Ibutilide


Article Author:
Michael Szymanski


Article Editor:
Manouchkathe Cassagnol


Editors In Chief:
Stacy Mandras


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Trevor Nezwek
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
7/18/2019 12:55:04 AM

Indications

Ibutilide indications include for 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 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 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 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, 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 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.

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 is commonly used in the treatment of torsades de pointes in hemodynamically stable patients.[7][8][7]

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 is not increased when ibutilide is given 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.

Adverse Effects

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: Use of Ibutilide may be considered in pregnancy; however, data regarding its effects are limited. Breastfeeding is not recommended.[11]

Contraindications

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

Monitoring

Patients require continuous monitoring via ECG for 4 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 4 hours. Equipment for the management of potentially fatal arrhythmias should be rapidly available.

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 team, including physicians, 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, as well as the serious potential with toxicity, the pharmacist should carefully review all orders for ibutilide, as well as perform medication reconciliation. Nursing will be delivering the IV in most cases 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 healthcare team. Ordering physicians need to rely on nursing and pharmacy to ensure optimal therapy results, creating a collaborative interprofessional team environment. [Level V]


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Ibutilide - Questions

Take a quiz of the questions on this article.

Take Quiz
A 58-year-old male patient presents with a chief complaint of heart palpitations. An immediate ECG reveals atrial flutter. The patient is alert and oriented. Blood pressure is 110/70 mmHg, heart rate 160 beats/min, respiratory rate 20, and oxygen saturation 96% on room air. What is the best pharmacologic option to convert atrial flutter to normal sinus rhythm?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which of the following is effective in converting atrial fibrillation (AF) into normal sinus rhythm (NSR)?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 72-year-old female presents to the emergency department with a chief complaint of heart palpitations. ECG reveals atrial fibrillation. Vital signs include blood pressure of 102/68 mmHg, heart rate of 142 bpm, a respiratory rate of 26/minute, and pulse oximetry of 97% on room air. The patient's past medical history is remarkable for a urinary tract infection currently being treated with ciprofloxacin. The attending physician decides to administer 1mg of ibutilide over a 10 minute period. What adverse effect is most likely to occur in this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 44-year-old female presents to the emergency department with a chief complaint of heart palpitations. ECG reveals an irregularly irregular rhythm with the absence of discernable P waves. The patient's past medical history is remarkable for a urinary tract infection currently being treated with ciprofloxacin. The provider decides to administer 1 mg of ibutilide over a 10 minute period. Which phase of the myocyte action potential is being augmented by ibutilide?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Ibutilide is an antiarrhythmic used for the treatment of hemodynamically stable atrial fibrillation/flutter that primarily blocks which of the following?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 65-year-old male presents to the emergency department with a chief complaint of weakness following mowing the yard. The patient appears alert and oriented, well nourished, well dressed, and slightly agitated. Vitals include a blood pressure of 106/58 mmHg, heart rate of 180 bpm, respiratory rate of 24/minutes, and oxygen saturation of 94% on room air. An ECG performed shows 2:1 atrial flutter. Past medical history is remarkable for a myocardial infarct three years ago. The patient is currently taking simvastatin, clopidogrel, and metoprolol. The provider administers ibutilide, 1 mg over 10 minutes, without a change in rhythm and decides to switch antiarrhythmics. Which antiarrhythmic is contraindicated in this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 28-year-old female presents to her primary care physician complaining of a "fluttering" feeling in her chest. Upon evaluation, the physician determines that the patient needs to be transferred to the emergency department for care. Several weeks later, the patient gets evaluated by a cardiologist who determines she has a rare genetic mutation affecting the protein structure of delayed rectifying potassium channels (IKr) in cardiac myocytes. Which of the following antiarrhythmics should be avoided in this patient due to a potential lack of efficacy?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Ibutilide - References

References

Murray KT, Ibutilide. Circulation. 1998 Feb 10     [PubMed]
Lee KS, Ibutilide, a new compound with potent class III antiarrhythmic activity, activates a slow inward Na current in guinea pig ventricular cells. The Journal of pharmacology and experimental therapeutics. 1992 Jul     [PubMed]
Yang T,Snyders DJ,Roden DM, Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K current (IKr) in AT-1 cells. Concentration-, time-, voltage-, and use-dependent effects. Circulation. 1995 Mar 15     [PubMed]
Glatter K,Yang Y,Chatterjee K,Modin G,Cheng J,Kayser S,Scheinman MM, Chemical cardioversion of atrial fibrillation or flutter with ibutilide in patients receiving amiodarone therapy. Circulation. 2001 Jan 16     [PubMed]
Hongo RH,Themistoclakis S,Raviele A,Bonso A,Rossillo A,Glatter KA,Yang Y,Scheinman MM, Use of ibutilide in cardioversion of patients with atrial fibrillation or atrial flutter treated with class IC agents. Journal of the American College of Cardiology. 2004 Aug 18     [PubMed]
Caron MF,Kluger J,Tsikouris JP,Ritvo A,Kalus JS,White CM, Effects of intravenous magnesium sulfate on the QT interval in patients receiving ibutilide. Pharmacotherapy. 2003 Mar     [PubMed]
Oral H,Souza JJ,Michaud GF,Knight BP,Goyal R,Strickberger SA,Morady F, Facilitating transthoracic cardioversion of atrial fibrillation with ibutilide pretreatment. The New England journal of medicine. 1999 Jun 17     [PubMed]
VanderLugt JT,Mattioni T,Denker S,Torchiana D,Ahern T,Wakefield LK,Perry KT,Kowey PR, Efficacy and safety of ibutilide fumarate for the conversion of atrial arrhythmias after cardiac surgery. Circulation. 1999 Jul 27     [PubMed]
Patsilinakos S,Christou A,Kafkas N,Nikolaou N,Antonatos D,Katsanos S,Spanodimos S,Babalis D, Effect of high doses of magnesium on converting ibutilide to a safe and more effective agent. The American journal of cardiology. 2010 Sep 1     [PubMed]
Regitz-Zagrosek V,Blomstrom Lundqvist C,Borghi C,Cifkova R,Ferreira R,Foidart JM,Gibbs JS,Gohlke-Baerwolf C,Gorenek B,Iung B,Kirby M,Maas AH,Morais J,Nihoyannopoulos P,Pieper PG,Presbitero P,Roos-Hesselink JW,Schaufelberger M,Seeland U,Torracca L, ESC Guidelines on the management of cardiovascular diseases during pregnancy: the Task Force on the Management of Cardiovascular Diseases during Pregnancy of the European Society of Cardiology (ESC). European heart journal. 2011 Dec     [PubMed]
Whayne TF Jr, Clinical Use of Digitalis: A State of the Art Review. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2018 Jul 31     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Cardiology-Failure/Transplant. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Cardiology-Failure/Transplant, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Cardiology-Failure/Transplant, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Cardiology-Failure/Transplant. When it is time for the Cardiology-Failure/Transplant board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Cardiology-Failure/Transplant.