Chronic Amiodarone Administration Research Articles

Results of preventive radioiodine therapy in euthyroid patients with history of hyperthyroidism prior to administration of amiodarone with permanent atrial fibrillation--a preliminary study.

Radioiodine (RAI) therapy is a standard procedure in the treatment of hyperthyroidism. However, the use of RAI in euthyroid patients requiring chronic administration of amiodarone (AM) where other antiarrhythmic drugs may lack efficacy is still controversial. The aim of this study was to assess the safety and efficacy of an AM therapy prior to treatment with radioiodine therapy in euthyroid patients with permanent atrial fibrillation (PAF), who had been treated for hyperthyroidism in the past. This was a retrospective observational study. Patients were assessed at baseline and two, six, eight, and 12 months after RAI therapy. 17 euthyroid patients with PAF were qualified to the RAI (female/male 3/14; age range 65 to 87, median 71). The patients required chronic administration of AM as a prophylaxis against sudden death. Each patient received an ablative dose of 800 MBq (22 mCi) of 131I. At baseline and during follow-up, no side effects of the therapy and no signs of drug intolerance were observed. Subclinical hyperthyroidism occurred in two (11.8%) cases after two months of RAI and five weeks of AM administration. In this situation, RAI therapy was repeated. Three patients (17.6%) after six months, and another two (11.8%) after eight months, required an additional dose of 131I due to amiodarone-induced thyrotoxicosis (AIT). Twelve patients (70.6%) returned to spontaneous sinus rhythm within two months. Fourteen patients (82.4%) had sinus rhythm during follow-up after six and 12 months of treatment. Preventive RAI in euthyroid (but previously hyperthyroid) patients with PAF before administration of AM may be the method of choice. This is particularly important for patients who will require permanent AM administration as a life-saving drug.

Atrial-selective sodium channel block as a novel strategy for the management of atrial fibrillation

Pharmacological management of atrial fibrillation (AF) remains an important unmet medical need. Because available drugs for rhythm control of AF are often associated with a significant risk for development of ventricular arrhythmias or extracardiac toxicity, recent drug development has focused on agents that are atrial selective. Inhibition of the ultrarapid delayed rectifier potassium current ( I Kur), a current exclusive to atria, is an example of an atrial-selective approach. Recent studies, however, have shown that loss-of-function mutations in KCNA5, the gene that encodes K V1.5, the α subunit of the I Kur channel, is associated with the development of AF and that inhibition of I Kur can promote the induction of AF in experimental models. Another potential atrial-selective approach has recently been identified. Experimental studies have demonstrated important atrioventricular differences in the biophysical properties of the sodium channel and have identified sodium channel blockers that can exploit electrophysiological distinctions between atria and ventricles. Atrial-selective/predominant sodium channel blockers such as ranolazine effectively suppress AF in experimental models involving canine-isolated right atrial preparations at concentrations that produce little to no effect on electrophysiological parameters in ventricular myocardium. Chronic administration of amiodarone was also found to exert atrial-selective depression of I Na-dependent parameters and thus to prevent the induction of AF. Ranolazine and amiodarone have in common the ability to rapidly dissociate from the sodium channel and to prolong the atrial action potential duration via inhibition of I Kr. Our observations suggest that atrial-selective sodium channel block may be a fruitful strategy for the management of AF.

Beat-to-beat variability of repolarization differentiates the extent of torsadogenic potential of multi ion channel-blockers bepridil and amiodarone

Bepridil and amiodarone are known to have a multiple ion channel-blocking property in the heart. In this study, we compared the effects of bepridil on beat-to-beat variability of repolarization, a new predictive marker of torsades de pointes arrhythmia, with those of amiodarone. Bepridil (30 mg/kg, n = 4) or amiodarone (200 mg/day for initial 7 days and 100 mg/day for following 21 days, n = 4) was orally administered to chronic atrioventricular block dogs under the Holter ECG monitoring. The QT interval was prolonged after the administration of bepridil and amiodarone, and torsades de pointes arrhythmia was induced in 3 out of 4 dogs after the bepridil administration, which was not observed during the chronic administration of amiodarone. Beat-to-beat variability of repolarization, quantified as the short-term variability of the QT interval, increased after the administration of bepridil by + 3.0 ms, whereas no significant change was detected in this parameter after the administration of amiodarone. These results suggest that the beat-to-beat variability of repolarization is a useful marker for differentiating the extent of torsadogenic potential of multi ion channel-blockers bepridil and amiodarone.

Chronic Administration of Amiodarone Does Not Affect Na+/Ca2+ Exchange Current in Guinea Pig Cardiac Ventricular Myocytes

We investigated chronic effects of amiodarone on Na+/Ca2+ exchange current (INCX) and on the level of Na+/Ca2+ exchanger (NCX1) mRNA in guinea pig ventricular myocytes using the whole-cell clamp technique and RT-PCR analysis, respectively. Guinea pigs were intraperitoneally injected with 80 mg/kg per day of amiodarone or the vehicle (saline) for 1 or 4 weeks. Single ventricular cells were isolated from the hearts of both groups of animals. Action potential duration at 90% repolarization level was prolonged to 143% and 165% of the control values by treatment with amiodarone for 1 and 4 weeks, respectively. INCX density and the level of NCX1 mRNA were not significantly changed by chronic treatment with amiodarone. The level of thyroid hormone (T4) within the blood was not changed by the treatments. These results suggest that chronic treatment with amiodarone does not affect the Na+/Ca2+ exchanger, with respect to the level of its mRNA and current density in guinea pig ventricular myocytes.

ICD-antiarrhythmic drug and ICD-pacemaker interactions.

Antiarrhythmic drugs and separate bradycardia pacing systems are prescribed commonly in patients with implantable cardioverter defibrillators (ICDs). Adverse effects of antiarrhythmic drugs on ICD function and adverse interactions between ICDs and pacemakers have been documented. The effect of antiarrhythmic drugs on the defibrillation threshold (DFT) in patients has not been well assessed. Most studies have been performed in animal models in which cardiac function was normal and drug doses were supraphysiologic. In addition, most studies have utilized monophasic defibrillation shock waveforms and epicardial lead systems. Despite the lack of clinical data applicable to current defibrillation systems, it appears that chronic amiodarone administration causes a significant DFT increase. In addition, antiarrhythmic drugs can influence antitachycardia pacing and tachycardia sensing. Defibrillation shocks can cause transient failure of pacemaker sensing and pacing, and cause spurious pacemaker reprogramming. Pacemaker function can result in ICD oversensing, leading to inappropriate therapy, or cause ICD undersensing, potentially resulting in failure to deliver therapy during ventricular fibrillation. The susceptibility of an ICD to undersensing appears related to the amplitude of the pacing stimulus artifact recorded by the ICD rate-sensing circuit and to the characteristics of the fibrillation electrogram. Preliminary data suggest that undersensing of ventricular fibrillation by current ICDs is an unlikely event.

Vitamin E reduces accumulation of amiodarone and desethylamiodarone and inhibits phospholipidosis in cultured human cells

Chronic administration of amiodarone (AMIO), widely used by clinicians for the treatment of therapy-resistant cardiac arrhythmias, is frequently associated with serious side-effects. AMIO and its main metabolite desethylamiodarone (DEA) are known to induce phospholipidosis in vivo and in cultured cells presumably by inhibition of lysosomal phospholipid degradation. D- α-Tocopherol = vitamin E ( α-TOC) was able to reduce AMIO and DEA toxicity in cell cultures. Results from the present study showed that α-TOC reduced phospholipidosis in cultured human skin fibroblasts chronically exposed to micromolar concentrations of AMIO and DEA and inhibited cumulative uptake of the drugs in a dose-dependent manner. A linear correlation was observed between cellular AMIO levels and phospholipid accumulation suggesting a stoichiometric relationship. α-TOC was also effective in clearing previously accumulated phospholipids after discontinuation of the drug treatment. The results can best be explained by an interference of α-TOC (a) with drug-phospholipid complex formation responsible for both phospholipid storage and drug accumulation, and (b) with pre-existing drug-phospholipid complexes, accelerating their dissociation and rendering phospholipids to substrates for lysosomal phospholipases. The finding raises hope that side-effects of AMIO and DEA can be prevented or made reversible by the administration of α-TOC. It must, however, be proven that the antiarrhythmic drug will still be effective.

Divergent effects of chronic amiodarone administration on systolic and diastolic function in patients with heart disease

The purpose of this study was to determine the effects of chronic amiodarone treatment on systolic and diastolic function in patients with cardiac disease undergoing treatment for resistant ventricular arrhythmias. Previous studies have shown that chronic amiodarone treatment either has no effect or increases left ventricular ejection fraction, but the effects on diastolic properties of the ventricle have not been defined. Twelve male patients were given loading doses of amiodarone followed by a maintenance regimen. Serial measurements of heart rate, blood pressure, and indexes of systolic and diastolic function were measured by Doppler echocardiographic techniques at baseline conditions and at 2, 8, and 12 weeks of drug therapy. Changes in altered thyroid state were excluded by serial determinations of thyroid function. Amiodarone increased left ventricular ejection fraction (+16%, p < 0.01 by 8 weeks), decreased presystolic ejection period/left ventricular ejection time (−12%, p < 0.01 by 8 weeks), and increased velocity of circumferential fiber shortening (+22%, p < 0.05 by 8 weeks). Amiodarone decreased mitral inflow velocity peak E/peak A (−7%, p < 0.01 by 12 weeks), and increased deceleration and isovolumic relaxation times incrementally (+36% [p < 0.001] and +23% [p < 0.001], respectively, at 12 weeks). Chronically administered amiodarone can improve systolic function and exert a negative lusitropic action in patients with heart disease.

The Use‐Dependent Effects of Acute and Chronic Amiodarone Administration on His‐Purkinje Conduction and the Interaction of β‐Adrenergic Stimulation

Use‐Dependent Effects of Amiodarone. Amiodarone is a highly effective antiarrhythmic agent. However, its exact mechanism of action remains uncertain. Prior studies suggest that intravenous amiodarone produces different electrophysiologic effects than chronic amiodarone administration. In addition, the effects of other antiarrhythmic agents and β‐adrenergic stimulation on the electrophysiologic effects of amiodarone have not been well defined. In this study, we sought to evaluate the use‐dependent effects of intravenous (acute) versus oral (chronic) amiodarone administration on His‐Purkinje conduction in a closed‐chest canine model. We also sought to evaluate the effects of intravenous lidocaine and isoproterenol on the use‐dependent effects of chronically administered oral amiodarone. We found: (1) Acutely administered intravenous amiodarone (5 mg/kg bolus, followed by a 0.05 mg/kg/min infusion) does not produce a significant use‐dependent effect on His‐Purkinje conduction (serum amiodarone level 2.7 ± 1.1 mg/L), and acute beta blockade did not enhance use‐dependent effects of amiodarone; (2) Chronically administered oral amiodarone (1,000 mg/day ± 2 weeks) produced significant use‐dependent effects on His‐Purkinje conduction at similar serum drug concentrations (mean level 2.6 ± 1.5 mg/L; (3) Intravenous lidocaine (10 mg/kg bolus, 0.2 mg/kg/min infusion) produced significant additional use‐dependent effects to that of chronic oral amiodarone but only at rapid paced rates (cycle length 300‐210 msec); and (4) Isoproterenol (5 μg/min infusion) significantly attenuated the use‐dependent effects of chronically administered amiodarone. The mechanism of action of acutely administered intravenous amiodarone appears to be different from that of chronic oral amiodarone. In addition, the marked use‐dependent effects observed after chronic amiodarone administration were reversed after catecholamine administration suggesting that attenuation of use dependence by sympathetic stimulation may negate some of salutary effects of amiodarone.

Amiodarone in patients with previous drug-mediated torsade de pointes. Long-term safety and efficacy.

The safety and efficacy of long-term amiodarone therapy were examined in 12 patients who had previously developed torsade de pointes as a complication of previous antiarrhythmic therapy. The QTc intervals were determined at the time of torsade de pointes (570 +/- 40 ms), after 7 days of amiodarone loading (490 +/- 70 ms), and after 3 months of chronic amiodarone administration (580 +/- 80 ms). Compared to a drug-free control period, QTc was significantly prolonged (P less than 0.05) at the time of torsade de pointes, after amiodarone loading, and after 3 months of amiodarone therapy. The QTc intervals at the time of torsade de pointes and after chronic amiodarone treatment were not significantly different. At 16 +/- 7 months of follow-up, all patients remained free of subsequent torsade de pointes, syncope, or sudden death. In addition, 5 of 6 patients with a history of sustained ventricular tachycardia remained free from arrhythmic recurrence despite persistence of inducible ventricular tachycardia during programmed stimulation studies done before discharge. We conclude that amiodarone can often be used safely and effectively in patients who have previously had an episode of drug-mediated torsade de pointes. Amiodarone-induced QTc prolongation, even when marked, does not predict recurrent torsade de pointes. These observations also suggest that the propensity for a drug to produce this arrhythmia is dependent on other electrophysiologic effects in addition to its ability to simply lengthen repolarization.

A Comparison of the Electrophysiologic Effects of Acute and Chronic Amiodarone Administration on Canine Purkinje Fibers

The electrophysiologic effects of acutely and chronically administered amiodarone on canine Purkinje fibers were assessed using microelectrode techniques to record intracellular action potentials. Chronically treated dogs received amiodarone for 3 weeks (serum levels, 0.91 +/- 0.09 microgram/ml or 1.42 X 10(-6) M). Acute studies were performed using fibers from untreated dogs superfused for 1 h with 5 X 10(-5) M amiodarone (32 micrograms/ml) in Tyrode's solution (KCl = 4 mM). Acute superfusion shortened the action potential duration to 50 and 90% repolarization by 41 and 8%, respectively (p less than 0.01), and decreased Vmax of phase 0 from 418 +/- 20 to 309 +/- 23 V/s (p less than 0.01) (paced cycle length of 500 ms). Prominent use-dependent depression of Vmax was noted. Acute exposure of fibers from untreated dogs to blood from dogs chronically treated with amiodarone using the blood cross-perfusion technique decreased the action potential duration to 50% repolarization and Vmax, similar to acute exposure in Tyrode's solution. Blood cross-perfusion was used to study fibers from treated dogs superfused with blood from another amiodarone-treated dog. Chronic amiodarone prolonged the action potential duration to 90% repolarization by 13% (p less than 0.02) and did not change Vmax when compared to control studies using fibers obtained from untreated dogs superfused with blood from untreated dogs. Thus, the effects of acutely superfused amiodarone on action potentials of canine Purkinje fibers differ from the effects of chronically administered amiodarone.

A Comparison of the Electrophysiologic Effects of Acute and Chronic Amiodarone Administration on Canine Purkinje Fibers

A Comparison of the Electrophysiologic Effects of Acute and Chronic Amiodarone Administration on Canine Purkinje Fibers

Amiodarone alters thyroxine transfer and distribution in humans

Previous studies indicate that increased serum total and free T 4 levels may be secondary to a proportionally greater decrease in serum T 4 clearance rates than in production rates after short-term amiodarone administration, to increased T 4 production rates as well as reduced serum clearance rates in selective hyperthyroxinemia without overt hyperthyroidism following chronic amiodarone administration, and to a relatively greater increase in T 4 production rates than in clearance rates in classical hyperthyroidism. To further evaluate amiodarone-induced alterations of T 4 metabolism, serum T 4 transfer and distribution were evaluated by compartmental analysis of T 4 kinetic studies from eight normal subjects receiving short-term amiodarone or an equivalent amount of iodide, five patients with selective hyperthyroxinemia induced by chronic amiodarone therapy (n = 4) or ioxithalamic acid (n = 1), and five with classical hyperthyroidism. The model consisted of rapidly and slowly equilibrating pools exchanging with serum, with all losses occurring from the tissue pools. Short-term amiodarone administration reduced the fractional T 4 transfer rates between serum and the rapidly equilibrating pool to 82% of baseline. In selective hyperthyroxinemia the fractional rates of T 4 transfer between serum and both extravascular pools were increased sixfold, whereas minimal alterations were present in the hyperthyroid group. The serum equivalent volume of T 4 distribution in the slow pool was significantly reduced following short-term amiodarone, whereas serum and rapid pool volumes were reduced in selective hyperthyroxinemia and slow pool volume was increased in hyperthyroidism. The total mean residence times were increased in the serum and rapid pools following short-term amiodarone, increased in the slow pool in selective hyperthyroxinemia, and decreased in the serum pool with hyperthyroidism. The single-pass mean transit times were increased in the serum and rapid pools after short-term amiodarone, reduced in all three pools with selective hyperthyroxinemia, and reduced only in the rapid pool in the hyperthyroid patients. The reduced bidirectional fractional transfer rates of T 4 between serum and rapidly equilibrating tissues after short-term amiodarone administration may be secondary to amiodarone-induced inhibition of the T 4 transfer process. The decreased serum clearance and disappearance rates may be related to an inhibitory effect of amiodarone on the T 4 degradative process. Altered T 4 metabolism in selective hyperthyroxinemia may be due to a combination of subclinical hyperthyroidism and the effects of amiodarone or the iodinated contrast agent. The rapid exchange of T 4 between serum and both extravascular pools suggests an increase in the T 4 transfer process that cannot be accounted for by decreases in serum or extravascular hormone binding, or by severe hyperthyroidism.

Sensitive method for the measurement of amiodarone and desethylamiodarone in serum and tissue and its application to dispostion studies

A high-performance liquid chromatographic (HPLC) method for the measurement of amiodarone (AM) and its metabolite(s) in serum and tissues was developed. The method uses a 5-μm silica column, methanol containing 0.02% perchloric acid at pH 4 as the mobile phase, and ultraviolet detection at 240 nm. The standard curves for AM and desethylamiodarone (DAM) were linear for serum (range 0.025–6.0 μg/ml) and tissues (range 0.1–0.5 μg for 10–25 mg wet weight). There was a significant decrease as a function of time in AM and DAM concentrations in patients' sera left at ambient temperature in the presence of light. This HPLC method was applied to studies on serum AM elimination kinetics in patients and on tissue uptake during chronic AM administration to rabbits. The elimination half-life (5.8 h) of AM after a 5 mg/kg intravenous dose to a patient was similar to that after acute oral doses. AM, being lipophilic, accumulated maximally in the fat tissue (56 μg/g wet weight), followed by lung and liver in rabbits injected with AM for six weeks. The latter two tissues also contained nearly equal quantities of DAM. The high concentrations of AM and DAM in the liver and lungs may be related to the hepatic toxicity and pulmonary fibrosis associated with chronic AM therapy. Two new metabolites were found in the lung and bile of AM-treated rabbits, but these have not yet been identified.

Amiodarone and N-desethylamiodarone concentrations in plasma, red blood cells, and myocardium after a single oral dose: Relation to hemodynamic effects in surgical patients

In an attempt to assess their respective values for purposes of drug monitoring, plasma, red blood cell, atrial, and ventricular concentrations of amiodarone and N-desethylamiodarone (NDA) were measured, in 50 surgical patients, after a single oral dose (30 mg/kg); hemodynamic changes were assessed also. Amiodarone concentration was lower in red blood cells than in plasma and in myocardium. A relationship was found between the red blood cell concentration and plasma or myocardial concentrations of amiodarone ( r = 0.79 and r = 0.68, p < 0.00001). Hemodynamic studies were available in 17 treated patients and 13 control subjects before and at the time of surgery. In control subjects, hemodynamics did not change with time and general anesthesia. Oral amiodarone decreased the cardiac index ( p < 0.05) and heart rate ( p < 0.001) index. The increase in capillary wedge pressure was related to amiodarone or NDA plasma, myocardial, and red blood cell concentrations (for amiodarone: r = 0.61, p = 0.006; r = 0.69, p < 0.001; and r = 0.53, p = 0.02, respectively). We concluded that oral amiodarone impairs hemodynamics and that measurement of the amiodarone plasma concentration rather than the red blood cell concentration is the easiest method of monitoring the drug. However, establishment of the clinical utility of drug monitoring during chronic administration of amiodarone needs further investigation.

Amiodarone-induced sinoatrial block

We observed sinoatrial block due to chronic amiodarone administration in a 5-year-old boy with primary cardiomyopathy, Wolff-Parkinson-White syndrome and supraventricular tachycardia. Reduction in the dosage of amiodarone resulted in the disappearance of the sinoatrial block and the persistence of asymptomatic sinus bradycardia.

Chronic administration of amiodarone and thyroid function: A follow-up study

In order to evaluate the effects of amiodarone on thyroid function in chronically treated patients, 43 consecutive patients, who had been taking a mean weekly dose of 1420 ± 488 mg for more than 9 months (mean 16.5 months), were studied. In a first evaluation, three patients with hypothyroidism and two with hyperthyroidism were discovered. In the remaining 38 patients, mean T 4 (131 ± 38 nmol/L) and rT 3 (0.85 ± 0.3 nmol/L) levels were significantly higher than reference values ( p < 0.05 and p < 0.001, respectively), and mean T 3 levels (1.89 ± 0.73 nmol/L) were significantly lower ( p < 0.001). Thirteen patients showed hyperresponsiveness to thyrotropin-releasing hormone (TRH) stimulation testing. In a second evaluation, performed 12 to 18 months later, two new cases of hypothyroidism were discovered. T 3 levels showed significantly lower values ( p < 0.02) than in the first evaluation, whereas basal thyroid-stimulating hormone levels and levels 30 and 60 minutes after TRH stimulation were significantly higher than those in the first evaluation ( p < 0.001). Five new hyperresponders to TRH were found. In the present series, the progressive appearance of clinical thyroid dysfunction with an elevated total incidence (16%) is demonstrated. Moreover, a progressively high prevalence of hyperresponsiveness to TRH stimulation is shown. These findings indicate that chronic amiodarone administration may carry a high risk of thyroid dysfunction.

Effects of chronic administration of amiodarone on kinetics of metabolism of iodothyronines.

Treatment with amiodarone, an iodinated anti-arrhythmic drug, is associated with increases in serum rT3 and serum L-T4 with a mild variable decrease in T3. We have examined the metabolic basis for these changes by studying the kinetics of metabolism of 125I-labeled iodothyronines in rabbits given amiodarone (20 mg/kg BW) for 3 weeks. The mean +/- SE MCR of rT3 was significantly (P less than 0.05) lower in amiodarone-treated rabbits (1.88 +/- 0.14 liters/day) than that in the control animals (2.72 +/- 0.25 liters/day), with no appreciable changes in the MCR of T3. The mean MCR of T4 was also significantly lower in amiodarone-treated animals than in controls (0.23 +/- 0.03 vs. 0.37 +/- 0.04 liters/day; P less than 0.05). Amiodarone had no significant effect on daily production rates (PRs) of rT3 or T3, but the PR of T4 showed an increase which was significant (P less than 0.05) when expressed per unit BW. The mean +/- SE molar ratio of daily PRs of T3 and T4 was reduced significantly (P less than 0.05) from 0.75 +/- 0.12 in controls to 0.35 +/- 0.06 in drug-treated rabbits. Amiodarone treatment was also associated with a moderate reduction in the ratio of the PRs of rT3 and T4, but the change was not statistically significant. The overall data suggest that amiodarone administration is associated with a reduction in the MCRs of rT3 and T4 and a reduction in monodeiodination of T4 in the outer ring; monodeiodination of T4 in the inner ring either remains unaffected or decreases moderately.

Elevation of serum lipids after chronic administration of amiodarone in rabbits

Amiodarone hydrochloride is a potent, iodine-containing antiarrhythmic compound with a long elimination half-life, whose cardiac action appears to be mediated through an interference with thyroxine-dependent pathways in the heart. Whether it has any effect on lipid metabolism is not known. Its effect (20 mg/kg per day intraperitoneally) after 3 and 6 weeks of treatment on changes in serum lipoproteins were studied in male New Zealand white rabbits. Serum amiodarone levels reached a steady state (∼ 0.50 μg/ml) after 3 weeks, and serum reverse T 3 (an index of drug dose and duration of treatment) increased 3–4 fold by 3 and 6 weeks. In two discrete sets of studies, serum triglyceride (TG) and total cholesterol (CHOL) increased significantly ( P < 0.01) after 3 and 6 weeks on amiodarone when compared to the values in a control series of animals. Phospholipid (PL) levels were not changed. Very low density lipoproteins (VLDL) in the drug-treated groups showed a significant increase in triglyceride ( P < 0.01) and in apoprotein B ( P < 0.05). There was no change in low density lipoprotein (LDL)-total cholesterol levels, but there was a significant increase in low density lipoprotein-apoprotein B levels. Whether the abnormalities observed in serum lipids induced by amiodarone are mediated through changes in thyroid hormones or occur as a result of a direct effect on lipid metabolism is unknown, but the problem merits further investigation.

Hyperthyroxinemia with bradycardia and normal thyrotropin secretion after chronic amiodarone administration.

Pituitary-thyroid function was tested in 15 euthyroid patients before, during, and after long term oral treatment with amiodarone (2-n-butyl-3,4'-diethylaminoethoxy-3',5'-diiodobenzoylbenzofurane; 600-1200 mg daily), an iodine-containing potent antiarrhythmic drug. The drug caused increases in serum total T4, free T4, and rT3, with a concomitant decrease in T3. Baseline serum TSH was significantly higher after 1 week of drug treatment and returned to normal levels after 12 weeks of treatment. All patients receiving amiodarone had a slowing of their heart rate (P less than 0.01), and heart rate gradually increased 6 weeks after drug withdrawal, concurrent with the slow fall in T4 and rT3 levels. Amiodarone did not cross-react in the iodothyronine RIAs. The results suggest that amiodarone inhibits the peripheral conversion of T4 to T3 and may block the metabolic action of thyroid hormone in man.