiome profiling, therefore, may well become an inevitable arm of all clinical trials in the future.     

Amiodarone as a first-line drug in the treatment of atrial fibrillation: The protagonist viewpoint

Summary The endpoint of pharmacologic therapy in patients with recurrent paroxysmal atrial fibrillation or in patients with chronic atrial fibrillation successfully cardioverted is to prevent recurrences. Recent studies have cautioned against the use of sodium channel blockers (class I agents) in terms of safety. A number of patients with atrial fibrillation have coronary artery disease and the use of class I agents may be of concern, as suggested by the CAST trial. Recently a concern was also raised, regarding the safety of quinidine following cardioversion of atrial fibrillation. In patients with congestive heart failure on antiarrhythmic therapy, the SPAF trial has shown an increase in cardiac mortality and arrhythmic deaths. In this review a case is made in favor of the use of low-dose amiodarone as a first-line agent in patients with atrial fibrillation. Amiodarone is a potent antiarrhythmic agent with little if any negative inotropic effect and, therefore, is the agent of choice in patients with heart failure. In patients with coronary artery disease, the antianginal properties may be useful, and recent studies have shown a decrease in sudden death in the amiodarone group. Therefore, a number of advantages do exist in favor of the use of amiodarone as a first-line drug, at least in selected indications.     

Digoxin is effective,but is it safe?

Summary In the last 15 years several double-blind, placebo-controlled clinical trials have unequivocally shown that digitalis decreases symptoms of cardiac failure, results in a reduction in the need for hospitalization for treatment of congestive heart failure, and improves cardiac function. The major unresolved question concerning digitalis use is its safety. There are experimental data and clinical evidence that digitalis use may be associated with an increased mortality, particularly in the first year or two after an acute myocardial infarction. This increased mortality appears to be present even after adjustment for predictor covariants. This conclusion depends on the ability of statistical methods to account for differences in comorbidity. Since the question of digitalis safety remains after myocardial infarction, the physician should carefully examine the indications for administration of digitalis. More than the usual surveillance is required during chronic digitalis administration.     

Probable early acute hepatitis with parenteral amiodarone

A patient with acute changes suggesting acute hepatitis after parenteral amiodarone administration is described. A 77-year-old man with previous myocardial infarction was admitted with chronic left heart failure and atrial tachycardia. Initial hepatic function tests were strictly normal. After therapy with parenteral amiodarone (2300 mg in 3 days) and other measures, signs of congestive heart failure disappeared; subsequently the patient developed jaundice, marked increase in serum transaminase levels and fall in prothrombin time, and histologic changes of severe centrilobular necrosis were observed in hepatic biopsy. Clinical, laboratory (absence of others markers of hepatic disease), and histological findings seem to rule out common causes of hepatic disease. Therefore, parenteral amiodarone was implicated as the cause of acute hepatitis in this patient. In addition, there were findings suggesting a possibly immunologically mediated mechanism.     

The captopril-digoxin multicenter resarch group study on the comparative steps of captopril and digoxin in patients with mildmoderate heart failure: Implications for therapy

Summary It is argued that the basis of therapy in a patient with mild-to-moderate congestive heart failure should be a combination of a diuretic and a converting enzyme inhibitor, with the further addition of digoxin if necessary.     

Use of fab fragments of digoxin-specific antibodies in the therapy of massive digoxin poisoning

A case of massive digoxin ingestion with multiple arrhythmias, consisting of high grade A-V block and ventricular ectopy not responsive to lidocaine, is described. The arrhythmias ceased following administration of digoxin-specific Fab fragments. The patient improved and was transferred to the psychiatric unit.     

普罗帕酮或胺碘酮联合福辛普利治疗心房颤动的研究

目的评价长期口服低剂量普罗帕酮或胺碘酮联合福辛普利治疗阵发性房颤的疗效及安全性。方法2004年1月～2005年1月在本院门诊及住院就诊的患者，共入选113例阵发性房颤患者，男性60例，女性53例，年龄61．2±5．4（52～72）岁，病程35．7±24．3（3～120）月，其中46例合并高血压，8例合并冠状动脉粥样硬化性心脏病。患者随机分为两组：胺碘酮组（A组）56例，普罗帕酮组（B组）57例。A组，先给予胺碘酮200meg次，3次，d，服用1周；继之200mg／次，2次，d，服用1周；第3周时剂量调整为200meg次，1次，d，以后维持此剂量。B组，给予普罗帕酮150mg／次，3次，d。所有患者均给予福辛普利，高血压患者10mg／d，血压正常者5mg／d。所有患者均随访1年。结果共有94例患者达到随访终点，其中A组46例，B组48例；在随访中，A组用药前1-4次／月，用药后为0．6次／月，p〈0．05，差异有显著性。用药前B组需住院或急诊治疗平均为1．2次／月，用药后为0．9次／月，差异没有显著性。随访结束时，B组复发者24例，47．8％患者仍维持窦律；A组复发者11例，77．1％的患者仍维持窦律，结果明显优于B组（p〈0．01）。A组11例复发者用药前3月平均发作14．2次，用药后3月、6月、9月、12月分别平均发作3．0次、2．6次、2．5次、2．4次，较用药前发作次数均有下降（p值均小于0．05），在随访中没有一例发展为持续性房颤。B组24例复发者用药前3月平均发作18．0次，用药后3月、6月、9月、12月分别平均发作9．5次、10．8次、12．1次、13．5次，较用药前发作次数均有下降（p值均小于0．05），但随着用药时间延长，发作次数呈上升趋势；而且在随访的一年内有3例发展为持续性心房颤动。结论长期低剂量口服普罗帕酮或胺碘酮联合福辛普利均能有效减少阵发性房颤发作的频率，?     

Efficacy of intravenous amiodarone in the management of paroxysmal or new atrial fibrillation with fast ventricular response

We tested the efficacy of intravenous amiodarone (5 mg/kg) in slowing ventricular response and/or restoring sinus rhythm in 26 patients with paroxysmal or new atrial fibrillation with fast ventricular response. There were 16 men and 10 women with ages ranging from 35 to 84 years, mean 63 years. Intravenous amiodarone initially slowed the ventricular response in all patients from 143 +/- 27 to 96 +/- 10 beats/min (P less than 0.001). Twelve patients (46%) reverted to sinus rhythm within the first 30 min (range 5 to 30 min, mean 14 +/- 9 min). One patient reverted to atrial flutter after 10 min and 40 min later to sinus rhythm. Six patients (23%) converted to sinus rhythm after 2 to 8 hr and in these 6 cases, the initial slowing in ventricular response obtained with amiodarone persisted until conversion. Seven patients (27%) did not convert to sinus rhythm following amiodarone administration and they required further medical therapy to slow the ventricular response and/or to convert to sinus rhythm. No serious side effects from drug administration were noted. Intravenous amiodarone appears as a highly effective medication in the conversion or control of new onset atrial fibrillation with fast ventricular response.     

How to digitalize and to maintain optimal digoxin levels in cogestive heart failure

Summary Due to the narrow therapeutic-to-toxic ratio of digoxin, numerous studies have been done to assess the optimal digoxin level in patients with congestive heart faiiure. A digoxin level of 0.7–1.5 ng/mL (or 0.9–2.0 nMol/L) is generally considered optimal, but even at these levels toxicity may occur in certain clinical situations such as severe pulmonary disease or when electrolyte or metabolic disturbanees are present. The optimal daily maintenance dose of digoxin depends on the preparation given and can be calculated by the equation of Jelliffe, which is largely based on the creatinine clearance of the patient. The daily digoxin dose must also be adjusted to take into consideration disease processes or concomitant drug therapy that can alter the volume of distribution, the biotransformation, or the excretion of the drug.