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Ibutilide A Class III Antiarrhythmic Drugs ZHANG Dai-fu Shanghai East Hospital Tongji University September 10, 2010 Ibutlide Classified as Class III according to Vaughan Williams Classification Manufactured by Pharmacia & Upjohn, USA and approved by FDA in 1995 Approved by SFDA in 2007 Chemistry Systematic name: N-(4-{4-[ethyl(heptyl)amino]-1hydroxybutyl}phenyl)methanesulfonamide Formula: C20H36N2O3S Mol. Mass: 384.578 g/mol Mechanism of Action Ibutilide prolongs action potential duration, socalled class III antiarryhthmic drug The class III drugs block IKr, the rapid component of delayed rectifier potassium current, thereby prolonging repolarization, the action potential duration, and the refractory period But ibutilide does not have a sodium-blocking, antiadrenergic, and calcium blocking activity Mechanism of Action Ibutilide activates slow sodium channel and promotes the influx of sodium, Its mechanism of action is unique among available class III drugs Ibutilide may enhance the conductance of Ca++ through the L- type calcium channel Mechanism of Action Na Ca Slow Na (Ibutilide) plateau V Max + - APD Action Potential Duration QT T N Electrophysiologic Effects No clinically significant effect on QRS Produces a dose related prolongation of the QT interval Prolongation of QT interval is similar in men and women Prolongs action potential duration and effective refractory periods in both atria and ventricles Electrophysiologic Effects Lengthens effective refractory period in both atrium and ventricle Enhances slow Na+ inward plateau current and blocks delayed-rectifier outward K+ current Maintains Class III effects even at rapid heart rates Hemodynamic Effects • No clinically significant effects on cardiac output (CO), mean pulmonary arterial pressure (PAPm) or capillary wedge pressure (PCWP) in patients with ejection fractions > 35 or < 35% Pharmacokinetics Absorption Ibutilide is intravenously administered It has a high first-pass metabolism, which results in a poor bioavailability when taken orally Individual pharmacokinetic properties are highly viable Pharmacokinetics Distribution Ibutilide has a relatively large volume of distribution among individual subjects, which is about 11L/kg Approximately 40% of the drug is bound with plasma albumin Pharmacokinetics Metabolism Ibutilide has a high systemic plasma clearance that closes to the hepatic blood flow (29mL/min/kg). Its metabolic pathway is via liver’s cytochrome P450 system Only one in eight metabolites has active property of the Class III antiarrhythmic agents, and is only less than 10% of ibutilide Pharmacokinetics Excretion After administration of ibutilide, it is quickly excreted by renal pathway with a half-life of approximately 6 hours Approximately 82% metabolites is excreted in the urine, and The reminder of the drug is excreted in feces (about 19%) Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Figure. Mean (SD) plasma concentration-time profiles after a single intravenous dose of ibutilide fumarate in healthy Chinese men Clin Ther. 2007;29:1957-66. Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Clin Ther. 2007;29:1957-66. Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Clin Ther. 2007;29:1957-66. Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Clin Ther. 2007;29:1957-66. Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Figure. Mean (SD) QTc intervals after a single intravenous dose of ibutilide fumarater in healthty Chinese men Clin Ther. 2007;29:1957-66. Summary Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men PK properties of ibutilide are linear with respect to dosing A single intravenous dose of ibutilide prolonged the QTc interval in a dose- and concentrationdependent manner Ibutlide was well tolerated Clin Ther. 2007;29:1957-66. Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and AF Am Heart J. 1998;136(4 Pt 1):632-42. Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and AF Am Heart J. 1998;136(4 Pt 1):632-42. Am Heart J. 1998;136(4 Pt 1):632-42. Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and AF Am Heart J. 1998;136(4 Pt 1):632-42. Clinical Trial Conversion efficacy of intravenous ibutilide compared with intravenous amiodarone in patients with recent-onset AF and atrial flutter Int J Cardiol. 2007; 118(3):321-5 Conversion efficacy of intravenous ibutilide compared with intravenous amiodarone in patients with recent-onset AF and atrial flutter Int J Cardiol. 2007; 118(3):321-5 Conversion efficacy of intravenous ibutilide compared with intravenous amiodarone in patients with recent-onset AF and atrial flutter Int J Cardiol. 2007; 118(3):321-5 Clinical Trial Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or AF JACC. 1998; 31:1414-9 Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or AF Figure. Mean chang from baseline in systolic and diastolic blood Pressure and in pulse rate in Ibutilide- and procainamide-treated patient JACC. 1998; 31:1414-9 Clinical Trial Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation Int J Clin Pract. 2005;59:1395-400 Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation Int J Clin Pract. 2005;59:1395-400 Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation Int J Clin Pract. 2005;59:1395-400 Clinical Trial Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79:568-75 Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79:568-75 Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79:568-75 Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79:568-75 Clinical Trial Efficacy of intravenous ibutilide for rapid termination of AF and atrial flutter: a dose-response study JACC. 1996; 28:130-6 Efficacy of intravenous ibutilide for rapid termination of AF and atrial flutter: a dose-response study JACC. 1996; 28:130-6 Efficacy of intravenous ibutilide for rapid termination of AF and atrial flutter: a dose-response study ++ Figure. The mean±SD change in corrected QT interval from the baseline interval at 1 h for patients receiving placebo and those receiving each dose of intravenous ibutilide infusion. A, Date for the groups as a whole. B, Date for patients with and without successful conversion to sinus rhythm *P≤0.00, P≤0.001 JACC. 1996; 28:130-6 Clinical Trial Pre-injection of magnesium sulfate enhances the efficacy of ibutilide for the conversion of typical but not of atypical persistent atrial flutter Int J Cardiol. 2010;141:260-5 Pre-injection of magnesium sulfate enhances the efficacy of ibutilide for the conversion of typical but not of atypical persistent atrial flutter Int J Cardiol. 2010;141:260-5 Use of ibutilide in cardioversion of patients with AF or AFL treated with class IC agents Clinical Trial JACC. 2004;44:864-8 Use of ibutilide in cardioversion of patients with AF or AFL treated with class IC agents JACC. 2004;44:864-8 Indication The rapid conversion of AF and AFL of recent onset to sinus rhythm Patients with atrial arrhythmias of longer duration are less likely to respond to ibutilide fumarate The effectiveness of ibutilide has not been determined in patients with arrhythmias of more than 90 days in duration Usage Patient Weight Dose 60 kg iv infusion over 10 min. 1.0 mg (one 10 ml. Vial) < 60 kg iv infusion over 10 min. 0.01 mg/kg ( 0.1 ml/kg) Second iv Infusion If arrhythmia does not terminate within 10 min. after the end of the initial infusion, a second 10 min. infusion of equal strength maybe given. CORVERT product monograph Dosing Post Cardiac Surgery Patient Weight Dose 60 kg iv infusion over 10 min. 0.5 mg (5 ml) Second iv Infusion If arrhythmia does not terminate within 10 min. after the end of the initial infusion, a second 10 min. < 60 kg iv infusion over 10 min. 0.005 mg/kg ( 0.05 ml/kg) infusion of equal strength maybe given. CORVERT product monograph Adverse effects Ibutilide fumarate injecction insert. Revised 2009 Ibutilide-induced changes in the temporal lability of ventricular repolarization in patients with and without structural heart disease J Cardiovasc Electrophysiol. 2009;20:873-9 Ibutilide-induced changes in the temporal lability of ventricular repolarization in patients with and without structural heart disease J Cardiovasc Electrophysiol. 2009;20:873-9 Ibutilide-induced changes in the temporal lability of ventricular repolarization in patients with and without structural heart disease J Cardiovasc Electrophysiol. 2009;20:873-9 Contraindication Patients with previous demonstrated hypersensitivity to ibutilide fumarate or any of the other product components Warning Before treatment of ibutilide, hypokalemia and hypomagnesemia should be corrected Patients should be observed with continous ECG monitoring for at least 4 h Ibutilide Summary Conversion efficacy - AFL 60 – 80%, AF 30 – 50% - AF arrhythmia duration (46% AF < 7 days vs. 18% AF 7 days) Superior to iv procainamide, amiodarone, propafenone Mean time to termination < 30 min. Enhances efficacy of rapid pacing termination of AFL Proarrhythmia risk (torsade de pointes) ˜ 2% sustained, 3% non-sustained