Pleiotropic Effects of Antiarrhythmic Agents: Dronedarone in the Treatment of Atrial Fibrillation

Abstract

Atrial fibrillation remains the most common arrhythmia in clinical practice. Dronedarone is an antiarrhythmic drug for the maintenance of sinus rhythm in patients with atrial fibrillation. Dronedarone is an amiodarone derivative developed to reduce the number of extracardiovascular side effects. Dronedarone has undergone extensive experimental and clinical testing during the last decade. On the aggregate, these studies have highlighted a complex set of pleiotropic actions that may contribute to dronedarone’s antiarrhythmic effects. In this review, we summarize the clinical studies that have evaluated dronedarone and provide an overview of dronedarone’s electrophysiological and nonelectrophysiological pleiotropic actions.

Pharmacokinetic and pharmacodynamic profile of dronedarone, a new antiarrhythmic agent for the treatment of atrial fibrillation

“…As well as amiodarone [6,17,18], dronedarone in vitro has showed electrophysiologic characteristics of all four classes of antiarrhythmic action and a wide range of pleiotropic electrophysiological effects either by directing inhibiting atrial ion channels or indirectly by the inhibition of G-protein-coupled receptors.…”

“…Instead, long-term administration of dronedarone, unlike amiodarone, does not cause marked electrophysiological changes [9]. Compared to N-desethylamiodarone, the highly potent metabolite of amiodarone, which accumulates in cardiac tissue [16], the metabolite N-desbutyldronedarone does not reach electrophysiologically active plasma and cardiac tissue levels and proves to be less potent, so it may be speculated that Ndesethylamiodarone could be, at least in part, responsible for the differences in the chronic electrophysiological effects [6].…”

“…It has electrophysiological properties similar to amiodarone but with fewer side effects; it restores sinus rhythm and reduces hospitalizations or death in intermittent AF. Furthermore, it has various useful pleiotropic effects [6], which will be discussed in this paper.…”

In silico study of the effects of anti-arrhythmic drug treatment on sinoatrial node function for patients with atrial fibrillation

“…The effects of amiodarone were incorporated into the cellular model by modifying ionic currents, involving beta-adrenergic receptor and membrane targets. For the block effects of amiodarone on the beta-adrenergic receptor, we decreased the effects of ISO stimulation by 15.2% 28 . For the effects of amiodarone on membrane targets, we integrated the block effects of amiodarone on funny current (I f ) 29 , sodium currents (I Na ) 30 , and sodium/potassium pump current I NaK .…”

Cytochrome P450 2J2: Potential Role in Drug Metabolism and Cardiotoxicity

“…Both these drugs are multi-ion channel blockers designed to reduce cardiac arrhythmias but paradoxically are potentially also cardiotoxic, resulting in bradycardia, hypotension, congestive heart failure, and ventricular tachycardia (Dixon et al, 2013). Dronedarone has been demonstrated to cause a reduction in a recurrent atrial fibrillation in patients compared with amiodarone (Piccini et al, 2009) but can lead to QT prolongation and subsequently TdP in some instances (Heijman et al, 2013). As both amiodarone and dronedarone are substrates for CYP2J2, the interaction between these drugs and CYP2J2 may modulate cardiac side effects and drug-drug interactions, leading to further toxicity.…”