Effects of the antiarrhythmic drug dofetilide on myocardial electrical activity: a computer modelling study

Abstract

Dofetilide selectively inhibits the rapid component of the delayed potassium current (I Kr IntroductionThe antiarrhythmic efficacy of drugs that induce prolongation of action potential duration (APD), through the blockade of the delayed rectifier current, I K , has been widely probed in reentrant arrhythmias. In different species, as guinea pig, I K consist on two components: a slowly activating component, I Ks , and a rapidly activating component, I Kr , sensitive to E -4031 or sotalol [1]. Dofetilide is an antiarrhythmic drug that specifically blocks the rapid component of the delayed rectifier potassium current I Kr [2][3][4]. In 1999, the U.S. Food and Drug Administration (FDA) approved dofetilide for the treatment of persistent atrial fibrillation and flutter. Dofetilide is classified as a pure class III antiarrhythmic agent because it produces only prolongation of action potential duration (APD), without any effect on the resting membrane potential, action potential amplitude or maximum rate of depolarization [4]. The effect of dofetilide on APD has been recorded in different myocardial tissues and species [5,6]. In all the myocardial tissues, blockade of I Kr by dofetilide induces a higher prolongation of APD, and hence, of the QT interval, as the concentration of dofetilide increases. Prolongation of APD is related with the increment of refractory period in cardiac tissue.While the efficacy of dofetilide as antiarrhythmic drug is related to the increment in refractoriness, the prolongation of QT may trigger the polymorphic ventricular tachycardia called torsade de pointes [7]. Different studies have found antiarrhythmic action of dofetilide in preventing and in terminating ventricular tachycardias [8] and in the prevention of atrioventriclar re-entrant tachycardia [9]. It has been also suggested that dofetilide may be useful in reducing the frequency of multiple episodes of monomorphic ventricular tachycardia and in increasing the efficacy of antitachycardia pacing in patients with implantable cardioverter-desfibrillator [10].Dofetilide is a potent blocker of I Kr . An IC 50 in the nanomolar range has been experimentally measured in guinea pig ventricular myocytes, namely 8. [3,13,16]. Once the block has been produced, the effect persists during a long period at rest, suggesting that the drug does not dissociate when the channel is closed; the drug seems to be trapped within the channel [3,16]. It has been recently suggested that dofetilide interacts with the channels in both the open and the inactivated states [17]. The interaction between dofetilide and receptor presents a very slow kinetics [11,13] and exhibits reverse use-dependence [2,16]. The increment in the dofetilide dose enhances the reverse-use dependence [2].The main objective of the present work is to develop a mathematical model of the I Kr block by dofetilide and to study the effect of different concentrations on the action potential characteristics.

Dofetilide effect on human atrial action potential under normal and atrial fibrillation conditions. In silico study

“…In 1999 dofetilide (Tikosyn) was approved by Food and Drug Administration (FDA) for the treatment of persistent (nonparoxysmal) AF and flutter [5]. Dofetilide induces the prolongation of action potential duration (APD) in reentrant arrhythmias and hence, causing the prolongation of the QT interval and the increment of refractory period [6]. However, the FDA cautioned: "Because Tikosyn can cause lifethreatening ventricular arrhythmias, it should be reserved for patients in whom AF/flutter is highly symptomatic" [5].…”

Modelización matemática y simulación de los efectos de la lidocaína sobre la actividad eléctrica cardíaca en tejido ventricular.

“…La dispersión en la refractariedad y la lenta velocidad de conducción en la zona isquémica provee un sustrato significativo para el establecimiento de circuitos de reentradas. En la Figura 6.8 se ilustra la iniciación de una reentrada en forma de ocho; ésta fue obtenida a través de un modelo bidimensional en el que se destaca una zona central isquémica [Ferrero et al 2003]. El estímulo prematuro induce un frente de onda, el cual se propaga por la zona saludable además de la zona de borde de la isquemia, pero éste es bloqueado en la zona isquémica donde la refractariedad es extendida.…”

“…Para estudiar el efecto de la combinación de fármacos antiarrítmicos se ha utilizado todas las concentraciones de lidocaína utilizadas por esta tesis doctoral, además se consideró un bloqueo del 70 % de la I Kr, ya que corresponde aproximadamente al valor de bloqueo alcanzado por las concentraciones comúnmente utilizadas tanto teórica como experimentalmente [Saiz et al 2003]. Para el desarrollo de las simulaciones se simuló de manera general la acción de fármacos clase III, los cuales actúan prolongando la duración del potencial de acción.…”