Download Ibutilide

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