Drug-induced QTC prolongation dangerously underestimates proarrhythmic potential: lessons from terfenadine.
J Cardiovasc Pharmacol
; 57(5): 589-97, 2011 May.
Article
en En
| MEDLINE
| ID: mdl-21346598
BACKGROUND: Terfenadine's proarrhythmia prompted market withdrawal; therapeutic antihistaminic concentration is less than 1 nM, whereas IC50 of IKr and INa exceed 200 nM. METHODS AND RESULTS: Rabbit hearts were perfused with terfenadine (1-10,000 nM; 10-450 minutes). A dosage of 1 nM tended to shorten action potential duration (APD60) (-30 ± 30.5 ms; n = 6); 10 nM (450 minutes) significantly prolonged APD60 (46 ± 11 ms; n = 6), but after 1 hour washout, APD60 further prolonged. Above 30 nM, APD60 shortening was followed by prolongation; net effect depended on exposure time (n = 33). In the µM range, cardiac wavelength (λ) shortened (APD60 shortened, conduction slowed; P < 0.05). Terfenadine induced triangulation, reverse use dependence, instability and dispersion of repolarization (TRIaD) at 1 to 1000 nM, increasing with concentration (450 minutes: 1 nM yielded 50% of hearts, 10 nM 100%) and exposure (100 nM: 10 minutes yielded 16%, 30 minutes 33%, 150 minutes 66%, 450 minutes 100%). TRIaD with APD prolongation preceded two Torsade de Pointes, with shortening seven ventricular tachycardia and five ventricular fibrillation. Terfenadine causes normally little QTc prolongation in patients and Food and Drug Administration records suggest that incidence of ventricular tachycardia/ventricular fibrillation exceeds Torsade de Pointes. CONCLUSION: For terfenadine, TRIaD predicts drug-induced proarrhythmia: with λ prolongation, Torsade de Pointes is preferred, otherwise ventricular tachycardia/ventricular fibrillation. APD/QTc alone is clearly inadequate for proarrhythmia evaluation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Síndrome de QT Prolongado
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Terfenadina
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Taquicardia Ventricular
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Antagonistas de los Receptores Histamínicos H1 no Sedantes
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Corazón
Tipo de estudio:
Etiology_studies
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Prognostic_studies
Límite:
Animals
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Female
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Humans
Idioma:
En
Revista:
J Cardiovasc Pharmacol
Año:
2011
Tipo del documento:
Article
País de afiliación:
Bélgica
Pais de publicación:
Estados Unidos