ibutilide ibutilide a class iii antiarrhythmic drugs zhang dai-fu shanghai east hospital tongji...
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IbutilideIbutilide A Class III Antiarrhythmic Drugs
ZHANG Dai-fuZHANG Dai-fu
Shanghai East HospitalShanghai East Hospital Tongji UniversityTongji University
September 10, 2010
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
IbutlideIbutlide
ChemistryChemistry
Systematic name:Systematic name: N-(4-{4-[ethyl(heptyl)amino]-1- hydroxybutyl}phenyl)methanesulfonamide
Formula: C20H36N2O3S
Mol. Mass: 384.578 g/mol
Mechanism of ActionMechanism of Action Ibutilide prolongs action potential duration, so-called cl
ass 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 notdoes not have a sodium-blocking, antiadrenergic, and calcium blocking activity
Mechanism of ActionMechanism 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 ActionMechanism of Action
+
-
V Max
plateau
Slow Na
(Ibutilide)CaN
a
N
TQT
APD
Action Potential Duration
Electrophysiologic EffectsElectrophysiologic 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 EffectsElectrophysiologic 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 EffectsHemodynamic 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%
PharmacokineticsPharmacokinetics
Ibutilide is intravenously administered
It has a high first-pass metabolism, which results It has a high first-pass metabolism, which results in a poor in a poor bioavailability when taken orally when taken orally
Individual pharmacokinetic properties are highlyIndividual pharmacokinetic properties are highly viable
AbsorptionAbsorption
PharmacokineticsPharmacokinetics
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
DistributionDistribution
PharmacokineticsPharmacokinetics
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
MetabolismMetabolism
PharmacokineticsPharmacokinetics
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%)
Excretion
Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men
Clin Ther. 2007;29:1957-66.
Figure.Figure. Mean (SD) plasma concentration-time profiles after a single intravenous dose of ibutilide fumarate in healthy Chinese men
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.
Clin Ther. 2007;29:1957-66.
Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men
Figure.Figure. Mean (SD) QTc intervals after a single intravenous dose of ibutilide fumarater in healthty Chinese men
Clin Ther. 2007;29:1957-66.
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 concentration-dependent manner
Ibutlide was well tolerated
Pharmacokinetic and pharmacodynamic properties of ibutilide in healthy Chinese men
SummarySummary
Clin Ther. 2007;29:1957-66.
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.
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.
Am Heart J. 1998;136(4 Pt 1):632-42.
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.
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 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 and safety of intravenous ibutilide compared with intravenous procainamide in patients with atrial flutter or AF
JACC. 1998; 31:1414-9
Clinical Trial
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
Comparison of intravenous ibutilide vs.propafenone for rapid termination of recent onset atrial fibrillation
Int J Clin Pract. 2005;59:1395-400
Clinical Trial
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
Superiority of ibutilide over DL-sotalol in conversion atrial flutter and AF
Heart. 1998; 79:568-75
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
Efficacy of intravenous ibutilide for rapid termination of AF and atrial flutter: a dose-response study
JACC. 1996; 28:130-6
Clinical Trial
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
Efficacy of intravenous ibutilide for rapid termination of AF and atrial flutter: a dose-response study
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
Clinical Trial
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
Use of ibutilide in cardioversion of patients with AF or AFL treated with class IC agents
JACC. 2004;44:864-8
Clinical Trial
Use of ibutilide in cardioversion of patients with AF or AFL treated with class IC agents
JACC. 2004;44:864-8
IndicationIndication
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
UsageUsage
Patient Weight
DoseSecond iv Infusion
60 kg
iv infusion over 10 min.
1.0 mg
(one 10 ml. Vial)
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.< 60 kg
iv infusion over 10 min.
0.01 mg/kg
( 0.1 ml/kg)
CORVERT product monograph
Dosing Post Cardiac SurgeryDosing Post Cardiac Surgery
Patient Weight
DoseSecond iv Infusion
60 kgiv infusion over 10 min.0.5 mg (5 ml)
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.< 60 kgiv infusion over 10 min.0.005 mg/kg ( 0.05 ml/kg)
CORVERT product monograph
Adverse effectsAdverse 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
ContraindicationContraindication
Patients with previous demonstrated hypersensitivity to ibutilide fumarate or any of the other product components
WarningWarning
Before treatment of ibutilide, hypokalemia and hypomagnesemia should be corrected
Patients should be observed with continous ECG monitoring for at least 4 h
Ibutilide SummaryIbutilide 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