RESUMO
Amiodarone is a structural analogue of thyroid hormone, and some of its anti-arrhythmic actions and toxicity are attributable to its interaction with nuclear receptors of thyroid hormones. Being highly lipophilic, amiodarone is concentrated in many tissues and is eliminated, consequently, very slowly. It is preferably employed to manage life-threatening arrhythmias, including ventricular fibrillation and unstable ventricular tachycardia. Other indications include atrial fibrillation and flutter, severe congestive heart failure, prevention of atrial fibrillation recurrence, and even in emergency medical situations to prevent sudden cardiac death. The aim of this review is to provide an updated approach on amiodarone and its influence on thyroid physiology and to discuss and analyze in depth its potential and not infrequent thyroidal adverse effects such as hypothyroidism and thyrotoxicosis.
Assuntos
Amiodarona/efeitos adversos , Antiarrítmicos/efeitos adversos , Hipotireoidismo/induzido quimicamente , Glândula Tireoide/efeitos dos fármacos , Tireotoxicose/induzido quimicamente , Amiodarona/análogos & derivados , Amiodarona/química , Amiodarona/farmacocinética , Amiodarona/uso terapêutico , Antiarrítmicos/química , Antiarrítmicos/farmacocinética , Fibrilação Atrial/tratamento farmacológico , Dronedarona , Humanos , Hipotireoidismo/terapia , Iodo/análise , Glândula Tireoide/fisiopatologia , Tireotoxicose/terapiaRESUMO
A dosing algorithm including genetic (VKORC1 and CYP2C9 genotypes) and nongenetic factors (age, weight, therapeutic indication, and cotreatment with amiodarone or simvastatin) explained 51% of the variance in stable weekly warfarin doses in 390 patients attending an anticoagulant clinic in a Brazilian public hospital. The VKORC1 3673G>A genotype was the most important predictor of warfarin dose, with a partial R(2) value of 23.9%. Replacing the VKORC1 3673G>A genotype with VKORC1 diplotype did not increase the algorithm's predictive power. We suggest that three other single-nucleotide polymorphisms (SNPs) (5808T>G, 6853G>C, and 9041G>A) that are in strong linkage disequilibrium (LD) with 3673G>A would be equally good predictors of the warfarin dose requirement. The algorithm's predictive power was similar across the self-identified "race/color" subsets. "Race/color" was not associated with stable warfarin dose in the multiple regression model, although the required warfarin dose was significantly lower (P = 0.006) in white (29 +/- 13 mg/week, n = 196) than in black patients (35 +/- 15 mg/week, n = 76).
Assuntos
Algoritmos , Hidrocarboneto de Aril Hidroxilases/genética , Oxigenases de Função Mista/genética , Farmacogenética , Polimorfismo Genético , Varfarina/farmacocinética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial , Amiodarona/administração & dosagem , Amiodarona/farmacocinética , Análise de Variância , Hidrocarboneto de Aril Hidroxilases/efeitos dos fármacos , Brasil , Estudos de Coortes , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada , Etnicidade/genética , Feminino , Genótipo , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista/efeitos dos fármacos , Análise Multivariada , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Sinvastatina/administração & dosagem , Sinvastatina/farmacocinética , Resultado do Tratamento , Vitamina K Epóxido Redutases , Varfarina/administração & dosagem , Adulto JovemRESUMO
Antecedentes: Amiodarona (A) es la droga antiarrítmica más utilizada en la actualidad. No obstante, algunos aspectos de su compleja farmacología son todavía poco conocidos en ciertos grupos de pacientes. Objetivo: Estudiar los parámetros farmacocinéticos de A después de una alta dosis de carga oral en pacientes (P) sometidos a cirugía coronaria. Métodos: Cuarenta y tres P sometidos a cirugía coronaria recibieron una dosis oral de 30 mg/kg en dosis fraccionada como tratamiento profiláctico de arritmias en el post operatorio. Las concentraciones sanguíneas de la droga fueron medidas a tiempos sucesivos, por HPLC, hasta las 96 h de su administración. En base a la curva obtenida de concentración sanguínea vs tiempo, los parámetros farmacocinéticos fueron calculados mediante un programa computacional independiente del modelo compartimental. Resultados: La concentración sanguínea de A alcanzó un valor máximo de 2,3 +/- 1,5µg/ml a las 10 h de la administración de la droga. Posteriormente, se observó un descenso gradual con un valor de 0,4 +/- 0,1 µg/ml a las 96h de administración. Los parámetros farmacocinéticos obtenidos fueron: Vida media 29,1 +/- 11,3h; Area bajo la curva 096 63,6 +/- 22,3 (µg/ml)h; Clearance total 6,1 +/- 2,2 ml/min/kg; Volumen de distribución 15,6 +/- 5,4 L/kg. Conclusiones: La farmacocinética de A presenta diferencias con lo encontrado en estudios de dosis única en otros grupos de pacientes. El presente trabajo puede servir para esquemas de dosificación menos empíricos de A.
Background: Amiodarone is currently the most commonly used antiarrhythmic drug. However, some aspects of its complex pharmacokinetics in particular groups of patients are not well known. Aim: to study the pharmacokinetics of amiodarone after a high loading oral dose in patients undergoing coronary revascularization surgery. Methods: Forty three patients operated on for coronary artery disease received oral dose amiodarone, 30mg/Kg, in a fractioned dose as a prophylactic antiarrhythmic medication following surgery. Blood amiodarone concentration was measured at successive intervals for 96 hr. A software based on a non compartmental model was used to determine pharmacokinetic parameters. Results: Maximal blood concentration of amiodarone was 2.3 +/-1.5µg/ml 10hr after drug administration. A subsequent gradual decrease of amiodarone blood level was observed, down to 0.4 +/- 0.1µg/ml at 96hr post drug administration. The half-life time was 29.1 +/- 11.3hr. The area under de 0 to 96hr curve was 63.6 +/- 22.3µg/ml.Total clearance was 6.1 +/- 2.2 ml/min/kg. The distribution volume was 15.6 +/- 5,4 L/kg. Conclusion: Pharmacokinetics of amiodarone differs from that obtained following a single dose in other groups of patients. The data provided may be used to determine more objective amiodarone dosing schemes.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Amiodarona/farmacocinética , Coração , Administração Oral , Antiarrítmicos/farmacocinética , Amiodarona/administração & dosagem , Amiodarona/sangue , Procedimentos Cirúrgicos Cardíacos , Sistema de Condução Cardíaco , Fatores de TempoRESUMO
OBJECTIVE: The aim was to assess the comparative bioavailability of two formulations (200 mg tablet) of amiodarone (CAS 19774-82-4) in healthy volunteers of both sexes, with and without food. METHODS: The study was conducted using an open, randomized, two-period crossover design with a 3-week washout interval, in two groups, with and without food. Plasma samples were obtained for up to 240 h post dose. Plasma amiodarone concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). From the amiodarone plasma concentration vs. time curves, the following pharmacokinetic parameters were obtained, with and without food: AUC(last), AUC(inf), AUC(0-240h), AUC(0-72h) and C(max). RESULTS: The limit of quantification was 1 ng/mL for plasma amiodarone analysis. The geometric mean and 90% confidence interval CI of Test/Reference percent ratios were, without and with food, respectively: 107.61 (92.73-124.89) and 100.6 (94.1-107.5) for C(max), 107.05 (95.88-119.51) and 100.2 (96.0-104.7) for AUC(last), 107.27 (95.78-120.15) and 100.8 (97.0-104.8) for AUC(0-72h), 106.76 (95.84-118.94) and 100.2 (96.0-104.7) for AUC(0-240h) and AUC(inf) 105.15 (94.18-117.41) and 100.7 (96.6-105.0). CONCLUSION: Since the 90% CI for AUC(0-72) and C(max) ratios were within the 80-125% interval proposed by the US FDA, it was concluded that the amiodarone 200 mg tablet (test formulation) with and without food was bioequivalent to the reference 200 mg tablet for both the rate and extent of absorption.
Assuntos
Amiodarona/administração & dosagem , Amiodarona/farmacocinética , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Adulto , Amiodarona/sangue , Antiarrítmicos/sangue , Área Sob a Curva , Disponibilidade Biológica , Química Farmacêutica , Cromatografia Líquida , Estudos Cross-Over , Feminino , Alimentos , Humanos , Absorção Intestinal , Masculino , Espectrometria de Massas por Ionização por Electrospray , Comprimidos , Espectrometria de Massas em TandemRESUMO
Amiodarone (AM) is an antiarrhythmic agent widely used in the treatment of ventricular and supraventricular arrhythmias. Dronedarone (DR) is a new compound with a pharmacological profile similar to that of AM, but iodine free. We previously demonstrated that chronic AM treatment reduces transmural dispersion of repolarization (TDR) in the canine heart. We used standard microelectrode technique to evaluate the effects of acute AM (100 microM) and DR (30 microM) on epicardial (EPI), endocardial (ENDO), and M region tissues obtained from the left ventricular wall of the canine heart. Amiodarone (100 microM, 120 min of exposure) produced little change in the action potential duration of ENDO and EPI tissues, but it shortened the action potential of M cells, especially at slow rates, leading to a decrease in TDR. Similar results were observed with DR. Acute AM (100 microM) and DR (30 microM) eliminated d-sotalol-induced early afterdepolarizations (EADs) and triggered activity in 3 of 3 and 2 of 6 M cell preparations, respectively. The reduction of TDR and the elimination of EAD-induced triggered activity differentiates AM and DR from other class III agents. These effects may explain the efficacy and low arrhythmogenicity of acute AM and suggest a potential safe use of DR as an antiarrhythmic agent.
Assuntos
Amiodarona/análogos & derivados , Amiodarona/farmacologia , Antiarrítmicos/farmacologia , Endocárdio/efeitos dos fármacos , Miocárdio/citologia , Pericárdio/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Amiodarona/administração & dosagem , Amiodarona/farmacocinética , Análise de Variância , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Cães , Dronedarona , Endocárdio/fisiologia , Ventrículos do Coração/citologia , Técnicas In Vitro , Masculino , Pericárdio/fisiologia , Sotalol/farmacologia , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
En México se utiliza ampliamente la presentación intravenosa de la amiodarona, y aunque de la misma sustancia que la que se administra por vía oral, su fórmula galénica, así como los efectos de plasticidad celular que esta sustancia tiene sobre el miocardio cuando se administra crónicamente, hacen que estas dos formas de administración se comporten como si se tratara de dos antiarrítmicos diferentes con nombre igual. Se presenta una breve revisión sobre la farmacodinamia de esta sustancia, uno de los antiarrítmicos más indicados en nuestro país
Assuntos
Humanos , Animais , Amiodarona/administração & dosagem , Amiodarona/farmacocinética , Eletrofisiologia , Injeções Intravenosas , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacocinética , Hemodinâmica , Liberação de HistaminaRESUMO
INTRODUCTION: Amiodarone is a potent antiarrhythmic agent used in the management of both atrial and ventricular arrhythmias. In addition to its beta-blocking properties, amiodarone is known to block the sodium, potassium, and calcium channels in the heart. Its complex electropharmacology notwithstanding, the reasons for the high efficacy of the drug remain unclear. Also not well understood is the basis for the low incidence of proarrhythmia seen with amiodarone relative to other agents with Class III actions. The present study was designed to examine the effects of chronic amiodarone in epicardial, endocardial, and M cells of the canine left ventricle. METHODS AND RESULTS: We used standard microelectrode techniques to record transmembrane activity from endocardial, epicardial, mid-myocardial, and transmural strips isolated from the canine left ventricle. Tissues were obtained from mongrel dogs receiving amiodarone orally (30 to 40 mg/kg per day) for 30 to 45 days or from untreated controls. Chronic amiodarone produced a greater prolongation of action potential duration in epicardium and endocardium, but less of an increase, or even a decrease at slow rates, in the M region, thereby reducing transmural dispersion of repolarization. In addition, chronic amiodarone therapy suppressed the ability of the IKr blocker, d-sotalol, to induce a marked dispersion of repolarization or early afterdepolarization activity. CONCLUSION: Our data demonstrate for the first time a direct effect of chronic amiodarone treatment to differentially alter the cellular electrophysiology of ventricular myocardium so as to produce an important decrease in transmural dispersion of repolarization, especially under conditions in which dispersion is exaggerated. These results may contribute to our understanding of the effectiveness of amiodarone in the treatment of life-threatening arrhythmias as well as to our understanding of the low incidence of proarrhythmia attending therapy with chronic amiodarone in comparison with other Class III agents.
Assuntos
Amiodarona/farmacologia , Antiarrítmicos/farmacologia , Coração/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Amiodarona/farmacocinética , Animais , Cães , Coração/fisiologia , MasculinoRESUMO
We measured plasma concentrations of amiodarone and desethylamiodarone by HPLC in 44 outpatients aged 24 to 67 years old (21 male), receiving the drug during at least three months. The drug was indicated for supraventricular arrythmias in 37 patients and ventricular arrhytmias in seven. Plasma concentrations of amiodarone, desethylamiodarone and their ratio were 1.71ñ0.82, 0.85ñ0.42 µg/ml and 2.02 respectively, for a mean daily dose of 223ñ88 mg. In 41 patients, arrhytmias were succesfully treated. These patients received a mean daily dose of 220ñ86 mg and concentrations of amiodarone, desethylamiodarone and their ratio were 1.75ñ0.86, 088ñ0.45 µg/ml and 1.99 respectively. In 3 patients with treatment failure, receiving a daily dose of 257ñ115 mg, these figures were 1.2ñ0.3, 0.5ñ0.1 µg/ml and 2.4 respectively. We conclude that our patients had lower plasma concentrations of desethylamiodarone and higher amiodarone/desethylamiodarone ratios than those reported in other countries
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Arritmias Cardíacas/tratamento farmacológico , Amiodarona/farmacocinética , Amiodarona/sangue , Doença Crônica/tratamento farmacológicoRESUMO
We studied amiodarone absorption and disposal in eight male healthy subjects aged 21 +/- 1 years old and weighting 69.8 +/- 7.1 kg. An intravenous dose of 5 mg/kg and an oral dose of 600 mg of amiodarone were administered. Amiodarone concentrations were measured by HPLC and calculations were performed using a compartment model independent pharmacokinetic analysis program. After oral administration a Cmax of 1.17 +/- 0.3 mg/ml was achieved at 3.25 +/- 0.46 h (tmax). Absolute bioavailability ranged from 50.4 to 87.8% (68.6 +/- 12.6%). Compared to previous reports, the variability of this parameter is similar and the mean value is one of the highest informed. After intravenous administration, Amiodarone had a half life of 7.53 +/- 0.96 h, a total body clearance of 4.25 +/- 0.73 ml/kg/min and a distribution volume of 2.99 +/- 0.71 l/kg. Except the later figure, which is in the inferior range, all other parameters are within previously reported values. It is concluded that amiodarone absorption and disposal values found in Chilean subjects are similar to those reported abroad.
Assuntos
Amiodarona/farmacocinética , Antiarrítmicos/farmacocinética , Administração Oral , Adulto , Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Disponibilidade Biológica , Humanos , Injeções Intravenosas , Masculino , Fatores de TempoRESUMO
We studied amiodarone absorption and disposal in 8 male helathy subjects aged 21ñ1 years old and weighting 69.8ñ7.1 kg. An intravenous dose of 5 mg/kg and an oral dose of 600 mg of amiodarone were administrated. Amiodarone concentrations were measured by HPLC and calculations were performed using a compartment model independent pharmacokinetic analysis program. After oral administration a Cmax of 1.17ñ0.3 mg/ml was achieved at 3.25ñ0.46 h (tmax). Absolute bioavailability ranged from 50.4 to 87.8 percent (68.6ñ12.6 percent). Compared to previous reports, the variability of this parameter is similar and the mean value is one of the highest informed. After intravenous administration, amiodarone had a half life of 7.35ñ0.96 h, a total body clearence of 4.25ñ0.73 ml/kg/min and a distribution volume of 2.99ñ0.71 l/kg. Except the later figure, which is in the inferior range, all other parameters are within previously reported values. It is concluded that amiodarone absorption and disposal values found in chilean subjects are similar to those reported abroad
Assuntos
Humanos , Masculino , Adulto , Amiodarona/metabolismo , Amiodarona/farmacocinética , Injeções Intravenosas , Absorção/fisiologia , Administração Oral , Disponibilidade Biológica , Experimentação HumanaRESUMO
In severe heart failure many deaths are sudden and are presumed to be due to ventricular arrhythmias. The GESICA trial evaluated the effect of low-dose amiodarone on two-year mortality in patients with severe heart failure. Our prospective multicentre trial included 516 patients on optimal standard treatment for heart failure. Patients were randomised to 300 mg/day amiodarone (260) or to standard treatment (256). Intention-to-treat analysis showed 87 deaths in the amiodarone group (33.5%) compared with 106 in the control group (41.4%) (risk reduction 28%; 95% CI 4%-45%; log rank test p = 0.024). There were reductions in both sudden death (risk reduction 27%; p = 0.16) and death due to progressive heart failure (risk reduction 23%; p = 0.16). Fewer patients in the amiodarone group died or were admitted to hospital due to worsening heart failure (119 versus 149 in the control group; risk reduction 31%; 95% CI 13-46%; p = 0.0024). The decrease in mortality and hospital admission was present in all subgroups examined and independent of the presence of non-sustained ventricular tachycardia. Side-effects were reported in 17 patients (6.1%); amiodarone was withdrawn in 12. Low-dose amiodarone proved to be an effective and reliable treatment, reducing mortality and hospital admission in patients with severe heart failure independently of the presence of complex ventricular arrhythmias.
Assuntos
Amiodarona/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Amiodarona/efeitos adversos , Amiodarona/farmacocinética , Morte Súbita Cardíaca/etiologia , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de RiscoRESUMO
Carbamazepine and amiodarone may often be used together, especially in countries where cardiomyopathies are common. In this study single doses of carbamazepine (400 mg) were given to patients with cardiac disease before and after one month of therapy with amiodarone, 400 mg daily. The kinetic profile of carbamazepine, its free fraction, and serum amiodarone, were measured at the two occasions. There was no statistically significant change in carbamazepine kinetics or free fraction, before and after the introduction of amiodarone. The concentrations of amiodarone after one month of therapy were low. It is suggested that the possible interaction in the hepatic metabolism was not demonstrated because amiodarone concentrations were not enough to inhibit carbamazepine metabolism.
Assuntos
Amiodarona/administração & dosagem , Carbamazepina/farmacocinética , Doença de Chagas/metabolismo , Isquemia Miocárdica/metabolismo , Adulto , Idoso , Amiodarona/farmacocinética , Carbamazepina/administração & dosagem , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
Carbamazepina e amiodarona podem frequentemente ser usadas em conjunto, especialmente em países em que as cardiomiopatias säo comuns. Neste estudo doses de carbamazepina (400 mg) foram administradas a pacientes com doenças cardíacas antes e depois de um mês de terapia com amiodarona, 400 mg ao dia. O perfil cinético da carbamazepina, sua fraçäo livre e o nível sérico da amiodarona, foram avaliados nas duas ocasiöes. Näo foram observadas diferenças estatísticamente significantes na cinética da carbamazepina ou mesmo em sua fraçäo livre, antes e depois da introduçäo da amiodarona. A concentraçäo da amiodarona após um mês de terapia foi baixa. Conclui-se que a possível interaçäo no metabolismo hepático näo foi demonstrada devido as baixas concentraçöes de amiodarona, que provavelmente tenham sido suficientes para inibir o metabolismo da carbamazepina
Assuntos
Adulto , Pessoa de Meia-Idade , Humanos , Masculino , Feminino , Amiodarona/administração & dosagem , Carbamazepina/farmacocinética , Cardiomiopatias/tratamento farmacológico , Amiodarona/farmacocinética , Carbamazepina/administração & dosagem , Interações Medicamentosas , Quimioterapia Combinada , Estudos ProspectivosRESUMO
Se realizó el análisis retrospectivo de 130 pacientes, tratdos con amiodarona, vistos en la Clínica de Arritmias de este Instituto desde marzo de 1981 hasta mayo de 1988, con el fin de conocer la frecuencia de los efectos colaterales del fármaco. El grupo estuvo constituído por 67 hombres y 63 mujeres, con edades extremas de 20 meses y 82 años; el tiempo promedio semanal empleado fue de 1.05 g. Todos tuvieron un examen clínico completo, radiológico, ECG y de laboratorio. De ellos, 86 tuvieron además por lo menos un estudio electrofisiológico; a los 118, se les realizaron pruebas periódicas de la función tiroidea. Todos fueron revisados cada 3 a 6 meses. Resultados: la respuesta terapéutica fue buena o excelente en el 83% de los casos. No se observaron cambios electrocardiográficos estadísticamete significativos (duración del PR, QRS, QT). En los exámenes oftalmológicos se documentaron depósitos corneales en el 48% de los pacientes, en ning'n caso fue motivo para la suspensión del tratamiento y en diez se observó regresión espontánea de los depósitos. HUbo alteraciones tiroideas en el 33.8%: 14 tuvieron hipotiroidismo y siete hipertiroidismo, el resto bocio simple; en cuatro casos se descontinuó la medicación por alteraciones tiroideas. Se encontraron lesiones dermatológicas en el 4% de los casos; en ninguno se documentaron datos de toxicidad pulmonar. La respuesta terapéutica fue adecuada en la mayoría de los pacientes; aunque la frecuencia de efectos colaterales fue alta, la suspensión del tratamiento se realizó en un porcentaje reducido