benzofurans and Thyroid-Diseases

Amiodarone and dronedarone are two clinically important benzofuran derivatives. Amiodarone has been used widely for treating resistant tachyarrhythmias in the past three decades. However amiodarone and its main metabolically active metabolite desethylamiodarone can adversely affect many organs, including the thyroid gland. Amiodarone-induced thyroid disorders are common and often present as a management challenge for endocrinologists. The pathogenesis of amiodarone-induced thyroid dysfunction is complex but the inherent effects of the drug itself as well as its high iodine content appear to play a central role. The non-iodinated dronedarone also exhibits anti-arrhythmic properties but appears to be less toxic to the thyroid. This review describes the biochemistry of benzofuran derivatives, including their pharmacology and the physiology necessary for understanding the cellular mechanisms involved in their actions. The known effects of these compounds on thyroid action are described. Recommendations for management of amiodarone-induced hypothyroidism and thyrotoxicosis are suggested. Dronedarone appears to be an alternative but less-effective anti-arrhythmic agent and it does not have adverse effects on thyroid function. It may have a future role as an alternative agent in patients being considered for amiodarone therapy especially those at high risk of developing thyroid dysfunction but not in severe heart failure.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Benzofurans; Dronedarone; Humans; Hypothyroidism; Receptors, Thyroid Hormone; Thyroid Diseases; Thyroid Gland; Thyrotoxicosis

Topics: Administration, Oral; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Cardiomyopathy, Hypertrophic; Heart; Heart Conduction System; Humans; Tachycardia, Paroxysmal; Thyroid Diseases; Thyroid Gland; Wolff-Parkinson-White Syndrome

Amiodarone induces a decrease in serum T3 whereas T4 and rT3 increase. An increase of the thyroid iodine content (TIC) is observed in all patients at the exception of those who develop hypothyroidism under treatment. Actually, no method are available to predict an induced thyroid toxicosis (ITT) and there is no reason to perform systematically thyroid function tests except if past of the patient or clinical or morphological thyroid examinations suggest thyroid abnormality. In case of suspicion of ITT it is necessary to perform T4, T3 determinations and a TRH test. TIC measurement can be useful in order to eliminate a subacute or silent thyroiditis. Hypothyroidism is generally observed in patients with autoimmune thyroiditis. Antithyroid antibodies and TSH determinations after some months of treatment can detect subclinical hypothyroidism which is due to a high susceptibility to iodide.

Topics: Amiodarone; Animals; Benzofurans; Biotransformation; Humans; Hyperthyroidism; Hypothyroidism; Iodine; Thyroid Diseases; Thyroid Gland; Thyroid Hormones

Topics: Amiodarone; Arrhythmias, Cardiac; Autonomic Nervous System; Benzofurans; Blood Coagulation; Digitalis Glycosides; Drug Synergism; Electrocardiography; Heart; Heart Conduction System; Hemodynamics; Humans; Kinetics; Quinidine; Sick Sinus Syndrome; Thyroid Diseases; Thyroid Gland

Interest in amiodarone has increased because of its remarkable efficacy as an antiarrhythmic agent. The purpose of this report is to review what is known about the electrophysiologic actions, hemodynamic effects, pharmacokinetics, alterations of thyroid function, response to treatment of supraventricular and ventricular tachyarrhythmias and adverse effects of amiodarone. Understanding the actions of amiodarone and its metabolism will provide more intelligent use of the drug and minimize the development of side effects. The mechanism by which amiodarone suppresses cardiac arrhythmias is not known and may relate to prolongation of refractoriness in all cardiac tissues, suppression of automaticity in some fibers, minimal slowing of conduction in fast channel-dependent tissue, or to interactions with the autonomic nervous system, alterations in thyroid metabolism or other factors. Amiodarone exerts definite but fairly minor negative inotropic effects that may be offset by its vasodilator actions. Amiodarone has a reduced clearance rate, large volume of distribution, low bioavailability and a long half-life that may last 2 months in patients receiving short-term therapy. Therapeutic serum concentrations range between 1.0 and 3.5 micrograms/ml. The drug suppresses recurrences of cardiac tachyarrhythmias in a high percent of patients, in the range of 80% or more for most supraventricular tachycardias and in about 66% of patients with ventricular tachyarrhythmias, sometimes requiring addition of a second antiarrhythmic agent. Side effects, particularly when high doses are used, may limit amiodarone's usefulness and include skin, corneal, thyroid, pulmonary, neurologic, gastrointestinal and hepatic dysfunction. Aggravation of cardiac arrhythmias occurs but serious arrhythmias are caused in less than 5% of patients. Amiodarone affects the metabolism of many other drugs and care must be used to reduce doses of agents combined with amiodarone.

Topics: Administration, Oral; Amiodarone; Animals; Arrhythmias, Cardiac; Atrioventricular Node; Benzofurans; Biological Availability; Drug Interactions; Electrophysiology; Eye Diseases; Half-Life; Heart Conduction System; Humans; Injections, Intravenous; Kinetics; Lung Diseases; Metabolic Clearance Rate; Photosensitivity Disorders; Purkinje Fibers; Tachycardia; Thyroid Diseases; Wolff-Parkinson-White Syndrome

Topics: Amiodarone; Benzofurans; Brain Diseases; Cardiovascular Diseases; Eye Diseases; Humans; Skin Diseases; Thyroid Diseases

Changes in thyroid function may occur during treatment with amiodarone. A double blind prospective trial of amiodarone and placebo was performed in 37 patients in the subacute phase of myocardial infarction. Though none of the patients assigned to receive placebo developed any antibody, six of 13 patients treated with amiodarone developed antithyroid microsomal antibodies. There was no difference in triiodothyronine and thyroxine concentrations between the two groups, but a significant difference in concentrations of thyroid stimulating hormone was noted on day 30 (p less than 0.05). Six months after the withdrawal of amiodarone autoantibodies could not be detected and concentrations of thyroid stimulating hormone were normal. These antibodies have not previously been reported to develop during short term treatment with amiodarone. They could have an important role in the detection of early thyroid changes in patients given amiodarone.

Topics: Adult; Aged; Amiodarone; Antibody Formation; Autoantibodies; Autoimmune Diseases; Benzofurans; Double-Blind Method; Female; Humans; Male; Microsomes; Middle Aged; Myocardial Infarction; Prospective Studies; Thyroid Diseases; Thyroid Gland; Thyrotropin

Topics: Amiodarone; Arrhythmias, Cardiac; Benzofurans; Clinical Trials as Topic; Drug Evaluation; Eye Diseases; Humans; Lung Diseases; Risk; Thyroid Diseases

We measured thyrotropin in plasma by an ultrasensitive immunoradiometric assay (TSH-IRMA, "Sucrosep," Boots-Celltech), before and after thyroliberin (TRH) stimulation, in 71 patients with suspected thyroid-function disorders. Thirty-three were taking amiodarone; none was receiving (anti)thyroid drugs. The patients were divided into four groups, according to their TSH response to TRH (as measured previously by conventional TSH-RIA) and the concentrations of thyroxin (T4) and triiodothyronine (T3) in their plasma. Observed ranges of plasma TSH-IRMA (milli-int. units/L) before and after TRH were: euthyroid (n = 20), 0.2-3.0 and 1.7-15.5; subclinically hypothyroid (n = 14), 4.3-18.5 and 20-75; hyperthyroid (n = 17), less than 0.09 and less than 0.09-0.4; and subclinically hyperthyroid (n = 20), less than 0.09-1.1 and less than 0.09-2.6. Evidently TSH-IRMA results for a single sample completely distinguish hyperthyroidism from euthyroidism. However, TSH-IRMA values may also be undetectable in subclinical hyperthyroidism. The TSH response to TRH can be predicted from basal TSH-IRMA results less than 0.09 or greater than or equal to 0.8 milli-int. unit/L, intermediate values can be associated with either a normal TSH response (euthyroidism) or a decreased TSH response (subclinical hyperthyroidism only). We advocate TSH-IRMA as the first diagnostic test of thyroid function for amiodarone-treated patients.

Topics: Adult; Aged; Amiodarone; Benzofurans; Female; Humans; Hyperthyroidism; Hypothyroidism; Immunoassay; Male; Middle Aged; Thyroid Diseases; Thyroid Function Tests; Thyrotropin; Thyrotropin-Releasing Hormone

Topics: Amiodarone; Benzofurans; Humans; Thyroid Diseases; Thyroid Gland; Thyroid Hormones

T cell subsets in 10 patients receiving amiodarone were evaluated, and their thyroid function and antithyroid antibodies were assessed. A generalized increase in a recently discovered subset of T cells expressing a complex ganglioside antigen reacting with monoclonal antibody 3G5 was found. Two patients, one with hyperthyroidism and the other with euthyroid Graves' ophthalmopathy, had an additional T cell abnormality--marked increase in Ia-positive T cells (an abnormality typical of patients with spontaneous Graves' disease). In the hyperthyroid patient, the Ia-positive T cells disappeared within three weeks after amiodarone was discontinued. The other patients receiving amiodarone had normal numbers of Ia-positive T cells. These studies indicate that amiodarone alters a major resting T cell subset for almost all patients and is associated with T cells expressing the Ia antigen in selected patients. These T cell abnormalities suggest that amiodarone precipitates organ-specific autoimmunity in susceptible persons.

Topics: Adult; Aged; Amiodarone; Antibodies, Monoclonal; Autoantibodies; Autoimmune Diseases; Benzofurans; Female; Flow Cytometry; Histocompatibility Antigens Class II; Humans; Male; Microsomes; Middle Aged; T-Lymphocytes; Thyroglobulin; Thyroid Diseases; Thyroid Gland

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Child; Drug Interactions; Eye Diseases; Female; Humans; Lung Diseases; Male; Peripheral Nervous System Diseases; Skin Diseases; Thyroid Diseases; Time Factors

To assess the incidence of adverse effects associated with long-term amiodarone therapy, we reviewed the records of 217 consecutive patients who were treated for refractory arrhythmia. After an average of 11.8 months of therapy, one or more side effects occurred in 113 patients (52%). These were considered clinically significant in 42 patients (19.3%), mandating discontinuation of amiodarone in 18 (8.3%). The untoward reactions requiring discontinuation of amiodarone included thyroid dysfunction, visual disturbances, pulmonary infiltrates, ataxia, cardiac conduction abnormalities, and drug interactions. The mild side effects included corneal microdeposits, skin rashes, and gastrointestinal symptoms. There was a weak correlation between blood levels of amiodarone, the daily dose, and the cumulative dose (r = 0.23, p = 0.015). Drug levels were higher in symptomatic patients (p less than 0.03), although they received lower doses of amiodarone. While amiodarone is associated with frequent side effects, they are generally mild and do not necessitate drug discontinuation. Careful monitoring of therapy is essential to detect the potentially serious adverse reactions which are encountered in nearly 20% of patients.

Topics: Amiodarone; Arrhythmias, Cardiac; Ataxia; Benzofurans; Drug Eruptions; Drug Interactions; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Respiratory Tract Diseases; Thyroid Diseases; Time Factors; Vision Disorders; Warfarin

Topics: Adult; Aged; Amiodarone; Benzofurans; Female; Humans; Male; Middle Aged; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones

Topics: Amiodarone; Benzofurans; Humans; Thyroid Diseases; Thyroid Hormones

Topics: Amiodarone; Benzofurans; Humans; Iodine; Thyroid Diseases; Thyroid Gland; Thyroid Hormones; Triiodothyronine, Reverse

Topics: Amiodarone; Autoantibodies; Benzofurans; Humans; Retrospective Studies; Thyroid Diseases; Thyroid Gland

Topics: Adult; Aged; Amiodarone; Benzofurans; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Middle Aged; Propylthiouracil; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroxine

Serum thyroxine (T4), triiodothyronine (T3), resin uptake of T3 (RT3U), thyroid stimulating hormone (TSH) and TSH response to thyrotropin releasing hormone (TRH) were measured in 92 patients treated with amiodarone for up to 4 years. Two patients developed thyrotoxicosis, while euthyroid hyperthyroxinemia occurred in 29 (32%). Hypothyroidism was diagnosed in 11 patients (12%), and a further 11 had tests consistent with a "failing thyroid." Of 39 patients with normal values of T4, 15 had abnormal responses to TRH. Of the 92 patients, 24 were tested before administration of amiodarone and then sequentially; alterations in thyroid function were frequent within the first 3 months. A scheme is proposed for early recognition of disturbed thyroid function due to amiodarone.

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Female; Humans; Hyperthyroidism; Hypothyroidism; Longitudinal Studies; Male; Middle Aged; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine

Amiodarone, an iodine-containing drug used frequently in the treatment of cardiac arrhythmias and angina pectoris, has many effects on thyroid hormone metabolism, including decreasing the production of triiodothyronine (T3) and decreasing the clearance of thyroxine and reverse T3. These effects result in elevated serum thyroxine and reverse T3 concentrations and decreased serum T3 concentrations. In addition, iodine-induced hyperthyroidism or hypothyroidism may occur in patients chronically treated with amiodarone. This study is a retrospective analysis of the incidence of thyroid dysfunction in Lucca and Pisa, West Tuscany, Italy, and in Worcester, Massachusetts. Hyperthyroidism was a more frequent (9.6%) complication of amiodarone therapy in West Tuscany, where iodine intake is moderately low; hypothyroidism was more frequent (22%) in Worcester, where iodine intake is sufficient. In patients receiving chronic amiodarone therapy, clinically suspected hyperthyroidism is best confirmed by showing elevations in serum T3 or free T3 concentrations; hypothyroidism is best diagnosed by showing an elevated serum thyrotrophin concentration. Thyroid function should be carefully monitored in patients receiving amiodarone chronically, especially if they have goiter or Hashimoto's thyroiditis.

Topics: Adult; Aged; Amiodarone; Benzofurans; Female; Goiter; Heart Diseases; Humans; Hyperthyroidism; Hypothyroidism; Iodine; Italy; Long-Term Care; Male; Massachusetts; Middle Aged; Retrospective Studies; Thyroglobulin; Thyroid Diseases; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Amiodarone is a very active antiarrhythmic agent, but true incidence of Amiodarone-related side effects is still questionable. In a prospective trial of 400 or 200 mg of Amiodarone day for 56 days in 58 patients, we monitored thyroid and liver function, blood count, chest x-ray, ecg. In addiction we took regularly notice of subjective disturbances and physical signs. Side effects were: conduction disturbances 6%, bradycardia less than 50/min. 2%, gastrointestinal 12%, sleep disorders 12%, hyperthyroidism 4,15% and hypothyroidism 6.25%. Blood levels of Amiodarone and desethylamiodarone were not predictive of side effects. Noteworthy was the absence of cutaneous and pulmonary side effects. On the other hand, thyroid function should be monitored carefully because disfunction is not rare (10.4%) and in the case of hyperthyroidism could be related to worsening of arrhythmias.

Topics: Adolescent; Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Child; Female; Humans; Male; Middle Aged; Prospective Studies; Thyroid Diseases

We measured thyroid function in a cross-sectional survey of 37 unselected patients receiving chronic amiodarone treatment. Palpable goitre was presented in 17 patients and was a new finding in ten. Despite frequent elevations of serum free T4 (67%) or free T4 index (43%), all 37 patients were clinically euthyroid with a normal or decreased serum free T3 or free T3 index. Mean urine iodide/creatinine excretion was increased 13-fold. Three patterns of thyroid function were seen; in 21 patients with normal TRH responses, the mean basal serum TSH was significantly elevated. Five patients had biochemical hypothyroidism which did not require treatment. Eleven patients had evidence of thyroid autonomy and the three patients with absent TRH responses each gave a past history of goitre or thyrotoxicosis; a trial of carbimazole treatment in these three was without clinical benefit. The observed spectrum of subclinical goitre and thyroid dysfunction may result from an unpredictable thyroid response to excessive free iodide combined with a weak goitrogenic effect of amiodarone mediated by increased TSH secretion.

Topics: Adult; Amiodarone; Benzofurans; Female; Goiter; Humans; Male; Thyroid Diseases; Thyroid Function Tests; Thyrotropin

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Corneal Diseases; Dose-Response Relationship, Drug; Female; Heart Conduction System; Humans; Liver; Male; Middle Aged; Peripheral Nervous System Diseases; Photosensitivity Disorders; Pigmentation Disorders; Pulmonary Fibrosis; Thyroid Diseases; Time Factors

Amiodarone was administered to 154 patients who had sustained, symptomatic ventricular tachycardia (VT) (n = 118) or a cardiac arrest (n = 36) and who were refractory to conventional antiarrhythmic drugs. The loading dose was 800 mg/day for 6 weeks and the maintenance dose was 600 mg/day. Sixty-nine percent of patients continued treatment with amiodarone and had no recurrence of symptomatic VT or ventricular fibrillation (VF) over a follow-up of 6 to 52 months (mean +/- standard deviation 14.2 +/- 8.2). Six percent of the patients had a nonfatal recurrence of VT and were successfully managed by continuing amiodarone at a higher dose or by the addition of a conventional antiarrhythmic drug. One or more adverse drug reactions occurred in 51% of patients. Adverse effects forced a reduction in the dose of amiodarone in 41% and discontinuation of amiodarone in 10% of patients. The most common symptomatic adverse reactions were tremor or ataxia (35%), nausea and anorexia (8%), visual halos or blurring (6%), thyroid function abnormalities (6%) and pulmonary interstitial infiltrates (5%). Although large-dose amiodarone is highly effective in the long-term treatment of VT or VF refractory to conventional antiarrhythmic drugs, it causes significant toxicity in approximately 50% of patients. However, when the dose is adjusted based on clinical response or the development of adverse effects, 75% of patients with VT or VF can be successfully managed with amiodarone.

Topics: Aged; Amiodarone; Anorexia; Ataxia; Benzofurans; Female; Heart Arrest; Humans; Lung Diseases; Male; Middle Aged; Nausea; Recurrence; Tachycardia; Thyroid Diseases; Time Factors; Tremor; Ventricular Fibrillation; Vision Disorders

Topics: Amiodarone; Benzofurans; Central Nervous System Diseases; Drug Administration Schedule; Eye Diseases; Gastrointestinal Diseases; Heart Conduction System; Humans; Liver; Peripheral Nervous System Diseases; Pulmonary Fibrosis; Skin Diseases; Thyroid Diseases

Topics: Amiodarone; Benzofurans; Humans; Thyroid Diseases; Thyroid Function Tests

Topics: Amiodarone; Angina Pectoris; Arrhythmias, Cardiac; Benzofurans; Corneal Diseases; Coronary Vessels; Drug Interactions; Humans; Thyroid Diseases; Tremor

The effects of amiodarone on thyroid function tests in 100 patients treated for 6 weeks to 8 years are reported. One patient became thyrotoxic and 10 developed latent or overt hypothyroidism. Twenty-five patients remained clinically euthyroid throughout, but had free thyroxine indices above the normal range. In these patients with apparently anomalous results, total tri-iodothyronine was normal in 19 cases and low in 1; conversely, free thyroxine was high in all 17 cases in which it was measured. Thyrotrophin releasing hormone (TRH) tests were abnormal in 4 of the 13 patients who had the test. Reverse tri-iodothyronine was significantly raised after 2 weeks amiodarone in 5 healthy subjects, but an equivalent amount of iodine in 9 healthy individuals did not significantly affect any of these tests. We believe that these changes are due in part to inhibition of peripheral conversion of thyroxine to tri-iodothyronine with diversion to reversed tri-iodothyronine. Thyroid function tests should be checked once or twice a year in all patients on maintenance amiodarone. Tests indicating hypothyroidism are likely to be clinically relevant, whereas levels of thyroxine suggesting thyrotoxicosis may be misleading and do not usually imply the need to discontinue treatment with the drug.

Topics: Adult; Aged; Amiodarone; Benzofurans; Humans; Middle Aged; Thyroid Diseases; Thyroid Gland; Thyroxine

The author presents his experience with the thyroid complications of amiodarone therapy: exceptional but sometimes serious conditions. Both, hypo- and hyperthyroidism can occur, probably as a result of the iodine overload on a preexisting thyroid disorder. Amiodarone has an effect on the peripheral conversion of thyroxin which leads to misleading thyroid tests results. Its beta- and alpha-blocking actions affect the clinical features, so that overdiagnosis as well as underdiagnosis are frequent. It is suggested that past or present thyroid disorder, as well as presence of antithyroid antibodies are contraindications for amiodarone therapy.

Topics: Amiodarone; Animals; Benzofurans; Dogs; Humans; Hyperthyroidism; Hypothyroidism; Iodine; Thyroid Diseases; Thyroxine; Triiodothyronine

Topics: Administration, Oral; Adolescent; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Thyroid Diseases; Time Factors

Cardiac patients treated with the iodine-containing drug 'amiodarone' undergo a significant iodine overload which can last for months after the drug has been withdrawn. Some patients develop hyperthyroidism and others hypothyroidism. In the hyper- or hypothyroid patients, the indices of thyroid function are modified as usually observed in these situations. In the patients remaining euthyroid while taking amiodarone or after its withdrawal, but still under its influence as shown by the iodine overload, a 'low-T3 syndrome' is observed, this state being characterized by a high total T4, a low free T4, a normal T3 resin uptake, a low total T3, a normal free T3, a high r-T3 and a relative TSH-unresponsiveness to TRH.

Topics: Amiodarone; Benzofurans; Humans; Iodine; Thyroid Diseases; Thyroxine; Triiodothyronine

Amiodarone is a drug which is frequently used in cardiology, and which can lead to the appearance of hyper- of hypo-thyroidism in certain cases. A study of the various parameters of thyroid function has shown that these are abnormal in every case treated by this drug, without the biochemical abnormalities necessarily being reflected clinically. The authors outline a method which will allow a distinction to be drawn between patients with a true thyroid malfunction and those whose biochemical results do not appear at first sight to be of any consequence. Regular assays of the T3RIA level are suggested as a means of early detection of thyroid malfunction in patients undergoing treatment with amiodarone.

Topics: Amiodarone; Benzofurans; Coronary Disease; Thyroid Diseases