Download a new antiarrhythmic compound potent class iii

Indo American Journal of Pharmaceutical Research, 2013
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ISSN NO: 2231-6876
INDO AMERICAN
JOURNAL OF
PHARMACEUTICAL
RESEARCH
A NEW ANTIARRHYTHMIC COMPOUND POTENT CLASS III IBUTILIDE: AN
OVERVIEW
Sandhya Jaiswal1, G.D.Gupta2*
A.S.B.A.S.J.S.M College of Pharmacy, Bela (Ropar)- 140111, Punjab, India
ARTICLE INFO
Article history
Received 30/05/2013
Available online
30/06/2013
Keywords
Ibutilide,
Antiarrhythmic,
Atrial Fibrillation,
Atrial Flutter.
ABSTRACT
This article reviews the safety and efficacy of ibutilide for use in patients with
atrial fibrillation and flutter. Ibutilide, a methanesulfonamide derivative is a class
III antiarrhythmic drug that was approved by the Food & Drug Administration for
use on December 28, 1995, is available only for intravenous use because of its
extensive first-pass metabolism. It prolongs repolarization time, action potential
duration, and refractory period of atrial and ventricular myocardium through its
action as a potassium channel blocker, affecting the rapid component of the cardiac
delayed rectifier potassium current. The drug is indicated for the rapid restoration
of normal sinus rhythm in patients with atrial fibrillation or atrial flutter of recent
onset who are hemodynamically stable. The ibutilide effects is dependent on
concentration. Clinical trials have established ibutilide's efficacy in converting
sustained atrial flutter and atrial fibrillation to normal sinus rhythm. Ibutilide has a
conversion rate of up to 75% to 80% in recent-onset atrial fibrillation and flutter;
the conversion rate is higher for atrial flutter than for atrial fibrillation.
Comparative studies have reported that ibutilide was a more effective intravenous
agent than amiodarone, DL-sotalol, procainamide for conversion of atrial flutter
and atrial fibrillation. The present review describe the efficacy of ibutilide for rapid
conversion of atrial fibrillation and atrial flutter to sinus rhythm is superior to most
of the other antiarrhythmic agents.
Corresponding author
Copy right © 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Page
Please cite this article in press as G.D.Gupta et.al. A new antiarrhythmic compound potent Class III ibutilide: An overview. Indo
American Journal of Pharm Research.2013:3(6).
4619
Prof.(Dr.)G.D.Gupta
ASBASJSM College of Pharmacy,
Bela (Ropar)- 140111, Punjab, India
Tel: +91-941-7862160
E.mail: [email protected]
Vol 3, Issue 6, 2013.
G.D.Gupta et al.
ISSN NO: 2231-6876
INTRODUCTION
Atrial arrhythmias after cardiac surgery occur in 15% to 40% of patients1-3. Atrial fibrillation (AF) is a
disturbance of the normally rhythmical beating of the cardiac atria, characterized by rapid (e.g., 400–600 beats/
min), irregular electrical and mechanical activation of the atrial muscle. It is the most common cardiac
arrhythmia encountered in clinical practice, and has multiple causes, such as coronary artery disease, heart
failure, valve disease and hypertension. Patients with AF have an increased risk of death from stroke due to
embolisation of atrial thrombi which form because the rapid and irregular activation causes uncoordinated atrial
contraction and hence disturbed and reduced atrial blood flow. AF can be treated with electrical cardioversion,
tissue ablation, and pharmacological therapy; the latter being the mainstay, particularly in the expanding elderly
population. However, currently available antiarrhythmic drugs are only moderately effective in preventing or
terminating AF or maintaining sinus rhythm after it is restored, and may also exert adverse effects such as
ventricular pro-arrhythmia, organ toxicity, or both4. Anti-arrhythmic drugs are conventionally grouped
according to their broad mechanism of action (Vaughan Williams, 1984), namely, Na+ channel blockade (class
I), β-adrenoceptor antagonism (II), action potential prolonging (III), and Ca2+ channel blockade (IV). Many
drugs that prevent AF possess activity in more than one class, and some in none. Although different
classification schemes have been proposed, the first scheme (Vaughan-Williams) is still the one that most
physicians use for antiarrhythmic drugs.
Table 1: Vaughan-Williams classification scheme of antiarrhythmic drugs.
Examples
Quinidine
Procainamide
Disopyramide
Mechanism
(Na+) channel
block
(intermediate
association/diss
ociation)
Ib
Do not affect
QRS complex
Lidocaine
Phenytoin
Mexiletine
Tocainide
(Na+) channel
block
(fast
association/diss
ociation)
Flecainide
Propafenone
Moricizine
(Na+) channel
block
(slow
association/diss
ociation)
Propranolol
Esmolol
Timolol
Metoprolol
Atenolol
Bisoprolol
Amiodarone
Sotalol
Ibutilide
Dofetilide
Dronedarone
E-4031
Verapamil
Diltiazem
Beta blocking
Propranolol also
shows
some
class I action
Adenosine
Digoxin
Magnesium
Sulfate
Work by other
or
unknown
mechanisms
(Direct
nodal
inhibition).
Ic
II
Beta-blockers
III
K+
channel
blocker
IV
Slow-channel
blockers
V
Clinical uses in
cardiology
Ventricular arrhythmias
Prevention of paroxysmal recurrent atrial fibrillation
(triggered by vagal overactivity)
Procainamide in Wolff-Parkinson-White syndrome
Treatment and prevention during and immediately after
myocardial infarction, though this practice is now
discouraged given the increased risk of a systole
ventricular tachycardia
atrial fibrillation
Prevents paroxysmal atrial fibrillation
Treats recurrent tachyarrhythmias of abnormal conduction
system.
Contraindicated immediately post-myocardial infarction.
Decrease myocardial infarction mortality
Prevent recurrence of tachyarrhythmias
Sotalol is also a
beta
blocker
Amiodarone has
Class I, II, III &
IV activity
In Wolff-Parkinson-White syndrome
(sotalol:) ventricular tachycardias and atrial fibrillation
(Ibutilide:) atrial flutter and atrial fibrillation
Ca2+
channel
blocker
Prevent recurrence of paroxysmal supraventricular
tachycardia
Reduce ventricular rate in patients with atrial fibrillation
Used in supraventricular arrhythmias, especially in Heart
Failure with Atrial Fibrillation, contraindicated in ventricular
arrhythmias. Or in the case of Magnesium Sulfate, used in
Torsades de Pointes
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4620
Known as
Fast-channel
blockers-affect
QRS
complex
Page
Class
Ia
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G.D.Gupta et al.
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Nevertheless, this classification serves as a useful basis for assessing and comparing electrophysiological effects
of drugs with broadly related activities. These arrhythmias, although not lethal, predispose to cerebrovascular
accidents can cause disabling symptoms (especially in patients with significant cardiac dysfunction) and are
responsible for a prolonged length of stay and an increased hospital cost3,5-9. Thus, measures to terminate these
arrhythmias acutely would be clinically useful. The purpose of the present review is to extend the awareness
about the safety and efficacy profile of ibutilide which is superior to most of the other antiarrhythmic agents.
Ibutilide fumarate is a class III antiarrhythmic drug recently approved for the acute termination of atrial
fibrillation (AF) and flutter (AFl)10,11.
USES:
a) In chemical cardioversion in acute atrial fibrillation and flutter
Ibutilide can be used as a first-line agent in chemical cardioversion of recent-onset atrial fibrillation and flutter.
Its rapid onset of action can be especially beneficial for patients with depressed left ventricular function, and
these patients tolerate the drug well18. It has been seen in various studies that the cardioversion rate in atrial
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It is a potent blocker of the rapid component of the cardiac-delayed rectifier potassium current and also
activates the slow inward sodium current12. Ibutilide has been shown to be modestly effective in terminating
both atrial flutter and atrial fibrillation, particularly if the arrhythmia is relatively short-lived, and may be more
effective than other anti-arrhythmic drugs for this purpose13. This drug, however, never enjoyed mainstream
success because of modest efficacy, a potentially high risk of torsade-de- pointes in some patients14, and the
time commitment for physicians and other personnel. Older drugs, such as quinidine and procainamide, are not
as effective as ibutilide and carry additional risks so that they have faded from the scene. Other drugs, including
intravenous b-blockers, terminate atrial fibrillation rarely, and most conversions noted after administration are
probably spontaneous reversions15. The only exception to this is post-operative atrial fibrillation, where
adrenergic activation plays an important role, and intravenous esmolol was associated with superior conversion
rates when compared with diltiazem16. Newer drugs such as vernakalant hydrochloride, a multi-channel and
partially specific atrial potassium channel blocker, also available as an intravenous infusion, but not yet
approved for use in many countries, can terminate atrial fibrillation (but not atrial flutter) with similar efficacy
and perhaps with a lower risk of developing torsade-de-pointes17. Given these limitations, improved conversion
rates and reduction in proarrhythmic risks with current pharmacological agents or newer agents are of
significant interest. Though ibutilide is similar to sotalol in chemical structure, it has a unique class III action by
prolonging the APD not only via HERG channel block (human cardiac delayed rectifier K+ channel) but also
via activation of a slow inward current carried by Na+. This dual mode of action is associated with QT
prolongation and enhanced risk of torsades-de-pointes arrhythmias. When used intravenously for
pharmacological conversion of AF the risk can be greatly reduced by administering simultaneously the short
acting β-adrenoceptor blocker esmolol .
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Chemistry:
Common Name : Ibutilide fumarate
Chemical Name : Methanesulfonamide, N-{4-{4-(ethylheptylamino)-1-hydroxybutyl}phenyl,
(+) (-), (E)-2-butenedioate (1:0.5) (hemifumarate salt)
Description
: Ibutilide fumarate: White to off-white powder with an aqueous solubility
of over 100 mg/mL at pH 7 or lower. Ibutilide fumarate (racemate) melts over the range of 117
to 121°C.
Chemical Structure:
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G.D.Gupta et al.
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fibrillation of <90 days’ duration was higher (31% to 44%) with ibutilide (a dose of 0.015 mg/kg or 2 mg)
compared with placebo19, sotalol (1.5 mg/kg)20, or procainamide 1200 mg21–23. In acute episodes with onset of 3
to 48 hrs, ibutilide has a higher efficacy in atrial flutter (87%) compared with atrial fibrillation (77%). More
than 80% of patients with recent-onset atrial flutter are converted to sinus rhythm within 30 minutes of drug
administration24. The same study24 compared the efficacy of intravenous ibutilide to intravenous amiodarone in
the conversion of atrial fibrillation or atrial flutter, and the conversion rate was found to be significantly higher
with ibutilide (80% vs 57%; P = 0.0054). A sub-analysis of the same study showed no significant difference in
the conversion rate between these drugs in patients with atrial fibrillation (77% vs 69%; P = NS); however,
when used for atrial flutter, ibutilide was superior to amiodarone (87% vs 29%; P = 0.003). It was concluded
that ibutilide was more effective than amiodarone in converting recent-onset atrial flutter to sinus rhythm, but
both drugs are equally effective in converting recent-onset atrial fibrillation to sinus rhythm24. In new-onset
arrhythmia, a single dose of ibutilide successfully converted 53% patients’ fibrillation or flutter into sinus
rhythm, and an additional 22% patients converted with the second dose, which resulted in an overall conversion
rate of 75% 25. Female sex and younger age were independent predictors of successful cardioversion with
ibutilide 26.
b) In postoperative atrial fibrillation and flutter
Ibutilide is safe and effective when used to terminate atrial fibrillation and flutter in the period after cardiac
surgery. There was an incremental increase in the overall conversion rate with increasing doses of ibutilide
(40% with a dose of 0.25 mg, 47% with a dose of 0.5 mg, and 57% with 1.0-mg dose). The time to conversion
also decreased with increasing doses of ibutilide27. The conversion rates were higher in all doses for atrial flutter
compared with atrial fibrillation. Ibutilide's efficacy and safety profile was compared with those of amiodarone
and propafenone in terminating postoperative atrial fibrillation28,29. It was as effective as amiodarone in
converting postoperative atrial fibrillation; however, the time to cardioversion was significantly lower in
patients receiving ibutilide. In a study that randomized patients in a double-blind fashion to either ibutilide or
amiodarone, these drugs had comparable conversion rates at 4 hrs 28. Ibutilide was superior in terms of
hemodynamic and systemic side effects; hypotension was seen more often in patients receiving amiodarone 28.
Table-2: Comparison of the Conversion Rates of Ibutilide, Amiodarone, Propafenone, Procainamide,
Dofetilide, and Flecainide in Recent-Onset Atrial Fibrillation, Persistent Atrial Fibrillation, and Recent-Onset
Atrial Flutter.
Flecainide
Recent-Onset Atrial
Flutter
63-76
29
40
14
64
13 (with intravenous
administration)
4622
Propafenone
Procainamide
Dofetilide
Conversion Rates (%)
Recent-Onset Atrial
Persistent
Fibrillation
Atrial Fibrillation/Flutter
31–77
48
34–69 (with bolus
15-48
regimen)
55–95 (with bolus
followed by continuous
infusion)
56–87.5
37.5-40
20–60
24
20 (dose of 125 mcg bid)
44 (250 mcg bid)
85 (500 mcg bid)
85 (500 mcg bid)
57–68 (at 2–4 hr)
75–91 (at 8 hr)
Page
Pharmacological
Agent
Ibutilide
Amiodarone
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Another study, in which 42 stable patients with new atrial fibrillation after cardiac surgery were randomized to
oral propafenone (600 mg, single dose), ibutilide (1 mg up to 2 doses if necessary), or rate control with,
preferably, a β-blocker, ibutilide was significantly superior to propafenone in terminating the arrhythmia. At 24
hrs, none of the patients in the ibutilide group were in atrial fibrillation, compared with 65% of patients in
propafenone29. However, none of these drugs affected the length of hospital stay or the rhythm at discharge
when compared with rate control. Therefore, it was suggested that, because of the transient nature of the
arrhythmia, routine attempts to cardiovert with antiarrhythmic agents is not necessary in stable patients with
postoperative atrial fibrillation.
c) In persistent atrial fibrillation and flutter
The efficacy data of the use of ibutilide in the cardioversion of persistent atrial fibrillation is not as impressive
as the data about use of ibutilide for acute atrial fibrillation. In the study by Vos et al20 the conversion rate of
persistent atrial fibrillation lasting for >30 days with ibutilide was 48%. The predictors of successful
cardioversion found in another study were lower duration of the arrhythmia, the presence of underlying atrial
flutter, the absence of heart failure, and the absence of concomitant digoxin therapy30. Ibutilide is also safe and
effective in cardioversion of patients with a history of persistent atrial fibrillation or flutter who are taking oral
amiodarone treatment for the prevention of recurrences of these arrhythmias. Because of the long half-life of
amiodarone it is often not feasible to discontinue it before ibutilide administration; both of these drugs are class
III antiarrhythmic agents and the prolongation of the QT interval could result in proarrhythmia. Glatter et al31
addressed this concern of the increased incidence of proarrhythmia. In their study, which assessed the efficacy
and safety of cardioversion with combination therapy in patients with atrial fibrillation or flutter, it was found
that within 30 minutes of infusion, ibutilide converted 54% of patients with atrial flutter and 39% of patients
with atrial fibrillation who had been treated with long-term amiodarone. The use of ibutilide was found to be
safe in these patients, with no excess occurrence of proarrhythmia31.
Ibutilide pretreatment also has been found to facilitate successful electrical cardioversion. Ibutilide significantly
facilitates cardioversion of atrial fibrillation with standard monophasic transthoracic defibrillation32. There was
a 100% conversion rate in patients receiving pretreatment with ibutilide compared with 72% in patients
receiving no pretreatment. In pretreated patients, transthoracic electrical cardioversion was performed 10
minutes after completion of infusion of 1 mg of ibutilide given intravenously over 10 minutes. Moreover, the
patients who did not convert with initial transthoracic cardioversion converted after pretreatment with ibutilide.
The energy requirement for defibrillation after pretreatment was significantly reduced (166±80 Joules vs
228±93 Joules) 32. Ibutilide pretreatment preceding biphasic shock defibrillation improves the efficacy of
cardioversion by reducing the number of attempts and the energy requirement, thereby lowering the risk of
muscle damage33.
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d) In terminating accessory pathway–mediated atrial fibrillation
Ibutilide was very effective in terminating accessory pathway–mediated atrial fibrillation. In a study by Glatter
et al38 it was found that the conversion rate of ibutilide to terminate such arrhythmia was as high as 95%. In this
study the atrial fibrillation was treated within minutes of development. In addition, a higher drug infusion rate
was used, which may have resulted in the high conversion rate. In another study by Volgman et al21 when
ibutilide was compared with procainamide, ibutilide's conversion rate to sinus rhythm in these patients was 58%
versus 18% for procainamide (P<0.0001). Moreover, procainamide caused hypotension whereas ibutilide
4623
Ibutilide has a greater efficacy in conversion of atrial flutter compared with atrial fibrillation, especially in
patients with recent-onset arrhythmia23. Ibutilide causes the prolongation of atrial flutter cycle length and
increases cycle length variability by fully abolishing the excitable gap34. Studies also have shown that ibutilide
increases the atrial effective refractory period that leads to significant variability in the cycle length of typical
atrial flutter before termination35,36. Pretreatment with ibutilide also has been shown to facilitate the
cardioversion of atrial flutter by atrial overdrive pacing37.
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infusion did not. Ibutilide was also effective in preventing the recurrence of atrial fibrillation for at least 60
minutes, which allowed successful completion of an ablation procedure38.
Pharmacology : Ibutilide is a methanesulfonamide derivative with structural similarities to the antiarrhythmic
agent sotalol. This drug increases action potential duration as its primary mechanism of action, so-called class
III effect, largely by blocking the rapid component of the cardiac delayed rectifier potassium current, IKr. In
isolated cardiac myocytes, ibutilide also prolongs action potential duration39,40, although its mechanism of
action is unique among available class III drugs. At nanomolar concentrations, ibutilide appears to activate a
slow inward current, largely carried by sodium ions, that is unresponsive to IKr blockers39-41. In addition,
ibutilide blocks IKr on the basis of both binding studies of 3H-dofetilide in guinea pig ventricular myocytes42
and patch-clamp studies in an atrial tumor cell line in which IKr is the major repolarizing current43. Over a
limited range of stimulation rates, ibutilide can increase action potential duration without significant reverse use
dependence or loss of effect at rapid pacing rates44-45. In humans, ibutilide causes a dose and concentrationrelated increase in the uncorrected and rate-corrected QT interval in both healthy volunteers and patients with
atrial fibrillation and atrial flutter46-48. Recent studies 49 indicate that the congenital long-QT syndrome can arise
from ion channel mutations that cause either reduced IKr current or enhanced inward sodium current. Therefore,
it is not surprising that ibutilide administration can cause excessive QT prolongation associated with the
development of triggered activity (early after depolarization) in animal models 50-51and torsade de pointes in
patient47,48. Action potential prolongation by ibutilide leads to an increase in atrial and ventricular refractoriness
in vivo45,52-54. In models of atrial flutter, this was associated with arrhythmia termination, with an increase in
atrial flutter cycle length before conversion, suggesting slowed conduction in some area of the reentrant
circuit52-54.
The drug was also effective in termination of atrial fibrillation in a model of coronary occlusion with ischemic
left ventricular dysfunction55. In patients with atrial flutter, ibutilide caused greater prolongation of
repolarization (and therefore refractoriness) than slowing of conduction56, this effect would cause a reduction in
the excitable gap of a reentrant circuit and likely contributes to arrhythmia termination under these
circumstances. 57 In a model of recent myocardial infarction, ibutilide was also effective at suppressing
inducible ventricular arrhythmias58. Additional evidence indicates that the drug can lower the energy threshold
required for ventricular defibrillation59. Although administration of ibutilide can cause mild slowing of sinus
rate and AV nodal conduction, 60 there was no significant effect on heart rate, PR interval, or QRS interval
during a dose-response study of ibutilide in healthy volunteers 46. Ibutilide administration is associated with
minimal hemodynamic effects both in animal models of ischemic left ventricular dysfunction55 and in
patients46,48,61.
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Mechanism of action : Unlike most other Class III antiarrhythmic drugs, ibutilide does not produce its
prolongation of action potential via blockade of cardiac delayed rectifier of potassium current IKr, nor does it
have a sodium-blocking, anti-adrenergic, and calcium blocking activity that other Class III agents possess. Thus
it is often referred as a ―pure‖ Class III antiarrhythmic drug. It does have action on the slow sodium channel and
promotes the influx of sodium through these slow channels. Although potassium current seems to play a role,
their interactions are complex and not well understood. Ibutilide’s unique mechanism works by an activation of
a specific inward sodium current, thus producing its therapeutic response in which a prolonged action potential
increases myocytes’ cardiac refractoriness in case of atrial fibrillation and flutter. The class III drugs block IKr,
4624
In a study of hemodynamic function in patients with a range of ejection fractions (including ,35%), intravenous
ibutilide had no clinically significant effects on cardiac output, mean pulmonary arterial pressure, or pulmonary
capillary wedge pressure after doses up to 0.03 mg/kg 61,62. There has been no clinically significant effect of
ibutilide to lower blood pressure or worsen congestive heart failure in published clinical trials 46,48,61. In
reproduction studies in rats, orally administered ibutilide was both teratogenic and embryocidal 63. The
excretion of the drug into breast milk has not been studied. Ibutilide has not been shown to be genotoxic in
multiple tests including the Ames assay, although no animal studies have been conducted to determine its
carcinogenic potential 62.
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the rapid component of the cardiac delayed rectifier potassium current. This results in prolonged repolarization,
increased action potential duration, and lengthening of the refractory period56,57. Ibutilide increases the
refractoriness of atrial and ventricular myocardium, the atrioventricular node, His-Purkinje system, and
accessory pathway . In addition, ibutilide activates a slow, delayed inward sodium current that occurs early
during repolarization45,52-54,60.
Pharmacokinetics: Ibutilide is not available for long-term oral use because of extensive first-pass metabolism
when administered by this route. After intravenous administration, the plasma concentration declines in a
multiexponential manner, with a high systemic plasma clearance that approximates liver blood flow 61,62.
Pharmacokinetic properties are linear with respect to dose 60.
Table-3: Pharmacokinetic properties of Ibutilide
Properties
Bioavailability
Metabolism
Half-life
Excretion
Protein Binding
Dose
Volume of distribution
Ibutilide
Hepatic oxidation
6 hours (2-12 hours)
Renal (82%), fecal
40%
1mg
11L/Kg
Co-administration of digoxin, calcium channel blockers, or β-adrenergic receptor blockers with ibutilide has no
apparent effect on the pharmacokinetics, safety, or efficacy of the drug in clinical trials 62. In healthy male
volunteers, about 82% of a 0.01 mg/kg dose of ibutilide was excreted in the urine (about 7% of the dose as
unchanged ibutilide) within 4 days of dosing, and the remainder (19%) was recovered in the faeces within 7
days of dosing. Clearance appears to be unaltered by either a reduction in creatinine clearance or left ventricular
dysfunction. However, abnormal liver function would likely lead to reduced clearance and prolonged
pharmacological effect and might necessitate longer periods of monitoring in these patients after ibutilide
administration62. In normal volunteers and patients with atrial fibrillation and atrial flutter, ibutilide
pharmacokinetics are not influenced by patient age, sex, or type of arrhythmia 60,62,64.
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Safety and efficacy of ibutilide in elderly: Ibutilide is a safe and effective antiarrhythmic agent for use in the
elderly. In a study done to assess the efficacy of ibutilide in elderly patients (age, ≥65 years), the overall rate of
successful conversion was 59%. In the same study on sub-analysis, the conversion rate for atrial fibrillation was
63% and was 54% for atrial flutter. The mean conversion time was 33 ± 45 minutes. Three fourths of the
conversions occurred within 45 minutes of treatment. Ibutilide-induced lengthening of the QTc interval was
17±21 milliseconds. This data showed that ibutilide seems to be a safe and effective drug for conversion of
recent-onset atrial fibrillation and flutter in elderly patients when monitored carefully75.
4625
Safety and efficacy of ibutilide in children: The safety and efficacy of ibutilide in the cardioversion of atrial
flutter and atrial fibrillation in the pediatric population and in patients with congenital heart disease is not well
known. A retrospective review of the data from 19 patients (range, 6 months to 34 years; median, 16 years) who
received ibutilide for atrial flutter or atrial fibrillation found that the overall conversion rate was 71%, with a
63% success rate with administration of the first dose. Fourteen episodes in 6 patients required electrical
cardioversion after failure of ibutilide treatment. Ibutilide was well tolerated with no episodes of symptomatic
bradycardia, but there was one episode of both torsade de pointes and unsustained ventricular tachycardia. It
was concluded that, with careful monitoring, ibutilide could be an effective tool for use in pediatric patients for
cardioversion of atrial flutter and fibrillation74. The approved dose of ibutilide in patients weighing >60 kg is 1
mg intravenously given as a 10 minute infusion. In patients weighing <60 kg, the dose is 0.01 mg/kg given as a
10-minute infusion.
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Adverse effects: Ibutilide causes prolongation of the QT interval, like any other Class III antiarrhythmic agent,
thus increasing the risk of fatal arrhythmias. The most common and the most serious of these arrhythmias is
torsade de pointes, which is a distinct, polymorphic, ventricular tachycardia occurring in the setting of a
prolonged QT interval 65,66. The predictors of occurrence of torsades de pointes in patients treated with ibutilide
are bradycardia, small body size, history of heart failure, nonwhite race, and female sex 66. Most episodes of
torsade-de-pointes occur during the first hour of treatment with ibutilide. The half-life of ibutilide is 3 to 6 hrs;
its clincal effect can be measured by the corrected QT interval, which disappears in 2 to 6 hrs. Hence, a
minimum of a 4 to 6 hrs observation period is recommended after ibutilide treatment 67,60. The rate of
administration may also be important because faster rates of administration of class III agents have been shown
in experimental models to increase the risk of torsade de pointes68. The risk is increased in patients with severe
left ventricular systolic dysfunction with an ejection fraction <20%. Caution should be used in patients with
ischemia, previous myocardial infarction, and uncompensated heart failure because ibutilide-induced torsadede-pointes maybe difficult to treat in these patients66.
The risk of developing torsade-de-pointes with ibutilide monotherapy is 4%69. However, the risk is reduced to
1% in patients who are already taking propafenone or flecainide. This reduction in risk is because of the
protective effect of the sodium channel blockade of type IC drugs70,71. The incidence of ventricular arrhythmias
including torsade-de-pointes may also be reduced with intravenous infusion of high-dose magnesium
sulfate72,73. Precautions should be taken to reduce this risk of fatal arrhythmia by the appropriate selection of
patients for ibutilide treatment, correction of serum potassium and magnesium abnormalities, ensuring
immediate availability of resuscitation equipment, and monitoring for at least 4 hrs after ibutilide infusion.
The risk of un-sustained monomorphic ventricular tachycardia is 4.9%67. This rate is decreased by the infusion
of intravenous magnesium before ibutilide administration. In view of the risk of ventricular arrhythmias,
patients should be monitored in an intensive care unit during and for at least 4 hrs after ibutilide infusion. The
administration of ibutilide should be under the supervision of a cardiologist or a physician who is trained in
emergent arrhythmia management and is certified in Advanced Cardiac Life Support. There is no increased risk
of hypotension, conduction block, or bradycardia.
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Dosage and administration: For intravenous administration, the recommended dose of ibutilide is 1 mg over a
10-minute period in patients weighing ≥60 kg62. Ten minutes after the end of the initial infusion, a second 10minute infusion of equal strength can be given if the arrhythmia has not terminated. For patients weighing ,<60
kg, the recommended dose is 0.01 mg/kg initially, with a second dose of the same strength 10 minutes later if
necessary. The ibutilide infusion should be stopped as soon as the arrhythmia is terminated or in the event of
nonsustained/sustained ventricular tachycardia or marked prolongation of the QT/QTc interval. Patients should
be monitored for at least 4 hrs after the infusion or until the QTc has returned to baseline, with a longer
monitoring period if nonsustained ventricular tachycardia develops. Patients with hepatic dysfunction should
also be monitored for an extended period of time given the likelihood of reduced drug clearance in this
situation. It is currently recommended that therapy with antiarrhythmic drugs that prolong the QT interval (class
Ia and class III) be withheld for at least 4 hrs after ibutilide administration. Ibutilide should not be administered
to pregnant women unless it is determined that the clinical benefit outweighs potential risks to the fetus. The
safety and efficacy of ibutilide in persons younger than 18 years of age has not been
determined.
4626
Adequate anticoagulation to reduce the risk of stroke is necessary before attempting cardioversion with
ibutilide. When attempting cardioversion with ibutilide, standard guideline recommendation for electrical
cardioversion should be followed. If the duration of atrial fibrillation or flutter is >48 hrs or if its onset is
unknown, a transesophageal echocardiogram should be performed to assess the presence of a left atrial
thrombus. Presence of an intracardiac thrombus is a contraindication for cardioversion.
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Drug interactions 62:
No specific or formal drug interaction studies have been conducted.
Antiarrhythmics: Class Ia antiarrhythmic drugs (Vaughan Williams classification), such as disopyramide,
quinidine and procainamide and other class III drugs, such as amiodarone and sotalol, should not be given
concomitantly with ibutilide or within 4 hrs post-infusion because of their potential to prolong refractoriness.
These antiarrhythmics may be administered 4 hrs after the ibutilide dosing.
Drugs that Prolong the QT Interval: The potential for proarrhythmia may increase with the administration of
ibutilide to patients who are being treated with drugs that prolong the QT interval. These include psychoactive
drugs such as phenothiazines, tricyclic antidepressants, tetracyclic antidepressants, and pimozide; antihistamine
drugs (eg. terfenadine, astemizole); antimicrobials (eg. erythromycin particularly intravenously); antimalarials
(eg. halofantrine); gastrointestinal prokinetic drugs (eg. cisapride).
Digoxin: Supraventricular arrhythmias might mask the cardiotoxicity associated with excessive digoxin levels.
Therefore, it is advisable to be particularly cautious in patients whose plasma digoxin levels are above or
suspected to be above the usual therapeutic range. Concomitant treatment with digoxin did not affect either
serum digoxin levels or the pharmacokinetics of ibutilide in clinical trials.
Calcium Channel Blocking Agents: Concomitant treatment with calcium channel blocking agents did not
affect the pharmacokinetics of ibutilide in clinical trials.
Beta Adrenergic Blocking Agents: Concomitant treatment with beta adrenergic blocking agents did not affect
the pharmacokinetics of ibutilide in clinical trials.
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The arrhythmia duration was ≤5 days in 19 of the 21 patients. In a comparative study with intravenous
flecainide79, procainamide at a dose of 1 g converted 25 (65%) of 40 patients with atrial fibrillation/flutter of
<24 hrs duration. Although these studies indicate that intravenous procainamide is useful in this clinical setting,
particular caution should be used when conversion rates are compared with other drugs such as ibutilide,
because most patients in these trials had arrhythmias of relatively recent onset. Substantial clinical data now
indicate that probably the most important predictor of successful pharmacological conversion of atrial
fibrillation/flutter with any agent is the pretreatment duration of the arrhythmia.Therefore, data regarding
comparative efficacy can only be obtained in randomized clinical trials in which drugs are compared in the
same patient population. More limited data are also available from noncomparable clinical studies for sotalol
and amiodarone. A group of 48 patients having atrial fibrillation/flutter for <7 days were randomized to receive
either placebo or sotalol at a dose of either 1.0 or 1.5 mg/kg IV80. Patients who received placebo initially could
subsequently receive 1.0 or 1.5 mg/kg sotalol in an open-label phase. In total, 5 (19%) of 26 patients receiving
placebo converted to normal sinus rhythm compared with 4 (17%) of 23 and 4 (18%) of 22 patients receiving
sotalol at doses of 1.0 and 1.5 mg/kg, respectively. The success rate of acute conversion with intravenous
amiodarone has been similarly disappointing. In a comparative trial81 with intravenous dofetilide, administration
4627
Comparison with other therapy: Although ibutilide is the only drug approved in the United States for acute
termination of atrial fibrillation and atrial flutter, other therapies have been used for this purpose, including
intravenous administration of procainamide as well as oral loading of multiple different agents such as
quinidine, procainamide, propafenone, and flecainide76. It is difficult to compare the efficacy of ibutilide with
other drugs using previously published studies given the differences in arrhythmia duration, drug
administration, and patient characteristics that exist in the patient populations studied. Several studies have
reported that intravenous procainamide can acutely terminate atrial fibrillation/flutter with moderate efficacy 7779
. One group of investigators77 reported a conversion rate of 58% (15 of 26 patients) after administration of
procainamide 1g IV. Patients who converted had a shorter duration of arrhythmia (6±7 days) than those who did
not convert (79±88 days). In another study 78of 21 patients who received 20 mg/kg procainamide, 43% (9
patients) converted to normal sinus rhythm.
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of amiodarone (5 mg/kg) led to a conversion rate of 4% compared with 4% for placebo and 35% for dofetilide
(8 mg/kg). Finally, a recent study82 reported on the success of oral loading regimens of propafenone (400 to 600
mg), propafenone plus digoxin (0.75 to 1.0 mg in 24 hrs), and quinidine (1100 mg) plus digoxin for atrial
fibrillation/ flutter of <24 hrs duration. Not surprisingly, a high rate of conversion was seen not only with
propafenone plus digoxin (89%) and quinidine plus digoxin (84%) but also with placebo (77%) at 24 hrs. In
studies (which have appeared in abbreviated form) that directly compare the efficacy of ibutilide to other
therapies, the drug was found to be superior to intravenous administration of either sotalol or procainamide in
terminating atrial fibrillation and atrial flutter 62,83,84. In a double-blind study 62, 319 patients with an arrhythmia
duration of 3 to 45 days were randomized to receive either ibutilide (1 or 2 mg) or sotalol (1.5 mg/kg). In
patients with atrial flutter, 53% and 70% of patients who received 1 and 2 mg of ibutilide, respectively,
converted to normal sinus rhythm compared with 18% receiving sotalol.
For patients with atrial fibrillation, the rates of conversion were 22% and 43% for 1 and 2 mg of ibutilide versus
10% for sotalol. Ibutilide has also been compared with intravenous procainamide in a double-blind, placebocontrolled trial of 127 patients with atrial fibrillation/flutter lasting 3 hrs to 90 days 83. Intravenous
administration of ibutilide (2 mg) led to conversion of 76% and 51% of patients with atrial flutter and atrial
fibrillation, respectively, compared with 12% and 20% for patients given intravenous procainamide (1200 mg).
In a nonrandomized comparison with intravenous procainamide in 67 patients, ibutilide (0.005 to 0.025 mg/kg)
converted 42% and 37% of patients with atrial fibrillation and flutter, respectively, versus 9% and 0% for
procainamide (12 to 15 mg/kg)84. The efficacy of ibutilide in that study was attributed to greater prolongation of
monophasic action potential duration relative to slowing of conduction; the resultant increase in refractoriness
would tend to close the excitable gap to facilitate arrhythmia termination57. In contrast, procainamide caused a
greater change in conduction than repolarization, which could account for its lack of success relative to
ibutilide. In a separate study56,both intravenous ibutilide and procainamide enhanced termination of drugrefractory atrial flutter by atrial overdrive pacing.
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The mean time to termination of the arrhythmia from beginning of infusion was 19±15 minutes (range, 3 to 70
minutes), with conversion in nearly 80% of patients within 30 minutes from the start of the infusion. The
duration of the arrhythmia was a predictor of successful conversion to normal sinus rhythm, with success in
42% of patients having atrial flutter/ fibrillation for ≤30 days compared with 16% of those with an arrhythmia
duration >30 days. Both QT and QTc intervals were significantly prolonged from baseline by ibutilide in all
dose groups, although the degree of prolongation did not predict efficacy of arrhythmia termination.
Polymorphic ventricular tachycardia developed in 6 patients (3.6%) receiving ibutilide. It occurred in patients
receiving doses ≥0.010 mg/kg and did not correlate with plasma ibutilide concentration. All 6 patients had
reduced left ventricular function, and 3 had a baseline QTc interval that was >440 ms. On the basis of these
results, a second clinical trial 48 was conducted in which 266 patients with atrial fibrillation or flutter with an
arrhythmia duration of 3 hrs to 45 days were randomized to receive up to two 10 minute infusions of ibutilide
(1.0 and 0.5 mg or 1.0 and 1.0 mg) or placebo. Patients at high risk for proarrhythmia, that is, those with
preexisting QT prolongation (QTc >440 ms), hypokalemia (<4.0 mEq/L), and previous torsade-de-pointes, were
4628
Clinical studies : Two full-length, peer-reviewed articles have been published to support the clinical efficacy of
ibutilide, 47,48 whereas other data have appeared in abstract form or from the pharmaceutical sponsor62. The first
major clinical study was a double-blind, randomized, placebo-controlled, dose-response trial 47 that evaluated
the efficacy and safety of ibutilide in 200 patients with atrial flutter or fibrillation from 3 hrs to 90 days in
duration. Patients were randomized to receive a single intravenous dose of either placebo or ibutilide at 0.005,
0.010, 0.015, or 0.025 mg/kg. The study population consisted of patients who were hemodynamically stable
without uncontrolled heart failure or angina. In the group, 72% of patients had structural heart disease, with a
similar percentage having significant left atrial enlargement. The rates of successful arrhythmia termination
were 3% for placebo and 12%, 33%, 45%, and 46%, respectively, for the doses of ibutilide administered. The
overall success rate of ibutilide-treated patients with atrial flutter (38%) tended to be higher than for those with
atrial fibrillation (29%).
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excluded. As in the previous trial, most patients had a history of heart disease and an enlarged left atrium.
Ibutilide administration resulted in arrhythmia conversion in 47% of patients compared with 2% of patients
receiving placebo. The two ibutilide dosing regimens did not differ with respect to conversion efficacy.
Conversion occurred in a higher percent of patients with atrial flutter than those with atrial fibrillation (63%
versus 31%). The average time for arrhythmia termination was 27 minutes (range, 5 to 88 minutes) after the
start of the first infusion. After adjustment for dose, there was a significant effect of arrhythmia duration on
efficacy in the atrial fibrillation but not the atrial flutter group, with a mean duration of 10±13 days for those
who were successfully converted compared with 18±15 days for those who did not convert. In addition, there
was a significant correlation between left atrial diameter and success in patients with atrial fibrillation but not in
those with atrial flutter. Once again, the change in QT or QTc interval with ibutilide administration did not
predict arrhythmia termination. Polymorphic ventricular tachycardia developed in 8.3% of ibutilide-treated
patients. In 1.7%, this arrhythmia was sustained and required DC cardioversion. The risk of torsade de pointes
was higher in patients with atrial flutter (12.5%) than in those with atrial fibrillation (6.2%). Episodes of late
polymorphic VT occurred in 1 patient at 2 to 2.5 hrs; this patient had a prior episode of nonsustained VT at the
end of initial drug infusion.
Plasma concentrations were not obtained in this patient, and therefore the relationship of late events to ibutilide
concentration could not be determined. Logistic regression analysis indicated that female sex, nonwhite race,
presence of heart failure, and low pulse rate were significant risk factors for the development of proarrhythmia.
Together, these two clinical trials demonstrate that ibutilide administration is superior to placebo in terminating
atrial fibrillation and flutter, with most patients converting within 30 minutes of the start of drug infusion. The
drug is more effective in patients with atrial flutter but with an increased risk of torsade de pointes. Predictors of
successful arrhythmia conversion include the duration of arrhythmia before treatment as well as left atrial size.
For atrial flutter, additional data suggest that development of variation in the flutter cycle length predicts
successful termination85. Initial clinical results from a randomized, double-blind, placebo-controlled trial
indicate that ibutilide is also effective in terminating atrial fibrillation and flutter after cardiac surgery 86.
Although it is not approved for this indication, preliminary results indicate that ibutilide can also prevent
reinduction of sustained ventricular tachycardia in patients with coronary artery disease undergoing
electrophysiological study 87.
Conclusion : Ibutilide is an effective agent for use in the termination of atrial fibrillation and atrial flutter. The
efficacy of ibutilide for rapid conversion of atrial fibrillation and atrial flutter to sinus rhythm is superior to most
of the other antiarrhythmic agents. In the new language of patient rights, close monitoring by a physician is
required during administration of this drug due to the relatively high incidence of torsade-de-pointes. However
alternative strategies are available, the risks and benefits of ibutilide administration should be carefully
considered for each patient to minimize proarrhythmic adverse events. Future work on this drug may be
extended because of ibutilide efficacy, which is comparable or superior to other agents it is not widely used due
to lack of awareness about its safety and efficacy profile.
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