Ibutilide

Ibutilide is an antiarrhythmic Class III agent belonging to a potassium channel blocker.

Ibutilide is used in the treatment for converting acute atrial flutter and atrial fibrillation to normal sinus rhythm (NSR). It is also used in pretreatment for electro cardioversion.

It is widely distributed in the body (after IV infusion) with plasma protein-binding with approx 40%. It is extensively metabolised in the liver via oxidation into several metabolites. It is mainly excreted via urine (approx 82%, approx 7% as unchanged drug); faeces (approx 19%) with approx 6 hours (range: 2-12 hours).

The common side effects are Nonsustained monomorphic ventricular tachycardia, Premature ventricular contractions, Nonsustained polymorphic ventricular tachycardia, Atrioventricular block, Bundle branch block, Hypotension, Torsades de pointes, etc.

Ibutilide is available in the form of dosage forms like an intravenous injection.

Ibutilide is available in the USA, UK, Canada, Australia, and India.

Ibutilide is a methanesulfonanilide derivative class III antiarrhythmic agent. It prolongs the myocardial action potential duration and enhances the atrial and ventricular refractoriness predominantly by activating slow inward Na current (Ina-s).

The onset of Action of Ibutilide was 90 minutes.

The Duration of Action of Ibutilide was 2 to 12 hours

The Tmax was about 6 hr. and Cmax was about 2.40 to 3.43 ng/ml.

Ibutilide is available in the form of a dosage form such as injection.

Ibutilide is used in the treatment for converting acute atrial flutter and atrial fibrillation to normal sinus rhythm (NSR). It is also used in pretreatment for electro cardioversion.

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.

Ibutilide is used in the treatment for converting acute atrial flutter and atrial fibrillation to normal sinus rhythm (NSR). It is also used in pretreatment for electro cardioversion.

Atrial fibrillation/flutter:

Rapid conversion of atrial fibrillation or atrial flutter of recent onset to sinus rhythm (effectiveness has not been determined in patients with arrhythmias >90 days in duration).

Although not approved, there have been certain off-label use documented for Ibutilide, which includes:-

Pretreatment for electro cardioversion.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Ibutilide is available in various dosage strengths : 0.1mg/ml.

Ibutilide is available in the form of a dosage form such as an intravenous injection.

Ibutilide is used in the treatment for converting acute atrial flutter and atrial fibrillation to normal sinus rhythm (NSR). It is also used in pretreatment for electro cardioversion.

Atrial Fibrillation: Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk.

Drinking too much alcohol can increase the risk of developing AFib.It may also trigger AFib episodes in people who already have AFib, especially if patients have existing cardiovascular disease or diabetes.

The dietary restriction should be individualized as per the patient's requirements.

Ibutilide may be contraindicated in the following

Concomitant use with class Ia (e.g. disopyramide, quinidine, procainamide) and other class III (e.g. amiodarone, sotalol) antiarrhythmic drugs or within 4 hours postinfusion of ibutilide.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

Concerns related to adverse effects:

Proarrhythmic effects: [US Boxed Warning]: Potentially fatal arrhythmias, particularly sustained polymorphic ventricular tachycardia can occur, usually in association with torsades des pointes (QT prolongation), but sometimes without documented QT prolongation. Studies indicate a 1.7% incidence of arrhythmias in treated patients. These arrhythmias can be reversed if treated promptly. It is essential that ibutilide be administered in a setting of continuous ECG monitoring and by personnel trained in identification and treatment of acute ventricular arrhythmias. Patients with atrial fibrillation of more than 2 to 3 days' duration must be adequately anticoagulated, generally for at least 2 weeks. The use of intravenous magnesium (2 g) immediately prior to and after ibutilide administration has been shown to be helpful in reducing QT interval prolongation due to ibutilide and may enhance the efficacy of ibutilide. Whether or not prophylactic magnesium reduces the incidence of TdP has yet to be determined; however, it is thought that this measure will reduce the incidence of TdP. Consider avoiding use in patients with QTc intervals >440 msec. Use is not recommended in patients who have previously demonstrated polymorphic ventricular tachycardia (eg, torsades de pointes).

Disease-related concerns:

• Chronic atrial fibrillation: [US Boxed Warning]: Patients with chronic atrial fibrillation may not be the best candidates for ibutilide since they often revert after conversion and the risks of treatment may not be justified when compared to alternative management. Patients to be treated with ibutilide should be carefully selected such that the expected benefits outweigh the immediate risks.

• Electrolyte imbalance: Correct electrolyte disturbances, especially hypokalemia or hypomagnesemia, prior to use and throughout therapy.

Other warnings/precautions:

• CAST trial:

In the Cardiac Arrhythmia Suppression Trial (CAST), recent (>6 days but <2 years ago) myocardial infarction patients with asymptomatic, non-life-threatening ventricular arrhythmias did not benefit and may have been harmed by attempts to suppress the arrhythmia with flecainide or encainide. An increased mortality or nonfatal cardiac arrest rate (7.7%) was seen in the active treatment group compared with patients in the placebo group (3%). The applicability of the CAST results to other populations is unknown. Antiarrhythmic agents should be reserved for patients with life-threatening ventricular arrhythmias.

Alcohol consumption with Ibutilide may increase the risk of low blood pressure and cause adverse effects, such as Dizziness, fainting, light-headedness, or Headache.

Ibutilide use in breastfeeding patients is not recommended.

Pregnancy Category C

Ibutilide administered orally was teratogenic (abnormalities included adactyly, interventricular septal defects, and scoliosis) and embryocidal in reproduction studies in rats. On a mg basis, corrected for the 3% oral bioavailability, the “no adverse effect dose” (5 mg/kg/day given orally) was approximately the same as the maximum recommended human dose (MRHD); the teratogenic dose (20 mg/kg/day given orally) was about four times the MRHD on a mg basis, or 16 times the MRHD on a mg/kg basis. Ibutilide should not be administered to a pregnant woman unless clinical benefit outweighs potential risk to the fetus.

Do not consume grapefruit or grapefruit juice during treatment with Ibutilide unless directed otherwise by your doctor. Grapefruit juice can increase the blood levels of Ibutilide to dangerous levels.

The adverse reactions related to molecule Ibutilide can be categorized as

• Common Adverse effects:

Reversible or complete heart block; non-sustained ventricular tachycardia (monomorphic or polymorphic).

Less Common adverse effects:

Supraventricular tachycardia, atrioventricular block, ventricular extrasystoles, bundle branch block, tachycardia, palpitations.

Rare adverse effects:

Hypotension, orthostatic hypotension, Erectile dysfunction. Respiratory, thoracic and mediastinal disorders: Dyspnoea.

The clinically relevant drug interactions of Ibutilide is briefly summarized here.

Digoxin

Supraventricular arrhythmias may mask the cardiotoxicity associated with excessive digoxin levels. Therefore, it is advisable to be particularly cautious in patients whose plasma digoxin levels are above or suspected to be above the usual therapeutic range. Coadministration of digoxin did not have effects on either the safety or efficacy of ibutilide in the clinical trials.

Calcium Channel Blocking Agents

Coadministration of calcium channel blockers did not have any effect on either the safety or efficacy of ibutilide in the clinical trials.

Beta-Adrenergic Blocking Agents

Coadministration of beta-adrenergic blocking agents did not have any effect on either the safety or efficacy of ibutilide in the clinical trials.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No dose adjustment is required..

Acute Experience In Animals

Acute overdose in animals results in CNS toxicity; notably, CNS depression, rapid gasping breathing, and convulsions. The intravenous median lethal dose in the rat was more than 50 mg/kg which is, on a mg/m² basis, at least 250 times the maximum recommended human dose.

Human Experience

In the registration trials with Ibutilide Injection, four patients were unintentionally overdosed. The largest dose was 3.4 mg administered over 15 minutes. One patient (0.025 mg/kg) developed increased ventricular ectopy and monomorphic ventricular tachycardia, another patient (0.032 mg/kg) developed AV block—3rd degree and nonsustained polymorphic VT, and two patients (0.038 and 0.020 mg/kg) had no medical event reports. Based on known pharmacology, the clinical effects of an overdosage with ibutilide could exaggerate the expected prolongation of repolarization seen at usual clinical doses. Medical events (eg, proarrhythmia, AV block) that occur after the overdosage should be treated with measures appropriate for that condition.

Pharmacodynamics:

Ibutilide prolongs the action potential duration and increases both atrial and ventricular refractoriness in vivo, i.e., class III electrophysiologic effects. Voltage clamp studies indicate that ibutilide, at nanomolar concentrations, delays repolarization by activation of a slow, inward current (predominantly sodium), rather than by blocking outward potassium currents, which is the mechanism by which most other class III antiarrhythmics act.

Pharmacokinetics:

Distribution:

Widely distributed in the body (after IV infusion). Plasma protein-binding: Approx 40%.

Metabolism:

Extensively metabolised in the liver via oxidation into several metabolites.

Excretion:

Mainly via urine (approx 82%, approx 7% as unchanged drug); faeces (approx 19%). Elimination half-life: Approx 6 hours (range: 2-12 hours).

1. https://www.ncbi.nlm.nih.gov/books/NBK526021/
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1728725/
3. https://reference.medscape.com/drug/Ibutilide -ibutilide-342301#3
4. https://www.drugs.com/dosage/ibutilide.html
5. https://go.drugbank.com/drugs/DB00308