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Ibutilide is a Class III antiarrhythmic agent that is indicated for acute cardioconversion of atrial fibrillation and atrial flutter of a recent onset to sinus rhythm. It exerts its antiarrhythmic effect by induction of slow inward sodium current, which prolongs action potential and refractory period (physiology) of myocardial cells. Because of its Class III antiarrhythmic activity, there should not be concomitant administration of Class Ia and Class III agents.

Ibutilide is marketed as Corvert by Pfizer. Administration resulted in successful heart rhythm control in 31-44% of patients within 90 minutes, with sustained polymorphic ventricular tachycardia in 0.9-2.5% of patients. It appears to show better results in atrial flutter as compared to atrial fibrillation.^[1]

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^{[citation needed]}, nor does it have a sodium-blocking, antiadrenergic, and calcium blocking activity that other Class III agents possess. Thus it is often referred as a “pure” Class III antiarrhythmic drug.^{[citation needed]}

Ibutilide, like other class III antiarrhythmic drugs, blocks delayed rectified potassium current.^[2]

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.^[3] 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.

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 during the clinical trial.^[3]^[4]

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 of healthy volunteers in a trial. This is also approximately close to patients with atrial fibrillation and flutter.^[4]

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 by isoenzymes other than CYP3A4 and CYP2D6 by which the heptyl side chain of ibutilide is oxidized.^[3]^[4] With eight metabolites are detected in the urine, however, only one is an active metabolite that shares the similar electrophysiologic property of the Class III antiarrhythmic agents.^[3]^[4]^[5] The plasma concentration of this metabolite is only less than 10% of ibutilide.^[4]

Excretion

After administration of ibutilide, it is quickly excreted by renal pathway with a half-life of approximately 6 hours. Approximately 82% of a 0.01 mg/kg dose is excreted in the urine during the trial. Among those, around 7% is excreted as unchanged drug. The reminder of the drug is excreted in feces (about 19%).^[3]

Adverse effects and contraindications

Like other antiarrhythmics, ibutilide can lead to arrhythmia, especially torsades de pointes. Consequently, the drug is contraindicated in patients that are likely to develop arrhythmia; this includes patients that had polymorphic ventricular tachycardia in the past, QT prolongation, sick sinus syndrome, recent myocardial infarction, and others.^[6]

Patient Information

This medication will be given intravenously for your heart disease. You will have continuously ECG monitoring during the infusion and 4 hours after your infusion. Some of the minor side effects are headache and irregular heartbeat. If you experience chest pain and respiratory difficulties, you should report to your doctors immediately.^[7]

References

^ Kowey, PR; Stoenescu, ML (2005). "Selection of drugs in pursuit of a rhythm control strategy". Progress in cardiovascular diseases 48 (2): 139–45. doi:10.1016/j.pcad.2005.06.009. PMID 16253653.
^ Murray, K. T. (10 February 1998). "Ibutilide". Circulation 97 (5): 493–497. doi:10.1161/01.CIR.97.5.493.
^ ^a ^b ^c ^d ^e Howard, P.A., Ibutilide: An antiarrhythmic agent for the treatment of atrial fibrillation or flutter. Annals of Pharmacotherapy, 1999. 33(1): p. 38-47. PMID9972384
^ ^a ^b ^c ^d ^e Pharmacia-Upjohn, Corvert (ibutilide fumarate) injection package insert. July 2002: Kalamazoo, MI.
^ Kelly C. Rogers, P., and Douglas A. Wolfe MD, Ibutilide: A class III rapidly acting antidysrhythmic for atrial fibrillation or atrial flutter. Journal of Emergency Medicine January 2001. Volume 20( Issue 1): p. 67-71.
^ Jasek, W, ed. (2007). Austria-Codex (in German) 1 (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. pp. 1768–71. ISBN 978-3-85200-181-4.
^ Lexi-Comp, Lexi-Drugs Online : Ibutilide.

UpToDate Contents

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1. イブチリドの治療使用 therapeutic use of ibutilide
2. 心房細動：洞調律への心臓除細動 atrial fibrillation cardioversion to sinus rhythm
3. 心房細動患者における洞調律維持のための抗不整脈薬：臨床試験 antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation clinical trials
4. 心房粗動における洞調律の回復 restoration of sinus rhythm in atrial flutter
5. 心房粗動の概要 overview of atrial flutter

English Journal

Investigation of the antifibrillatory drug interactions between Amiodarone and Ibutilide in isolated, perfused Rabbit hearts.

Almotrefi AA1, Bukhari IA1, Alhumayyd MS1.
Fundamental & clinical pharmacology.Fundam Clin Pharmacol.2015 Aug 24. doi: 10.1111/fcp.12141. [Epub ahead of print]
In view of the reliability of the serial-shock method of measuring ventricular fibrillation threshold (VFT) in quantitatively assessing the antifibrillatory potency of many anti-arrhythmic drugs and the alarming reports of the proarrhythmic effects of several anti-arrhythmic agents, it was decided t
PMID 26301534

Contemporary analysis of incidence of post-operative atrial fibrillation, its predictors, and association with clinical outcomes in lung transplantation.

Raghavan D1, Gao A2, Ahn C2, Torres F3, Mohanka M3, Bollineni S3, Peltz M4, Wait M4, Ring S4, Kaza V3.
The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.J Heart Lung Transplant.2015 Apr;34(4):563-70. doi: 10.1016/j.healun.2014.09.032. Epub 2014 Sep 28.
BACKGROUND: Atrial fibrillation (AF) is a common complication after lung transplantation (LT). Since the lung allocation score (LAS) was implemented in 2005, there has been significant evolution in the practice of LT, necessitating re-evaluation of this arrhythmia.METHODS: One hundred thirty-one pat
PMID 25476846

Increasing gap junction coupling suppresses ibutilide-induced torsades de pointes.

Ruan L1, Quan X1, Li L1, Bai R2, Ni M1, Xu R1, Zhang C1.
Experimental and therapeutic medicine.Exp Ther Med.2014 May;7(5):1279-1284. Epub 2014 Mar 4.
Drug-induced torsades de pointes (TdP) is common with class III antiarrhythmic drugs. Increased transmural dispersion of repolarization (TDR) contributes significantly to the development of TdP. Gap junctions play an important role in maintaining TDR in long QT syndrome. The present study examined t
PMID 24940425

Japanese Journal

Effects of Quinidine on the Action Potential Duration Restitution Property in the Right Ventricular Outflow Tract in Patients With Brugada Syndrome

ASHINO Sonoko,WATANABE Ichiro,KOFUNE Masayoshi,NAGASHIMA Koichi,OHKUBO Kimie,OKUMURA Yasuo,MANO Hiroaki,NAKAI Toshiko,KUNIMOTO Satoshi,KASAMAKI Yuji,HIRAYAMA Atsushi
Circulation journal : official journal of the Japanese Circulation Society 75(9), 2080-2086, 2011-08-25
… RVOT monophasic action potentials (MAPs) were recorded before and after intravenous administration of quinidine (n=6) or ibutilide (n=3). … Both quinidine and ibutilide increased steady-state and minimum RVOT MAP duration during programmed stimulation. …
NAID 10029339256

The Efficacy and Characteristics of Intraprocedural Use of Ibutilide during Stepwise Linear Catheter Ablation of Persistent Atrial Fibrillation

Shi Rui,Yang Long,Yao Yan,H. Zheng Li,S. Chen Wen,Huang Wen,R. Bao Jing,Zhang Shu
Journal of Arrhythmia 27(Supplement), BPC_2-BPC_2, 2011
… Ibutilide is commonly used for acute conversion of atrial fibrillation (AF) and flutter. … The purpose of this study was to determine the efficacy and safety of ibutilide for the rapid conversion of persistent AF during the procedure of radiofrequency catheter ablation (RFCA).<BR><B>Methods:</B> … Ibutilide was administered intravenously to 58 consecutive persistent AF patients which failed to restore sinus rhythm (SR) after extensive linear RFCA. …
NAID 130002129557

Molecular Determinants of hERG Channel Block by Terfenadine and Cisapride

Kamiya Kaichiro,Niwa Ryoko,Morishima Mikio [他],HONJO Haruo,SANGUINETTI Michael C.
Journal of pharmacological sciences 108(3), 301-307, 2008-11-20
… Unlike methanesulfonanilides (dofetilide, MK-499, E-4031, ibutilide) or clofilium, mutation of V625, G648, or V659 did not alter the sensitivity of hERG channels to terfenadine or cisapride. …
NAID 10024593080

Related Pictures

★リンクテーブル★

リンク元	「イブチリド」
拡張検索	「ibutilide fumarate」

「イブチリド」

Ibutilide
Systematic (IUPAC) name
	N-(4-{4-[ethyl(heptyl)amino]-1-hydroxybutyl}phenyl)methanesulfonamide
Clinical data
Trade names	Corvert
AHFS/Drugs.com	monograph
MedlinePlus	a601248
Pregnancy; category	C;
Routes of; administration	Intravenous
Pharmacokinetic data
Bioavailability	N/A
Protein binding	40%
Metabolism	Hepatic oxidation
Biological half-life	6 hours (2-12 hours)
Excretion	Renal (82%), fecal
Identifiers
CAS Registry Number	122647-32-9
ATC code	C01BD05
PubChem	CID: 60753
IUPHAR/BPS	7200
DrugBank	DB00308
ChemSpider	54755
UNII	9L5X4M5L6I
KEGG	D00648
ChEMBL	CHEMBL533
Chemical data
Formula	C20H36N2O3S
Molecular mass	384.578 g/mol
	SMILES O=S(=O)(Nc1ccc(cc1)C(O)CCCN(CC)CCCCCCC)C ;
	InChI InChI=1S/C20H36N2O3S/c1-4-6-7-8-9-16-22(5-2)17-10-11-20(23)18-12-14-19(15-13-18)21-26(3,24)25/h12-15,20-21,23H,4-11,16-17H2,1-3H3 ; Key:ALOBUEHUHMBRLE-UHFFFAOYSA-N ;
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