Ibutilide indications include the conversion of acute atrial flutter and atrial fibrillation to normal sinus rhythm (NSR).[1]

Off-Label Uses

Ibutilide has utility as a pretreatment for electro cardioversion. Pretreatment with ibutilide, sotalol, or dofetilide may help conversion to NSR in cases of refractory atrial fibrillation. Ibutilide may also be given post cardioversion to prevent recurrent atrial fibrillation.[2]

Ibutilide administration may be necessary following surgery.[3]

Ibutilide is a potassium channel blocker that prolongs phase 3 of the cardiac action potential, resulting in increased refractoriness of atrial and ventricular myocytes, the atrioventricular node, and the His-Purkinje system.[1]

The cardiac action potential divides into the following five stages:

Phase 0: Rapid Depolarization

During phase 0, fast sodium channels open when the cell reaches the threshold, which results in a rapid depolarization of the myocyte continuing until inactivation gates close, thus abolishing sodium conductance. A time-dependent mechanism mediates the closure of inactivation gates. Reopening of inactivation gates occurs during cell repolarization, specifically upon re-approaching the threshold.

Phase 1: Early repolarization

Potassium channels open, causing an efflux of potassium called the transient outward current (ito). The end of phase 1 is characterized by a balance between calcium influx and potassium efflux, thus leading to the plateau phase.

Phase 2: Plateau

The plateau phase consists of a balance between calcium influx and potassium efflux. The calcium channels are L-type dihydropyridine-receptor channels that inactivate slowly. Drugs that alter the conductance of calcium modulate this phase and belong to Class 4 of the Vaughn-Williams classification system.

During the latter stages of the plateau phase, delayed rectifying potassium channels (iKr) open and allow the myocyte to begin repolarization as the calcium current declines.

Phase 3: Repolarization

In phase 3 of the cardiac action potential, potassium efflux exceeds inward calcium current causing repolarization. When positively charged potassium ions move out of the cell, it restores the negative potential of the cardiac myocyte. Three potassium channels are involved in the repolarization phase. While the cell membrane remains depolarized, iKr and ito are the major contributors to potassium efflux. As the myocyte approaches the threshold, the inwardly rectifying current (iK1) channels open and contribute to repolarization. Although iK1 channels are termed “inwardly rectifying,” potassium efflux occurs due to the electrochemical potential of potassium derived from the cord conductance equation.

Ibutilide is a potassium-blocking agent that primarily exerts its effect on the delayed rectifying potassium channels (iKr). By blocking potassium channels, phase 3 is lengthened, prolonging the QTc interval and increasing the refractoriness of the atrial and ventricular myocytes. When a myocyte is in the absolute refractory period, a subsequent action potential cannot be propagated, thus causing a decrease in the heart rate of patients presenting with tachydysrhythmias.[4]

Ibutilide has also shown to activate a slow, delayed, inward sodium current during the early stages of repolarization. However, blockade of iKr channels is the major contributor to its antiarrhythmic properties.[5]

Phase 4: Resting

Na+/K+ ATPase dominates, phase 4. For every three Na+ ions pumped out of the cell, two K+ ions are pumped in, resulting in a negative resting membrane potential. 

A primary active transporter called the calcium ATPase re-sequesters the majority of the intracellular calcium into the sarcoplasmic reticulum. The sarcoplasmic calcium ATPase regulation occurs by an intracellular protein called phospholamban. When phospholamban undergoes phosphorylation via protein kinase A (PKA), the calcium ATPase is active and incorporates cytosolic calcium ions into the sarcoplasmic reticulum. During the next action potential, more calcium is released into the cytosol, thus causing increased contractility. When phospholamban is de-phosphorylated, it inhibits the sarcoplasmic calcium ATPase.

Remaining calcium ions get pumped out of the myocytes by secondary active transport through the Na+/Ca++ exchanger. 

It is important to note that the cardiac myocyte Na+/K+ ATPase is inhibited pharmacologically by the cardiac glycosides (digoxin). Inhibition of the Na+/K+ ATPase causes an increase in intracellular Na+ ions and leads to a series of biochemical changes, beginning with the reverse action of membrane-bound Na+/Ca++ exchangers. The change in polarity of Na+/Ca++ exchangers causes an efflux of Na+ and an influx of Ca++ to restore the resting membrane potential in the absence of Na+/K+ ATPase activity. The increased concentration of intracellular calcium is responsible for the positive inotropic properties of digoxin therapy.[6]

Notable ECG Changes

• Slowing of heart rate
• Prolongation of QT interval (risk of developing torsades de pointes)

Ibutilide is available as a solution administered intravenously (1 mg/10 mL)

For patients weighing less than 60 kg, the dose is 0.01 mg/kg over 10 minutes.

For patients weighing more than 60 kg, the dose is 1 mg over 10 minutes. 

Drug administration may be diluted or undiluted. Discontinue infusion upon resolution of presenting arrhythmia or new-onset ventricular tachycardia. If the arrhythmia does not abate within 10 minutes post-infusion, another dose may be given over 10 minutes.

Renal or Hepatic Impairment: Dosing for renal or hepatic impairment does not need to be adjusted.

Geriatrics: Start at the lower end of the dosing range

Addition of Magnesium Sulfate: Magnesium has been shown to enhance the ability of ibutilide to convert atrial flutter or fibrillation to normal sinus rhythm. Magnesium can also help prevent prolongation of the QT interval, and it sees frequent use in the treatment of torsades de pointes in hemodynamically stable patients.[7][8]

Class 1C Antiarrhythmics: Ibutilide can be given safely with Class 1C antiarrhythmics since class 1C antiarrhythmics do not affect the QT interval.[9]

Amiodarone: The risk of arrhythmia does not increase when giving ibutilide with amiodarone.[10]

Pharmacokinetics:  Conversion to sinus rhythm occurs in less than 90 minutes after the start of infusion. Ibutilide has a half-life of 2 to 12 hours, with an average half-life of 6 hours. It is metabolized extensively by the liver into eight metabolites (1 active). The volume of distribution is approximately 11 L/kg. The majority of the drug is excreted via the urine in the form of inactive metabolites.

According to the Institute for Safe Medication Practices (ISMP), this drug has a heightened risk of causing significant patient harm.

Cardiac Adverse Effects

• Nonsustained monomorphic ventricular tachycardia
• Premature ventricular contractions
• Nonsustained polymorphic ventricular tachycardia
• Atrioventricular Block
• Bundle branch block
• Hypotension
• Torsades de pointes
• Prolonged QT interval
• Hypertension
• Palpitations
• Bradycardia 

Extracardiac Adverse Effects

• Nausea
• Headache
• Renal failure
• Erythematous rash

Drug Interactions

Category X (avoid)

• Amifampridine
• Fingolimod
• Hydroxychloroquine
• Macimorelin
• Mifepristone
• Mizolastine
• Probucol
• Promazine
• Vinflunine

Category D (modify regimen)

• Indapamide

Category C (monitor)

• Bilastine
• Fluoxetine
• Pefloxacin
• Teneligliptin
• Xipamide

Pregnancy Implications: Clinicians may consider the use of ibutilide in pregnancy; however, data regarding its effects are limited. Breastfeeding is not recommended.[11]

• Hypersensitivity to ibutilide
• Prolonged QT interval (before ibutilide infusion)
• Sinus node disease
• Structural cardiac disease