RESUMO
QRS widening and QT prolongation are associated with bupropion. The objectives were to elucidate its cardiac electrophysiological properties. Patch-clamp technique was used to assess the I(Kr) -, I(Ks) -, and I(Na) -blocking effects of bupropion. Langendorff retroperfusion technique on isolated guinea-pig hearts was used to evaluate the MAPD(90) -, MAP amplitude-, phase 0 dV/dt-, and ECG-modulating effects of bupropion and of two gap junction intercellular communication inhibitors: glycyrrhetinic acid and heptanol. To evaluate their effects on cardiac intercellular communication, fluorescence recovery after photobleaching (FRAP) technique was used. Bupropion is an I(Kr) blocker. IC(50) was estimated at 34 µm. In contrast, bupropion had hardly any effect on I(Ks) and I(Na) . Bupropion had no significant MAPD(90) -modulating effect. However, as glycyrrhetinic acid and heptanol, bupropion caused important reductions in MAP amplitude and phase 0 dV/dt. A modest but significant QRS-widening effect of bupropion was also observed. FRAP experiments confirmed that bupropion inhibits gap junctional intercellular communication. QT prolongation during bupropion overdosage is due to its I(Kr) -blocking effect. QRS widening with bupropion is not related to cardiac sodium channel block. Bupropion rather mimics the QRS-widening, MAP amplitude- and phase 0 dV/dt -reducing effect of glycyrrhetinic acid and heptanol. Unlike class I anti-arrhythmics, bupropion causes cardiac conduction disturbances by reducing cardiac intercellular coupling.
Assuntos
Antidepressivos de Segunda Geração/toxicidade , Bupropiona/toxicidade , Ácido Glicirretínico/farmacologia , Heptanol/farmacologia , Animais , Antidepressivos de Segunda Geração/administração & dosagem , Antidepressivos de Segunda Geração/farmacologia , Bupropiona/administração & dosagem , Bupropiona/farmacologia , Células CHO , Comunicação Celular/efeitos dos fármacos , Linhagem Celular , Cricetinae , Cricetulus , Overdose de Drogas , Eletrocardiografia , Fenômenos Eletrofisiológicos , Recuperação de Fluorescência Após Fotodegradação , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Cobaias , Humanos , Concentração Inibidora 50 , Síndrome do QT Longo/induzido quimicamente , Masculino , Técnicas de Patch-Clamp , Bloqueadores dos Canais de Potássio/administração & dosagem , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Potássio/toxicidade , RatosRESUMO
Block of I(Kr) is of major concern in drug safety. The objective of this study was to assess prolongation of cardiac repolarization during the combined use of two I(Kr) blockers when administered concomitantly or sequentially. (1) When isolated hearts from male guinea pigs were perfused concomitantly with two I(Kr) blockers, prolongation of monophasic action potential duration measured at 90% (MAPD(90)) was less than the summation of effects observed for each drug perfused alone. (2) In sequential administration, when ketoconazole or erythromycin was perfused first, they antagonized MAPD(90)-prolonging effects of domperidone. This effect was absent when domperidone or dofetilide was perfused first. Patch-clamp experiments confirmed that the order of sequential perfusion impacts the decrease in HERG tail amplitude. In conclusion, this study does not support the concept that potentiation of drug effects is observed during the combined administration of two I(Kr) blockers. Furthermore, order of administration of two I(Kr) blockers together may be an important factor in drug-induced long QT syndrome.
Assuntos
Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Sistema de Condução Cardíaco/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Bloqueadores dos Canais de Potássio/toxicidade , Potenciais de Ação/efeitos dos fármacos , Animais , Linhagem Celular , Interações Medicamentosas , Canal de Potássio ERG1 , Estimulação Elétrica , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Cobaias , Sistema de Condução Cardíaco/metabolismo , Humanos , Técnicas In Vitro , Síndrome do QT Longo/metabolismo , Masculino , Técnicas de Patch-Clamp , Perfusão , Bloqueadores dos Canais de Potássio/administração & dosagem , TransfecçãoRESUMO
Drug-induced QT interval prolongation is a condition likely to be aggravated by diabetes. The objective of this study was to evaluate how glucose concentration may modulate drug effects on ventricular repolarization and on cardiac repolarizing potassium currents. Guinea pig hearts were Langendorff-retroperfused and monophasic action potential duration (MAPD) was measured. Glucose (1, 5 or 20 mmol/L) was tested with either dofetilide (a specific I(Kr) blocker), chromanol 293B (a specific I(Ks) blocker) or both. Effects of glucose (1, 5 or 20 mmol/L) on I(Kr) blockade mediated by dofetilide were also measured in HERG-transfected HEK293 cells in the absence vs presence of the P-glycoprotein drug transporter, using the whole cell patch-clamp technique. Our results suggest that both hypo- and hyperglycemia potentiate the MAPD-prolonging and I(Kr)-blocking properties of dofetilide. P-glycoprotein drug extrusion efficacy appears as a key determinant of dofetilide's I(Kr)-blocking effect. This efficacy appears to be affected by glucose concentration, particularly hyperglycemia.
Assuntos
Potenciais de Ação/efeitos dos fármacos , Cromanos/farmacologia , Glucose/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Fenetilaminas/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Sulfonamidas/farmacologia , Animais , Soluções Tampão , Linhagem Celular , Canais de Potássio Éter-A-Go-Go/metabolismo , Cobaias , Humanos , Técnicas In Vitro , Ativação do Canal Iônico/efeitos dos fármacos , Técnicas de Patch-Clamp , PerfusãoRESUMO
BACKGROUND: Women are at an increased risk of drug-induced long QT syndrome (LQTS). This major cardiac adverse effect may lead to malignant polymorphic ventricular tachycardias, termed torsades de pointes, which may degenerate into ventricular fibrillation and cause sudden death. OBJECTIVE: This article reviews current evidence and remaining gaps in knowledge about drug-induced LQTS in women. METHODS: Using the search terms gender, sex, and sex differences in combination with cardiac electrophysiology, long QT syndrome, HERG, membrane transporters, and cytochromes, we conducted a systematic review of the available literature in the PubMed database. Relevant English- and French-language publications (to October 2007) on sex differences in LQTS were identified. RESULTS: Clinical and experimental studies have reported that gonadal hormones play a role in sex-related differences of QT interval prolongation. Androgens may diminish drug effects on heart repolarization, and estrogens may facilitate arrhythmias. Furthermore, sex-related differences in the density of ion channels may partially explain this phenomenon. However, the magnitude of hormone-dependent differences observed in these studies remains very small compared with the large differences observed in clinical settings. Therefore, many scientists agree that the mechanisms responsible for sex-related differences in the risk of proarrhythmia from drugs remain largely undefined. CONCLUSIONS: Other factors, such as sex-related modulation of drug disposition in situ, may fill the gaps in our understanding of the sex differences observed in drug-induced LQTS. We suggest that mechanisms such as the modulation of the pharmacokinetics of IKr (rapid component of the delayed rectifier potassium current) blockers, via modulation of intra- and extracellular concentrations, may be of major importance. Sex-specific changes in drug transport and metabolism will result in different plasma and intracellular levels acting along a dose-response effect on IKr block. Consequently, important hormone-dependent factors such as metabolic enzymes and membrane transporters need to be investigated in new basic research studies.
Assuntos
Síndrome do QT Longo/induzido quimicamente , Saúde da Mulher , Animais , Causalidade , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Síndrome do QT Longo/epidemiologia , Síndrome do QT Longo/fisiopatologia , Proteínas de Membrana Transportadoras/metabolismo , Bloqueadores dos Canais de Potássio/efeitos adversos , Bloqueadores dos Canais de Potássio/farmacocinética , Fatores de Risco , Caracteres Sexuais , Distribuição por Sexo , Fatores Sexuais , Torsades de Pointes/induzido quimicamente , Torsades de Pointes/epidemiologia , Torsades de Pointes/fisiopatologiaRESUMO
Prolongation of the QT interval has been observed during treatment with olanzapine, a thienobenzodiazepine antipsychotic agent. Our objectives were 1) to characterize the effects of olanzapine on cardiac repolarization and 2) to evaluate effects of olanzapine on the major time-dependent outward potassium current involved in cardiac repolarization, namely I(Kr) (I(Kr): rapid component of the delayed rectifier potassium current).Isolated, buffer-perfused guinea pig hearts (n = 40) were stimulated at different pacing cycle lengths (150-250 msec) and exposed to olanzapine at concentrations ranging from 1 to 100 microM. Olanzapine increased monophasic action potential duration measured at 90% repolarization (MAPD90) in a concentration-dependent manner by 6.7 +/- 0.7 msec at 3 microM but by 26.0 +/- 4.3 msec at 100 microM (250 msec cycle length). Increase in MAPD(90) was also reverse frequency dependent; 30 microM olanzapine increased MAPD90 by 28.0 +/- 6.2 msec at a pacing cycle length of 250 msec but by only 18.9 +/- 2.2 msec at a pacing cycle length of 150 msec. Experiments in HERG-transfected (HERG: human ether-a-gogo-related gene) HEK293 cells (n = 36) demonstrated concentration-dependent block of the rapid component (I(Kr)) of the delayed rectifier potassium current: tail current was decreased 50% at olanzapine 3.8 microM. Olanzapine possesses direct cardiac electrophysiological effects similar to those of class III anti-arrhythmic drugs. These effects were observed at concentrations that can be measured in patients under conditions of impaired drug elimination such as renal or hepatic insufficiency, during co-administration of other CYP1A2 substrates/inhibitors or after drug overdose. These results offer a new potential explanation for QT prolonging effects observed during olanzapine treatment in patients.
Assuntos
Antipsicóticos/farmacologia , Arritmias Cardíacas/induzido quimicamente , Benzodiazepinas/farmacologia , Canais de Potássio de Retificação Tardia/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Animais , Antipsicóticos/administração & dosagem , Benzodiazepinas/administração & dosagem , Estimulação Cardíaca Artificial , Linhagem Celular , Canais de Potássio de Retificação Tardia/metabolismo , Relação Dose-Resposta a Droga , Eletrofisiologia , Canais de Potássio Éter-A-Go-Go/metabolismo , Cobaias , Ventrículos do Coração/metabolismo , Humanos , Técnicas In Vitro , Masculino , Contração Miocárdica , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Olanzapina , TransfecçãoRESUMO
Buprenorphine is an opioid agonist-antagonist with a 'ceiling effect' for respiratory depression. Compared with methadone, its unique pharmacology offers practical advantages and enhanced safety when prescribed as recommended and supervised by a physician. Buprenorphine has been approved in several countries as an efficient and safe maintenance therapy for heroin addiction. Its use resulted in a salutary effect with a reduction in heroin overdose-related deaths in countries that implemented office-based buprenorphine maintenance. In France, however, where high-dose buprenorphine has been marketed since 1996, several cases of asphyxic deaths were reported among addicts treated with buprenorphine. Death resulted from buprenorphine intravenous misuse or concomitant sedative drug ingestion, such as benzodiazepines. In these situations of abuse, misuse, or in association with elevated doses of psychotropic drugs, buprenorphine may cause severe respiratory depression. Unlike other opiates, the respiratory effects from buprenorphine are not responsive to naloxone. However, the exact mechanism of buprenorphine-induced effects on ventilation is still unknown. The role of norbuprenorphine, the main N-dealkylated buprenorphine metabolite with potent respiratory depressor activity, also remains unclear. Experimental studies investigating the respiratory effects of combinations of high doses of buprenorphine and benzodiazepines suggested that this drug-drug interaction may result from a pharmacodynamic interaction. A pharmacokinetic interaction between buprenorphine and flunitrazepam is also considered. As there are many questions regarding the possible dangers of death or respiratory depression associated with buprenorphine use, we aimed to present a comprehensive critical review of the published clinical and experimental studies on buprenorphine respiratory effects.