-
Clinical Endocrinology Jan 2009Amiodarone and dronedarone are two clinically important benzofuran derivatives. Amiodarone has been used widely for treating resistant tachyarrhythmias in the past three... (Review)
Review
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
PubMed: 18727707
DOI: 10.1111/j.1365-2265.2008.03350.x -
The American Journal of Cardiology Nov 1993Amiodarone is a complex molecule with multiple pharmacologic properties and a complex electrophysiologic profile. Its disposition kinetics and relation between plasma... (Review)
Review
Amiodarone is a complex molecule with multiple pharmacologic properties and a complex electrophysiologic profile. Its disposition kinetics and relation between plasma drug concentration and efficacy can be analyzed using principles identical to those applicable to other antiarrhythmic drugs. However, the drug's affinity for lipophilic tissues, its extremely slow elimination rate, and the likelihood that some of its effects may not be mediated by the usual antiarrhythmic mechanisms confounds traditional pharmacokinetic analysis. Further data that deal with the fundamental mechanisms of action of the drug, in addition to the nature of the relation between dose and uptake into cellular and subcellular fractions and its pharmacologic effects, will be of value in understanding how the drug exerts salutary actions in cardiac arrhythmias.
Topics: Amiodarone; Animals; Biological Availability; Humans; Protein Binding; Tissue Distribution
PubMed: 8237829
DOI: 10.1016/0002-9149(93)90962-c -
Clinical Pharmacology and Therapeutics Apr 1982Amiodarone serum kinetics after single oral doses and after long-term therapy were investigated in patients with ventricular tachyarrhythmias. When amiodarone was given...
Amiodarone serum kinetics after single oral doses and after long-term therapy were investigated in patients with ventricular tachyarrhythmias. When amiodarone was given as a single oral dose (1400 to 1800 mg, n = 6), serum levels of amiodarone and its metabolite, measured by high-performance liquid chromatography, correlated (r = 0.69, P less than 0.01). Peak concentrations (amiodarone, 3 to 14 microgram/ml; metabolite, 0.7 microgram/ml) were attained in 4.9 +/- 1.2 hr. Using computer fits to the data, amiodarone mean elimination rate constant and half-life (t 1/2 e) were 0.128 +/- 0.063 hr-1 and 7.2 +/- 5.0 hr. In 12 patients given a mean dose of 1327 +/- 338 mg/day of amiodarone for 4.1 +/- 2.3 wk, mean serum amiodarone level was 3.84 +/- 2.92 microgram/ml (range 0.92 to 11.99); in three patients simultaneous determination of concentrations of amiodarone and its metabolite revealed that concentration of the latter was about 50% of that of the parent drug during long-term therapy. In four patients on maintenance therapy (400 to 800 mg/day, serum level 1.08 +/- 1.3 microgram/ml) drug was discontinued and serum amiodarone levels were determined serially. Serum drug disappearance followed a single exponential function with an elimination rate constant of 0.030 +/- 0.012 day-1 and t 1/2 e of 29 +/- 19 days. Our kinetic data are consistent with the long therapeutic amiodarone t 1/2 noted in the treatment of cardiac arrhythmias.
Topics: Administration, Oral; Adult; Aged; Amiodarone; Benzofurans; Half-Life; Humans; Kinetics; Male; Middle Aged
PubMed: 7060325
DOI: 10.1038/clpt.1982.57 -
Nature Reviews. Drug Discovery Oct 2009
Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Dronedarone; Humans; Randomized Controlled Trials as Topic
PubMed: 19794441
DOI: 10.1038/nrd2998 -
Lung 1989A rat model of amiodarone-induced pulmonary toxicity is described. The rats were fed, by gavage, 175 mg/kg/day of amiodarone hydrochloride suspended in methyl cellulose....
A rat model of amiodarone-induced pulmonary toxicity is described. The rats were fed, by gavage, 175 mg/kg/day of amiodarone hydrochloride suspended in methyl cellulose. Controls received methyl cellulose alone. Groups of rats were examined after 1, 3, 6, 9, and 12 weeks of feeding. We found that drug-fed rats had significantly more macrophages, neutrophils, and lymphocytes in the bronchoalveolar lavage (BAL). The early increase in cellularity was due to an increase in macrophages, and the macrophage count peaked after 6 weeks of drug treatment. The number of neutrophils in the experimental animals remained high throughout the course of the experiment. An increasing number of lymphocytes was seen in the BAL between 6 and 12 weeks of drug treatment. Protein in the lavage fluid was significantly elevated after 12 weeks of amiodarone exposure. Histologic sections were abnormal after 3 weeks of drug treatment, characterized by interstitial thickening with accumulation of mononuclear cells and alveoli packed with large foamy macrophages. There was only minimal evidence of fibrosis. This model appears to be very similar to human amiodarone-induced pulmonary toxicity and should be useful for the study of the pathogenesis of amiodarone-induced toxicity.
Topics: Administration, Oral; Amiodarone; Animals; Body Weight; Bronchoalveolar Lavage Fluid; Cell Count; Lung; Proteins; Rats; Rats, Inbred F344
PubMed: 2507834
DOI: 10.1007/BF02714959 -
The Annals of Pharmacotherapy Jun 1995To discuss the role of amiodarone for the maintenance of normal sinus rhythm in patients with atrial fibrillation (AF) and review the clinical trial data evaluating the... (Review)
Review
OBJECTIVE
To discuss the role of amiodarone for the maintenance of normal sinus rhythm in patients with atrial fibrillation (AF) and review the clinical trial data evaluating the efficacy and safety of amiodarone in patients with AF.
DATA SOURCES
A MEDLINE search was used to identify pertinent literature. Additional references were identified from the articles obtained in the search. Key search terms were atrial fibrillation, amiodarone, and sinus rhythm.
STUDY SELECTION
All studies available at the time the article was prepared evaluating the efficacy and safety of amiodarone in AF were included. In addition, review articles discussing the role of amiodarone in AF were selected.
DATA EXTRACTION
No large, prospective, randomized trials have been performed. Data from 8 nonrandomized and 2 randomized trials are reported. Information derived from review articles is discussed.
DATA SYNTHESIS
In patients with AF, maintenance of normal sinus rhythm is desirable to eliminate symptoms, improve functional capacity, and reduce the risk of thromboembolic complications. Class IA agents traditionally have been used; however, concerns about long-term effects on mortality have focused attention on other agents such as amiodarone. A number of nonrandomized, uncontrolled trials have found amiodarone to be effective for maintaining normal sinus rhythm in patients with AF that is refractory to conventional agents. Two randomized, nonblind trials have found amiodarone's efficacy to be equal to or superior to that of class IA drugs. The findings of these trials must be weighed, however, against the significant potential for toxicity and drug interactions associated with amiodarone. Cardiovascular toxicities, including proarrhythmic effects, appear to be relatively rare. In contrast, noncardiovascular effects are common and potentially serious.
CONCLUSION
Although the preliminary data using amiodarone in AF are encouraging, many questions remain unanswered. Prospective, randomized trials are needed to evaluate the long-term efficacy and safety of amiodarone in patients with AF. Studies also are needed to determine the optimal dosing regimen. Until these data are available, each patient must be evaluated individually, taking into account the relative benefits and risks of therapy. Amiodarone may be particularly useful in patients with significant risks for proarrhythmia and those whose AF is refractory to traditional therapy.
Topics: Amiodarone; Atrial Fibrillation; Clinical Trials as Topic; Heart Rate; Humans; Risk Factors
PubMed: 7663033
DOI: 10.1177/106002809502900609 -
Medical Toxicology and Adverse Drug... 1989Amiodarone is an extremely effective antiarrhythmic agent for the treatment of both life-threatening ventricular arrhythmias and refractory supraventricular... (Review)
Review
Amiodarone is an extremely effective antiarrhythmic agent for the treatment of both life-threatening ventricular arrhythmias and refractory supraventricular tachyarrhythmias. Subjective minor side effects are common with amiodarone but rarely require discontinuation of therapy and are often handled by dose reduction. Serious end-organ toxicity, including pulmonary fibrosis and drug-induced hepatitis, have been the most common indications for discontinuing amiodarone therapy in these patients.
Topics: Amiodarone; Animals; Female; Humans; Pregnancy; Teratogens
PubMed: 2671595
DOI: 10.1007/BF03259911 -
The Medical Clinics of North America Mar 1988This article reviews current information on the clinical pharmacology, therapeutic utility, and adverse reactions of amiodarone, with emphasis on guidelines for its... (Review)
Review
This article reviews current information on the clinical pharmacology, therapeutic utility, and adverse reactions of amiodarone, with emphasis on guidelines for its rational use.
Topics: Amiodarone; Arrhythmias, Cardiac; Hemodynamics; Humans
PubMed: 3279284
DOI: 10.1016/s0025-7125(16)30773-8 -
Circulation Nov 1999
Review
Topics: Amiodarone; Anti-Arrhythmia Agents; Atrial Fibrillation; Death, Sudden; Humans; Tachycardia, Ventricular; Ventricular Fibrillation
PubMed: 10556230
DOI: 10.1161/01.cir.100.19.2025 -
Cardiovascular Drug Reviews 2005Dronedarone is a noniodinated benzofuran derivative that has been developed to overcome the limiting iodine-associated adverse effects of the commonly used... (Comparative Study)
Comparative Study Review
Dronedarone is a noniodinated benzofuran derivative that has been developed to overcome the limiting iodine-associated adverse effects of the commonly used antiarrhythmic drug, amiodarone. It displays a wide cellular electrophysiological spectrum largely similar to amiodarone, inhibiting the potassium currents I(Kr), I(Ks), I(KI), I(KACh), and I(sus), as well as sodium currents and L-type calcium currents in isolated cardiomyocytes. In addition, dronedarone exhibits antiadrenergic properties. In vivo, dronedarone has been shown to be more effective than amiodarone in several arrhythmia models, particularly in preventing ischemia- and reperfusion-induced ventricular fibrillation and in reducing mortality. However, an increased incidence of torsades de pointes with dronedarone in dogs shows that possible proarrhythmic effects of dronedarone require further evaluation. The clinical trails DAFNE, EURIDIS, and ADONIS indicated safety, antiarrhythmic efficacy and low proarrhythmic potential of the drug in low-risk patients. In contrast, the increased incidence of death in the dronedarone group of the discontinued ANDROMEDA trial raises safety concerns for patients with congestive heart failure and moderate to severe left ventricular dysfunction. Dronedarone appears to be effective in preventing relapses of atrial fibrillation and atrial flutter. Torsades de pointes, the most severe adverse effect associated with amiodarone, has not yet been reported in humans with dronedarone. Unlike amiodarone, dronedarone had little effect on thyroid function and hormone levels in animal models and had no significant effects on human thyroid function in clinical trials. In conclusion, dronedarone could be a useful drug for prevention of atrial fibrillation and atrial flutter relapses in low-risk patients. However, further experimental studies and long-term clinical trials are required to provide additional evidence of efficacy and safety of dronedarone.
Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Dronedarone; Humans; Ion Channels
PubMed: 16252015
DOI: 10.1111/j.1527-3466.2005.tb00167.x