Clinical uses of dronedarone
- Rod Passman, MD, MSCE
Rod Passman, MD, MSCE
- Professor of Medicine
- Northwestern University Feinberg School of Medicine
- Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA
Elsa-Grace Giardina, MD, MS, FACC, FACP, FAHA
- Professor of Medicine
- Director, Center for Women’s Health
- Columbia University Medical Center
Dronedarone, a noniodinated congener of amiodarone, was developed as an antiarrhythmic agent for the maintenance of sinus rhythm in patients with atrial fibrillation. Because of the molecular and structural differences between dronedarone and amiodarone, in particular the deletion of the iodine molecules which are present in amiodarone, researchers have hypothesized that dronedarone will have fewer thyroid and pulmonary effects than amiodarone. Clinical trials have shown the clinical use and short-term safety (up to 21 months) of dronedarone for the maintenance of sinus rhythm following cardioversion in patients with atrial fibrillation . The efficacy and tolerability of dronedarone in children and adolescents aged <18 years have not been established.
A review of the pharmacology of dronedarone, its clinical uses, adverse effects, and drug interactions will be presented here. The clinical uses and toxicities of amiodarone and the choice of antiarrhythmic agents in the management of atrial fibrillation are discussed separately. (See "Clinical uses of amiodarone" and "Monitoring and management of amiodarone side effects" and "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations".)
MECHANISMS OF ACTION AND PHARMOCOKINETICS
Dronedarone is a class III antiarrhythmic agent and a potent blocker of multiple intracardiac ion channels with many electrophysiological properties in common with amiodarone (table 1) . Like amiodarone, dronedarone has antiadrenergic (ie, beta blocking) properties and inhibits multiple transmembrane potassium currents, including the delayed rectifier current, the ultra-rapid delayed rectifier current, the inward rectifier current, and the transient outward current. In addition, dronedarone blocks inward depolarizing sodium and L-type calcium currents.
Limited pharmacokinetic data are available for dronedarone and are derived primarily from data in the United States Food and Drug Administration (FDA) prescribing information and from data in the FDA briefing document . Dronedarone is approximately 70 to 94 percent absorbed after oral administration, but its absolute bioavailability is only approximately 15 percent due to significant first pass metabolism. Peak plasma concentrations are achieved within three to six hours. However, there is a significant food effect which increases plasma dronedarone concentrations between two- and threefold when the drug is taken with food . Following the initiation of dronedarone 400 mg twice daily, steady-state plasma concentrations are reached within four to eight days .
The clearance of dronedarone is principally nonrenal, with a terminal half-life of approximately 24 hours . This is markedly shorter than the half life of amiodarone, which has an effective half-life of up to 50 days. Dronedarone is highly bound to plasma proteins and is not associated with significant tissue accumulation. Therefore, it has been postulated that systemic side effects secondary to long-term usage of the drug, such as liver toxicity, pulmonary fibrosis, or thyroid dysfunction will be minimized in comparison to amiodarone. However, long-term toxicity data are not yet available.
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- MECHANISMS OF ACTION AND PHARMOCOKINETICS
- METABOLISM AND DRUG INTERACTIONS
- CLINICAL USES
- Maintenance of sinus rhythm
- - Recommendations of major societies
- Chemical cardioversion of AF
- Ventricular rate control in AF
- Changing to another antiarrhythmic drug
- Effect on cardiovascular mortality
- - Heart failure
- Ventricular arrhythmia/ICDs
- ADVERSE EFFECTS
- Heart failure
- ECG effects and arrhythmias
- Liver toxicity
- Lung toxicity
- Systemic adverse effects
- SUMMARY AND RECOMMENDATIONS