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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 abnormal heart rhythms due to its ability to prolong the QT interval, which can lead to the potentially fatal abnormal heart rhythm known as torsades de pointes. Consequently, the drug is contraindicated in patients that are likely to develop abnormal heart rhythms; this includes persons that have had polymorphic ventricular tachycardia in the past, have a long QT interval, sick sinus syndrome, or a recent myocardial infarction, among 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. PMID 9972384
^ ^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 [show details]
…pharmacology of ibutilide use and the side effects that can occur will be reviewed here. The pharmacokinetics of ibutilide, drug interactions, and the various clinical settings in which ibutilide might be used …
2. 心房細動：洞調律への心臓除細動atrial fibrillation cardioversion to sinus rhythm [show details]
…success rate of cardioversion . Ibutilide, due to its propensity to prolong repolarization and the QT interval, has the potential to provoke torsade de pointes. Ibutilide is available only as an intravenous …
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 [show details]
…compared to those without (3 versus 1 percent). Amiodarone, dronedarone, sotalol, dofetilide, and ibutilide are classified as class III antiarrhythmic agents. There are, however, many dissimilarities among …
4. 心房粗動における洞調律の回復restoration of sinus rhythm in atrial flutter [show details]
…flecainide, dofetilide, propafenone, ibutilide, and amiodarone. Ibutilide and dofetilide have been better studied than the other drugs discussed below. Ibutilide - Ibutilide, approved by the United States …
5. 心房粗動の概要overview of atrial flutter [show details]
…procainamide, disopyramide, flecainide, propafenone, amiodarone, ibutilide, or dofetilide). If pharmacologic reversion is deemed necessary, ibutilide, which is approved by the United States Food and Drug Administration …

English Journal

Vernakalant for cardioversion of recent-onset atrial fibrillation: a systematic review and meta-analysis.

McIntyre WF, Healey JS, Bhatnagar AK, Wang P, Gordon JA, Baranchuk A, Deif B, Whitlock RP, Belley-Côté ÉP.
Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. 2019 Jul;().
To evaluate the efficacy and safety of vernakalant for the cardioversion of atrial fibrillation (AF). We reviewed the literature for randomized trials that compared vernakalant to another drug or placebo in patients with AF of onset ≤7 days. We used a random-effects model to combine quantitative
PMID 31292622

Association of hypokalemia with an increased risk for medically treated arrhythmias.

Phillips CT, Wang J, Celi LA, Zhang Z, Feng M.
PloS one. 2019 ;14(6)e0217432.
Potassium replenishment protocols are often employed across broad patient populations to prevent cardiac arrhythmias. Tailoring potassium thresholds to specific patient populations would reduce unnecessary tasks and cost. The objective of this retrospective cohort study was to determine the threshol
PMID 31206521
PMID 30252277

「イブチリド」

Ibutilide
Clinical data
Trade names	Corvert
AHFS/Drugs.com	Monograph
MedlinePlus	a601248
Pregnancy; category	C;
Routes of; administration	Intravenous
ATC code	C01BD05 (WHO);
Pharmacokinetic data
Bioavailability	N/A
Protein binding	40%
Metabolism	Hepatic oxidation
Biological half-life	6 hours (2-12 hours)
Excretion	Renal (82%), fecal
Identifiers
	IUPAC name N-(4-{4-[ethyl(heptyl)amino]-1-hydroxybutyl}phenyl)methanesulfonamide;
CAS Number	122647-31-8 ;
PubChem CID	60753;
IUPHAR/BPS	7200;
DrugBank	DB00308 ;
ChemSpider	54755 ;
UNII	2436VX1U9B;
KEGG	D00648 ;
ChEMBL	CHEMBL533 ;
ECHA InfoCard	100.213.279
Chemical and physical data
Formula	C20H36N2O3S
Molar mass	384.578 g/mol
3D model (Jmol)	Interactive image;
	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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