Increased cardiac risk in concomitant methadone and diazepam treatment: pharmacodynamic interactions in cardiac ion channels.
J Cardiovasc Pharmacol
; 56(4): 420-30, 2010 Oct.
Article
en En
| MEDLINE
| ID: mdl-20930594
ABSTRACT
Methadone, a synthetic opioid for treatment of chronic pain and withdrawal from opioid dependence, has been linked to QT prolongation, potentially fatal torsades de pointes, and sudden cardiac death. Concomitant use of diazepam or other benzodiazepines in methadone maintenance treatment can increase the risk of sudden death. Therefore, we determined the effects of methadone and diazepam singly and in combination on cardiac action potentials (APs) and on the major ion channels responsible for cardiac repolarization. Using patch clamp recording in human stem cell-derived cardiomyocytes and stably transfected mammalian cells, we found that methadone produced concentration-dependent AP prolongation and ion channel block at low micromolar concentrations hERG (IC50 = 1.7 µM), hNav1.5 (11.2 µM tonic block; 5.5 µM phasic block), and hCav1.2 (26.7 µM tonic block; 7.7 µM phasic block). Methadone was less potent in hKv4.3/hKChIP2.2 (IC50 = 39.0 µM) and hKvLQT1/hminK (53.3 µM). In contrast, diazepam blocked channels only at much higher concentrations and had no effect on AP duration at 1 µM. However, coadministration of 1-µM diazepam with methadone caused a statistically significant increase in AP duration and a 4-fold attenuation of hNav1.5 block (IC50 values were 44.2 µM and 26.6 µM, respectively, for tonic and phasic block), with no significant effect on methadone-induced block of hERG, hCav1.2, hKv4.3/hKChIP2.2, and hKvLQT1/hminK channels. Thus, although diazepam alone does not prolong the QT interval, the relief of methadone-induced Na channel block may leave hERG K channel block uncompensated, thereby increasing cardiac risk.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diazepam
/
Hipnóticos y Sedantes
/
Canales Iónicos
/
Metadona
/
Narcóticos
Tipo de estudio:
Etiology_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Revista:
J Cardiovasc Pharmacol
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos