Desethylamiodarone Levels Research Articles

A Significant Drug–Drug Interaction Detected Through Corneal Examination: Resolution of Cornea Verticillata While Using Amiodarone

To describe a patient with resolution of cornea verticillata while still using amiodarone as a result of a drug interaction lowering serum levels of amiodarone. An 83-year-old retired physician with long-standing cornea verticillata was noted to have complete resolution of cornea verticillata on a routine follow-up eye examination. The patient reported complete compliance with using amiodarone daily, with no recent changes in dosage or formulation. Despite this, he reported a recent increase in the frequency of palpitations. He had recently started rifampin for treatment of tuberculosis. Serum amiodarone and desethylamiodarone levels were obtained and found to be below therapeutic range. After rifampin was discontinued, serum amiodarone and desethylamiodarone levels increased to a therapeutic range and cornea verticillata returned after 4 months. In patients currently using amiodarone, clearing of cornea verticillata should alert the ophthalmologists to the possibility of decreased serum amiodarone levels.

Retrospective evaluation of the use of amiodarone in dogs with arrhythmias (from 2003 to 2010)

To evaluate the efficacy of amiodarone in dogs with refractory supraventricular and ventricular arrhythmias and to document the side effects in treated dogs. Records of 28 dogs were retrospectively searched to document indication for amiodarone administration, heart rate, alkaline phosphatase, alanine aminotransferase, thyroxine (T4) and thyroid stimulating hormone values before and after starting treatment and during follow-up periods. Sixteen dogs with supraventricular and 12 dogs with ventricular arrhythmias were treated with amiodarone. Amiodarone treatment significantly reduced the heart rate (P<0.001) and resulted in improvement in the severity of the arrhythmia and clinical signs in 26 dogs. There were no significant differences in alkaline phosphatase (P=0.596), alanine aminotransferase (P=0.842), T4 (P=0.789) and thyroid stimulating hormone (P=0.064) before and after starting amiodarone. On maintenance therapy, median amiodarone blood levels were within the accepted reference range (0.5 to 2.0 mg/L) at 0.8 mg/L (range 0.2 to 11.6 mg/L), but the majority of the desethylamiodarone levels were below normal at 0.1 mg/L (range 0.1 to 0.9 mg/L), based on human reference intervals (0.5 to 2.0 mg/L). Amiodarone may be an effective and safe alternative to treat supraventricular and ventricular arrhythmias in dogs, when common anti-arrhythmic drugs are not effective or contraindicated.

The effect of β-naphthoflavone on the metabolism of amiodarone by hepatic and extra-hepatic microsomes

Amiodarone is a potent antiarrhythmic drug with several limiting side effects, some of which have been correlated with increased levels of its more toxic metabolite, desethylamiodarone. Elevated serum desethylamiodarone to amiodarone ratios are associated with a risk of amiodarone-induced pulmonary toxicity. Polycyclic aromatic hydrocarbons such as β-naphthoflavone are known to increase desethylamiodarone levels in rat in vivo. In this article we investigated if this increase was solely due to increased formation as a result of cytochrome P450 (CYP) 1A1 and 1A2 induction in different rat hepatic and extra-hepatic tissues. Additionally, the effect of amiodarone treatment on CYP1A1 and 1A2 gene expression and activity was investigated. In rats, β-naphthoflavone was found to increase desethylamiodarone forming activity in lung and kidney microsomes. Amiodarone increased β-naphthoflavone mediated induction of CYP1A1 gene expression in liver, lung and kidney. However, there was no significant change in CYP1A activity. As expected, the data indicated that the increase in desethylamiodarone levels in vivo was partly due to increased formation through CYP1A1 induction, although increased formation was only evident in some extra-hepatic tissues. Amiodarone treatment did not affect basal or induced CYP1A activity.

Acute amiodarone toxicity due to an administration error: could excipient be responsible?

Acute amiodarone toxicity due to an administration error: could excipient be responsible?

Control of anti-arrhythmia therapy with amiodarone. Value of the determination of blood levels

An antiarrhythmic treatment was done in 56 patients with recurrent ventricular tachycardias using amiodarone. The dosage was 400 to 600 mg/d following a loading dosage of 1000 mg for 8 to 12 days. Amiodarone and desethylamiodarone concentration in serum (control group n = 33) and in erythrocyte haemolysate (control group n = 13) were determined in relapses of ventricular tachycardias (n = 7) and in pulmonary fibrosis as serious side effect (n = 3). It was shown that amiodarone levels rise continuously during loading treatment until the 8th to 12th day and that desethylamiodarone can be demonstrated after the 3rd day of treatment. The mean concentrations (+/- standard deviation) of amiodarone and desethylamiodarone were 2.21 +/- 0.89 microgram/ml and 1.3 +/- 0.74 microgram/ml in serum and 0.97 +/- 0.65 microgram/ml and 1.95 +/- 1.9 micrograms/ml in erythrocyte haemolysate. Amiodarone levels did not correlate with efficacy and with incidence of side effects. However, in pulmonary fibrosis high desethylamiodarone concentrations in serum (greater than 2.5 micrograms/ml) and in erythrocyte haemolysate (greater than 4 micrograms/ml) were found. Four out of 7 patients with recurrent ventricular tachycardia showed relatively low desethylamiodarone concentrations in serum (desethylamiodarone/amiodarone ratio less than 0.4). Thus control of amiodarone treatment can be enlarged by determination of desethylamiodarone levels as its concentrations correlate with relapses of ventricular tachycardias and serious side effects.

The Effect of Levosimendan during Long‐Term Amiodarone Treatment in Dogs

The haemodynamic and electrophysiological effects of levosimendan were studied in conscious dogs receiving long-term oral amiodarone treatment. Instrumented dogs were administered increasing doses of levosimendan (up to 0.9 microg/kg/min. intravenously) in three successive 30 min. infusions. This schedule was repeated on the 21st day of treatment with oral amiodarone 100 mg/kg/day. The extent of increase in left ventricular systolic pressure (LVSP) and the decrease in left ventricular end-diastolic pressure (LVEDP) seen with levosimendan were similar before and after long-term treatment with amiodarone. The levosimendan-induced increases in isovolumic contraction (+dP/dt) and in left ventricular contractility (dP/dt/P) seen prior to amiodarone administration were augmented during amiodarone treatment, an effect that was statistically significant (P<0.05) at the highest doses of levosimendan. A tendency towards a shortening of the QT interval and a rise in heart rate was observed for levosimendan alone but they did not exceed the physiological range when the drug was given in combination with amiodarone. QTc value was unaffected by levosimendan either alone or with amiodarone. These effects were apparent in animals with therapeutically meaningful plasma levels of levosimendan, amiodarone and desethylamiodarone levels. The results of this study show that the improvement in ventricular contractile performance usually associated with administration of levosimendan was somewhat enhanced by chronic oral treatment with amiodarone. It seems reasonable to infer that the inotropic potency and electrophysiological safety of parenteral levosimendan will be maintained in patients with heart failure during long-term treatment with oral amiodarone.

Myocardial amiodarone concentrations after short- and long-term treatment in patients with end-stage heart failure.

Pharmacokinetics and tissue concentrations of amiodarone may vary considerably in end-stage heart failure, but may be crucial for treatment efficiency and antiarrhythmic drug therapy. This study was undertaken to determine plasma amiodarone and desethylamiodarone concentrations and to determine whether they correlate with myocardial concentrations in explanted hearts from patients with end-stage heart failure. Eight patients with idiopathic dilated cardiomyopathy and normal coronary arteries were included in the present study. Myocardial tissue samples (seven sites) and epicardial fat were taken from each explanted heart, and drug concentrations of amiodarone and desethylamiodarone were determined. In addition, plasma drug levels were measured and compared with the myocardial amiodarone/desethylamiodarone concentrations. The mean cumulative amiodarone dose was 91 g and the mean plasma concentrations of amiodarone and desethylamiodarone were 0.68 and 0.84 microg.ml(-1), respectively. The tissue concentrations of amiodarone amounted to 13.2 and 28.3 microg.g(-1), respectively, in the atria and to 13.0 and 40.8 microg.g(-1), respectively, in the ventricles. The distribution of the drug and its metabolite were similar in the right and left ventricles. There was a good correlation between myocardial concentration of amiodarone and desethylamiodarone and the cumulative ingested dose of amiodarone. Tissue drug concentrations correlated only poorly with plasma amiodarone or desethylamiodarone levels. The highest drug levels were measured in the epicardial fat tissue, where the ratio of amiodarone 105 microg.g(-1) to desethylamiodarone 32 microg.g(-1) was reversed (3.3 compared with 0.29 in the ventricles). Thus, amiodarone concentrations in epicardial fat were approximately 10 times higher than myocardial and 150 times higher than plasma levels. Our data confirm the slow equilibrium of amiodarone and desethylamiodarone concentrations between plasma and myocardium. Myocardial tissue concentrations of desethylamiodarone and, to a lesser degree, amiodarone correlate with the cumulative ingested dose of amiodarone. Monitoring of the total cumulative dose may be more relevant clinically than monitoring plasma levels. These results support the clinical practice of reducing the maintenance dose of amiodarone in patients who are on long-term treatment.

Role of Oxidative Stress in Amiodarone-induced Toxicity.

BACKGROUND: The clinical usefulness of amiodarone for the treatment of cardiac arrhythmias is limited by multiorgan toxicity, especially pulmonary and hepatic. There are conflicting reports in the literature regarding the role of free radicals in the initiation of amiodarone-induced toxicity. We evaluated the possible oxidative stress in a chronic model that is known to manifest pulmonary toxicity. METHODS AND RESULTS: A group of 20 Fischer-344 rats were injected with 60 mg/kg/day of amiodarone for 21 days. A control group of 20 animals received only saline injections. The alveolar macrophages obtained by lung lavage were incubated with hydroethidine and opsonized green fluorescent zymosan particles to measure oxidative and phagocytic activities by flow cytometry. Malondialdehyde levels were measured to assess the extent of lipid peroxidation in lung, liver, spleen, kidney, and heart. Total phospholipid levels in all the collected tissues and distribution of phospholipid classes in the lung and the liver were measured. The levels of amiodarone and its metabolite desethylamiodarone in serum and all collected tissues were measured by high-performance liquid chromatography. The phagocytic activity of th emacrophages from treated animals was decreased by 18-22% (P <.03) compared to controls; however, the oxidative activities of control and treated groups were not significantly different. The tissue malondialdehyde levels were not significantly different except in the spleen where they increased after amiodarone treatment (18.2 +/- 1.1 vs 23.7 +/- 2.8 µM/g tissue, P <.0001). Malondyaldehyde levels were not significantly different when normalized to lipid phosphorous content. Lung, liver, and spleen showed significantly higher phospholipid levels in the treated group. The tissue amiodarone and desethylamiodarone levels in the treated group were highest in spleen followed by lung, liver, kidney, and heart. CONCLUSIONS: The results show that amiodarone-induced pulmonary and hepatic toxicity is not directly mediated by oxidative stress; however, increased lipid peroxidation in the spleen, although secondary to phospholipidosis, may be physiologically significant.

Measurement of tissue-bound amiodarone and its metabolites by computed tomography

Amiodarone is strongly tissue-bound and serum levels are a poor guide to therapeutic efficacy. The electrocardiographic measure of the QT interval corrected for heart rate (QTc) is a better guide but is unhelpful in patients with bundle branch block or U-waves on the electrocardiogram. Myocardial amiodarone levels are the most accurate guide but are not easy to obtain. There is, however, a relationship between myocardial concentration and hepatic concentration of amiodarone and its metabolites. Since amiodarone contains iodine, and there is hepatic uptake, the increased hepatic attenuation from single slice computed tomography was compared with serum levels and the electrocardiographic QTc in 12 patients before and during amiodarone therapy. Hepatic attenuation increased by a mean value of 18.25 HU over a 12 month study period. This increase correlated well with increased QTc (r = 0.83) and with serum amiodarone levels (r = 0.89), but less well with serum desethyl amiodarone levels (r = 0.43). An iodine-containing phantom was used to construct a curve of attenuation against iodine concentration in mol/l. Thus an indirect measurement of amiodarone concentration in g/l wet weight of liver could be determined.

High dose oral amiodarone loading: Electrophysiologic effects and clinical tolerance

Although amiodarone is an effective drug for the treatment of life-threatening ventricular arrhythmias, no standard oral loading dose protocol has been defined, and patients often undergo prolonged hospitalization for amiodarone loading. High dose (>1,800 mg/day) oral loading has usually been reserved for unstable patients with incessant ventricular tachyarrhythmias. The current study was designed to 1) examine the clinical and electrophyslologic effects of a high dose oral antiodarone loading regimen in more stable patients; and 2) ascertain its safety and tolerance, possibly allowing shortened amiodarone loading periods and potentially decreased length of hospital stay.The study group included 16 patients with a history of recurrent ventricular arrhythmias and decreased left ventricular function, who were refractory to prior antiarrhythmic drag therapy. The oral loading protocol was 50 mg/kg per day of amiodarone for 3 days, then 30 mg/kg per day for 2 days, followed by maintenance therapy of 300 to 400 mg twice daily. Electrophysiologic testing was performed at baseline, on days 1 and 5 and during week 6. Amiodarone and desethylamiodarone levels were measured and symptoms monitored.Clinically, the high dose loading protocol was well tolerated in 15 of the 16 patients. Arrhythmias were rendered noninducible by day 1 in three patients and remained noninducible throughout the study period in two of the three. The remaining patients continued to have inducible ventricular tachycardia. Ventricular tachycardia cycle length and right ventricular effective refractory period both progressively increased significantly over baseline, starting on day 1. The 15 patients who remained in the study had no significant side effects during the loading period. Eleven patients have teen followed up for >2 years without any clinical recurrence of their presenting arrhythmia.High dose oral amiodarone loading is clinically well tolerated in patients with life-threatening ventricular arrhythmias who have depressed ventricular function. This regimen may allow decreased loading periods, thereby permitting shorter hospital stays in this patient population.

Effect of amiodarone on non-deiodinative pathway of thyroid hormone metabolism

Amiodarone, an iodine containing anti-arrhythmic drug, causes a significant decrease in molar ratio of daily production rates of T3 and T4 from 0.75 in controls to 0.36 in amiodarone-treated rabbits. A model was constructed from the above data which showed that metabolism of T4 via non-deiodinative pathways (e.g. tetraiodothyroacetic acid and/or conjugates) increased from 29% in untreated controls to 66% in amiodarone-treated rabbits. In this study, we have examined the metabolic clearance rate of tetraiodothyroacetic acid in rabbits given amiodarone (20 mg.kg-1.day-1 ip for 3 weeks) or saline (controls). Serum amiodarone and desethylamiodarone levels under the above experimental conditions were 0.20 +/- 0.067 and 0.17 +/- 0.058 mg/l, respectively, which were in the near-therapeutic range observed in humans. Control and amiodarone-treated rabbits were administered [125I]-tetraiodothyroacetic acid (10 muCi/rabbit) iv and blood was collected at 0.5, 1, 2, 4, 6, 10, 32 and 48 h. Serum tetraiodothyroacetic acid radioactivity was determined by trichloroacetic acid precipitation and ethanol extraction and metabolic clearance rates were calculated from the area under the curve of computer fits to tetraiodothyroacetic acid radioactivity data. Amiodarone treatment decreased metabolic clearance rates significantly from 0.107 +/- 0.008 in controls to 0.074 +/- 0.009 l/day in amiodarone-treated rabbits (p less than 0.05). However, when expressed per unit body weight (1.day-1.kg-1), the metabolic clearance rates were not significantly different between the controls and amiodarone-treated rabbits. The terminal serum elimination half-life in the two groups were similar (32.0 +/- 6.7 h in controls vs 49.2 +/- 12.4 h in amiodarone-treated).(ABSTRACT TRUNCATED AT 250 WORDS)

Tissue drug accumulation and ultrastructural changes during amiodarone administration in rats

Pulmonary and hepatotoxicity are the two major side effects of chronic amiodarone therapy. We studied the accumulation of amiodarone and its principal metabolite, desethylamiodarone, in lung and liver of rats treated ip for 21 to 23 days with either 40 or 80 mg/kg/day amiodarone. The ultrastructural changes in liver, lung, and alveolar macrophages in saline controls and in rats on the two amiodarone dosage regimens were investigated. There was a dose-dependent increase in amiodarone and desethylamiodarone levels in serum and in tissues. The desethylamiodarone/amiodarone ratios in liver and lung, but not in serum, increased significantly with increasing dose. Serum also contained another metabolite, monodeiodinated desethylamiodarone. Increase in vacuolization and presence of whorled lamellar inclusion bodies in alveolar macrophages occurred with an increase in dose and higher lung amiodarone and desethylamiodarone levels. Electron microscopy of the liver of amiodarone-treated rats revealed the presence of large inclusion bodies partially filled with amorphous material in the cytoplasm. The quantitative relationship of the above changes to organ toxicity and to phospholipidosis that accompanies amiodarone administration remains to be established.

Tissue Drug Accumulation and Ultrastructural Changes during Amiodarone Administration in Rats

Pulmonary and hepatotoxicity arc the two major side effects of chronic amiodarone therapy. We studied the accumulation of amiodarone and its principal metabolite, desethylamiodarone, in lung and liver of rats treated ip for 21 to 23 days with either 40 or 80 mg/kg/day amiodarone. The ultrastructural changes in liver, lung, and alveolar macro-phages in saline controls and in rats on the two amiodarone dosage regimens were investigated. There was a dose-dependent increase in amiodarone and desethylamiodarone levels in serum and in tissues. The desethylamiodarone/amiodarone ratios in liver and lung, but not in serum, increased significantly with increasing dose. Serum also contained another metabolite, mono-deiodinated desethylamiodarone. Increase in vacuolization and presence of whorled lamellar inclusion bodies in alveolar macrophages occurred with an increase in dose and higher lung amiodarone and desethylamiodarone levels. Electron microscopy of the liver of amiodarone-treated rats revealed the presence of large inclusion bodies partially filled with amorphous material in the cytoplasm. The quantitative relationship of the above changes to organ toxicity and to phospholipidosis that accompanies amiodarone administration remains to be established.

Dissociation of electrophysiologic and pharmacologic stability during an abbreviated oral loading regimen of amiodarone

Thirty-three patients treated with an abbreviated oral amiodarone loading regimen for ventricular tachycardia underwent electrophysiologic testing in the control state, after 1 week of high-dose (1170 ± 88 mg/day) inpatient therapy; and after an 8-week intermediate (669 ± 129 mg/day) dosing phase. Serum levels of amiodarone and desethylamiodarone were measured by high-pressure liquid chromatography during follow-up electrophysiologic studies. Although the corrected sinus node recovery time, sinoatrial conduction time, and AH and HV intervals remained unchanged throughout the loading period, the sinus cycle length, Wenckebach cycle length, atrial and ventricular refractory periods, and ventricular tachycardia mean and return cycle lengths lengthened significantly by 1 week. They then remained stable for the remainder of the treatment period (control < 1 and 8 weeks, p < 0.05). In contrast, amiodarone and especially desethylamiodarone levels rose from 1 to 8 weeks: 1.29 ± 0.56 to 1.97 ± 0.90 μg/ml ( p = 0.001) and 0.63 ± 0.29 to 1.29 ± 0.61 μg/ml ( p < 0.0001), respectively. Because this regimen produces relatively prompt electrophysiologic changes, which then stabilize, early outpatient management becomes feasible before pharmacologic steady state is attained.

Amiodarone efficacy in a young population: Relationship to serum amiodarone and desethylamiodarone levels

Serum amiodarone and desethylamiodarone levels were measured in children and young adults receiving chronic amiodarone therapy. The study population consisted of 34 children and young adults with ventricular tachycardia (36%), atrial flutter (36%), and recurrent supraventricular tachycardia (27%). The mean age was 12.9 ± 8.6 years (range 4 months to 23 years) and the mean daily dose of amiodarone was 6.6 ± 3.7 mg/kg/day (range 2.5 to 25 mg). Serum amiodarone and desethylamiodarone levels after 10.1 months (range 1 to 40 months) were 0.85 ± 0.63 μg/ml and 0.67 ± 0.42 μg/ml, respectively. In three patients for whom amiodarone therapy was unsuccessful, serum amiodarone levels were 0.27, 0.85, and 1.18 μg/ml. There was no significant correlation between serum amiodarone or desethylamiodarone levels and dosage of amiodarone. Four patients, all 13 years or older, developed toxicity (skin rash [one patient], keratopathy [two patients], and hyperthyroidism [one patient]). There was no correlation between serum amiodarone and desethylamiodarone levels and toxicity; although there was a trend toward elevated reverse serum triiodothyronine levels in patients who developed toxicity, the values fell within the range of those of patients without toxic side effects. Serum amiodarone levels do not appear to be of great value in predicting efficacy and toxicity of amiodarone in children and young adults receiving chronic drug therapy.

Life-threatening postoperative pulmonary complications in patients with previous amiodarone pulmonary toxicity undergoing cardiothoracic operations

Amiodarone therapy for cardiac arrhythmias is increasingly being recognized to be associated with pulmonary toxicity. In this report, we describe the case histories of four patients with previously diagnosed amiodarone pulmonary toxicity in whom the adult respiratory distress syndrome developed after cardiothoracic operations for malignant ventricular arrhythmias. Three patients underwent endocardial resection (two died), and a fourth patient had implantation of an automatic defibrillator unit. Radiographic changes and results of pulmonary function testing are evaluated during initial toxicity and preoperatively. These four patients (mean amiodarone dosage of 420 mg/day for 20 months) are compared to 13 other patients undergoing cardiothoracic operations with prior amiodarone treatment (one patient with preoperative pulmonary toxicity) in whom life-threatening postoperative pulmonary complications did not develop (mean dosage of 550 mg/day for 10 months). Mean preoperative serum amiodarone levels for the four patients were 1.5 micrograms/ml. In the two patients who died, desethylamiodarone levels were 510 and 4,400 micrograms/gm in pulmonary tissue. Histologic examination showed "honeycomb" appearance of the lung with prominent septae, alveolar foamy macrophages, and hyperplasia of alveolar lining cells, consistent with amiodarone pulmonary toxicity. Causes including pump-oxygenator time, oxygen toxicity, anesthetic agents, congestive heart failure, and pulmonary infection superimposed on amiodarone pulmonary toxicity are discussed with a review of the literature.

Interrelationships between serum levels of amiodarone, desethylamiodarone, reverse T 3 and the QT interval during long-term amiodarone treatment

The interrelationships between serum levels of amiodarone, desethylamiodarone, and reverse T 3, and changes in the corrected QT interval (ΔQT c) were examined in 22 patients during long-term treatment with amiodarone. At 1, 3, and 6 months of follow-up, the correlation coefficient between serum levels of amiodarone or desethylamiodarone and reverse T 3 ranged from 0.01 to −0.2 ( p > 0.4). At the same time intervals, the correlation coefficient between both amiodarone and desethylamiodarone levels and ΔQT c ranged from 0.1 to −0.1 ( p > 0.6), and the correlation coefficient between reverse T 3 and ΔQT c also ranged between 0.1 to −0.1 ( p> 0.5). Substituting percent ΔQT c for ΔQT c also did not reveal a significant correlation. These data demonstrate that serum levels of reverse T 3 cannot be used as a substitute for serum levels of amiodarone in monitoring patients being treated with amiodarone. The absence of a correlation between serum reverse T 3 levels and ΔQT c suggests that the delay in repolarization which occurs during amiodarone therapy is not secondary to an amiodarone-induced abnormality in thyroid hormone metabolism.