Continuing Education Activity

Ibutilide is indicated for converting acute atrial flutter and atrial fibrillation to normal sinus rhythm (NSR). Off-label uses of ibutilide include as a pretreatment for electro cardioversion. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of ibutilide, pertinent for interprofessional team members in treating patients with cardiac disorders that will respond to such therapy.

Objectives:

• Describe the mechanism of action of ibutilide.
• Summarize the indications for using ibutilide.
• Review the potential adverse effects profile for ibutilide.
• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with ibutilide.

Indications

Ibutilide is a class III antiarrhythmic drug. FDA-approved 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]

Mechanism of Action

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 that continues 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, 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 been shown to activate a slow, delayed, inward sodium current during the early stages of repolarization. However, the 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.

The 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)

Administration

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; the dose may be repeated after 10 minutes if there is no response.
• For patients weighing more than 60 kg, the dose is 1 mg over 10 minutes; the dose may be repeated after 10 minutes if there is no response. 

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. The drug's half-life is around 6 hours, ranging between 2 and 12 hours.

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

Geriatrics: Start at the lower end of the dosing range.

Pediatrics: There are no approved indications for this drug in pediatric use; safety and efficacy are not established.

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][9][8]

Class 1C Antiarrhythmics: Ibutilide can be given safely with Class 1C antiarrhythmics since class 1C antiarrhythmics do not affect the QT interval.[10]

Amiodarone: The risk of arrhythmia does not increase when clinicians give patients ibutilide with amiodarone.[11]

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 as inactive metabolites.

Adverse Effects

According to the Institute for Safe Medication Practices (ISMP), this drug has a heightened risk of causing significant patient harm. It can cause potentially fatal arrhythmias, so clinicians must always weigh the benefits vs. ris=ks when considering using this agent.

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.[12]

Contraindications

Ibutilide is contraindicated in the following:

• Hypersensitivity to ibutilide or any compound in the formulation
• Congenital long QT syndrome
• A patient history of polymorphic ventricular tachycardia
• Uncorrected electrolyte abnormalities
• Sinus node disease
• Structural cardiac disease

Caution is advised in the following situations:

• QT prolongation
• A family history of QT prolongation
• Recent myocardial infarct
• Bradycardia
• Congestive heart failure (CHF)
• Age 65 and older
• Hepatic impairment; while no dining recommendations exist, the drug is metabolized by CYP450 enzymes, so caution is advised in such patients.

Significant drug interactions that contraindicate concurrent use with ibutilide include the following agents:

• Cisapride
• Dronedarone
• Levoketoconazole
• Ziprasidone
• Thioridazine
• Pimozide
• Fingolimod

Many other drugs have potential interactions with ibutilide; a thorough medication reconciliation involving the ordering clinician and a clinical pharmacist is recommended before dosing ibutilide.

Monitoring

Patients require continuous monitoring via ECG for four hours post discontinuation of ibutilide infusion or until the QTc returns to normal (less than 440 msec). If arrhythmia presents, continue monitoring patients for more than four hours and longer if the patient has impaired hepatic function. Equipment for the management of potentially fatal arrhythmias should be rapidly available. Electrolytes, particularly magnesium, should be established at baseline.

Toxicity

There is no antidote to ibutilide. In animal models, acute overdose has caused CNS toxicity, including CNS depression, rapid gasping, and convulsions.[13]

Enhancing Healthcare Team Outcomes

According to the Institute for Safe Medication Practices, this medication has a high risk of causing significant patient harm. The entire interprofessional team, including physicians and specialists (MDs, DOs), physician assistants, nurse practitioners, pharmacists, and nurses, must work together to monitor these patients for potential untoward cardiac and extracardiac events. Given the serious nature of both the conditions for which ibutilide is given and the serious potential for dangerous arrhythmias, the pharmacist should carefully review all orders for ibutilide and perform medication reconciliation to rule out potential drug-drug interactions. In most cases, nursing will deliver the IV and can verify the administration duration and dose and monitor closely for any adverse effects. Should there be any concerns, nursing must report these immediately to the interprofessional healthcare team for further clinical evaluation and intervention. Ordering clinicians need to rely on nursing and pharmacy to ensure optimal therapy results, creating a collaborative interprofessional team environment. [Level 5]