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Ibutilide A Class III Antiarrhythmic Drugs

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

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Ibutilide A Class III Antiarrhythmic Drugs

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  1. IbutilideA Class IIIAntiarrhythmicDrugs ZHANG Dai-fu Shanghai East Hospital Tongji University September 10, 2010

  2. 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

  3. Chemistry Systematic name:N-(4-{4-[ethyl(heptyl)amino]-1- hydroxybutyl}phenyl)methanesulfonamide Formula:C20H36N2O3S Mol. Mass:384.578 g/mol

  4. Mechanism of Action • Ibutilide prolongs actionpotentialduration, so-called 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

  5. 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

  6. Mechanism of Action Slow Na  (Ibutilide) Ca Na plateau V Max + - APD Action Potential Duration QT T N

  7. 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

  8. 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

  9. 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%

  10. 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 highlyviable

  11. 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

  12. 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

  13. 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%)

  14. 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.

  15. Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Clin Ther. 2007;29:1957-66.

  16. Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Clin Ther. 2007;29:1957-66.

  17. Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Clin Ther. 2007;29:1957-66.

  18. 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.

  19. PK properties of ibutilide are linear with respect to dosing A single intravenous dose of ibutilide prolonged the QTc interval in a dose- and concentration-dependent manner Ibutlide was well tolerated Summary Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men Clin Ther. 2007;29:1957-66.

  20. Conversion efficacy and safety of repeated dosesof ibutilide in patients with atrial flutter and AF Am Heart J. 1998;136(4 Pt 1):632-42.

  21. Conversion efficacy and safety of repeated dosesof ibutilide in patients with atrial flutter and AF Am Heart J. 1998;136(4 Pt 1):632-42.

  22. Am Heart J. 1998;136(4 Pt 1):632-42.

  23. Conversion efficacy and safety of repeated dosesof ibutilide in patients with atrial flutter and AF Am Heart J. 1998;136(4 Pt 1):632-42.

  24. Conversion efficacy of intravenous ibutilide compared with intravenous amiodarone in patients with recent-onset AF and atrial flutter Clinical Trial Int J Cardiol. 2007; 118(3):321-5

  25. 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

  26. 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

  27. Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or AF Clinical Trial JACC. 1998; 31:1414-9

  28. 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

  29. Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation Clinical Trial Int J Clin Pract. 2005;59:1395-400

  30. Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation Int J Clin Pract. 2005;59:1395-400

  31. Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation Int J Clin Pract. 2005;59:1395-400

  32. Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Clinical Trial Heart. 1998; 79:568-75

  33. Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79:568-75

  34. Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79:568-75

  35. Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF Heart. 1998; 79:568-75

  36. Efficacy of intravenous ibutilide for rapid termination of AF and atrial flutter: a dose-response study Clinical Trial JACC. 1996; 28:130-6

  37. Efficacy of intravenous ibutilide for rapid termination of AF and atrial flutter: a dose-response study JACC. 1996; 28:130-6

  38. 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

  39. Pre-injection of magnesium sulfate enhances the efficacy of ibutilide for the conversion of typical but not of atypical persistent atrial flutter Clinical Trial Int J Cardiol. 2010;141:260-5

  40. 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

  41. Use of ibutilide in cardioversion of patients with AF or AFL treated with class IC agents Clinical Trial JACC. 2004;44:864-8

  42. Use of ibutilide in cardioversion of patients with AF or AFL treated with class IC agents JACC. 2004;44:864-8

  43. 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

  44. Usage CORVERT product monograph

  45. Dosing Post Cardiac Surgery CORVERT product monograph

  46. Treatment-Emergent Medical Events with Frequency of More Than 1% and Higher Than that of placebo Treatment-Emergent Medical Events with Frequency of More Than 1% and Higher Than that of placebo Adverse effects Ibutilide fumarate injecction insert. Revised 2009

  47. 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

  48. 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

  49. 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

  50. Contraindication Patients with previous demonstrated hypersensitivity to ibutilide fumarate or any of the other product components *

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