ppt课件-drug induced q t prolongationand torsadede pointes（药物诱导q t prolongationand torsadede同构）.pptVIP

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ppt课件-drug induced q t prolongationand torsadede pointes（药物诱导q t prolongationand torsadede同构）.ppt

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Drug-Induced QT Interval Prolongation andTorsades de Pointes Drug-Induced Torsades de Pointes QT Prolongation Torsades de Pointes QT Prolongation Torsades de Pointes Drugs Which Prolong the QTc QT Prolongation Torsades de Pointes Action Potential and Ionic Currents Ventricular Action Potential Mechanisms Of Drug - Induced QT Prolongation and Tdp Block of repolarizing K+ currents Stimulation of ICa-l Stimulation of INa Torsades de Pointes Torsades de Pointes ECG - QT Interval Automated QT and QTc Analysis Rate-Corrected QT Interval (QTc) QT Interval corrected for heart rate = QTc (Bazett) QTc = General Population Average QTc = 380-400 msec Bazett correction has major limitations QT Correction Formulae Normal QTc Interval - Criteria QTc (msec) Male Female Normal 430 450 Borderline 431-450 451-470 Prolonged 450 470 QT Intervals in Drug Induced TdP TdP - High Risk Drugs ( 1%) TdP - Low Risk Drugs ( 0.1%) Drug-Induced Torsades de Pointes Effect of EC K+ on Drug Induced IKr Block CYP450 3A4 Inhibitors Amiodarone Cimetidine Fluoxetine Grapefruit juice Protease inhibitors Ketoconazole; itraconazole Macrolide antibiotics (not Azithromycin) Nefazadone Drug Induced Torsades de Pointes Drug EP Effects Metabolic Liability Terfenadine IKr blocker 3A4 substrate Cisapride IKr blocker 3A4 substrate Mibefradil IKr blocker 3A4 inhibitor Erythromycin IKr blocker 3A4 inhibitor Astemizole IKr blocker 3A4 substrate Dofetilide IKr blocker Renal excretion Sotalol IKr blocker Renal excretion QTc Changes with Terfenadine Effect of CYP3A4 Inhibition with Ketoconazole Terfenadine (Seldane) 60 mg BID Cisapride (Propulsid) Gastric prokinetic (GERD) IKr blocker (modest QT effect) CYP 3A4 substrate Clarithromycin - 3X increase in conc Ketoconazole - 8X increase in conc 30 million Rx’s since 1993; no arrhythmia signal in large database review 1993-1999: 270 cases of serious arrhythmias reported to FDA (70 d