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(Circulation. 2000;102:2665.)
© 2000 American Heart Association, Inc.

Cardiovascular Drugs

Dofetilide

J. Paul Mounsey, BM BCh, PhD; John P. DiMarco, MD, PhD

From the Electrophysiology Laboratory, Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville, Va.

Correspondence to Dr J.P. DiMarco, Cardiovascular Division, Department of Medicine, PO Box 800158, University of Virginia Health System, Charlottesville, VA 22908-0158. E-mail jdimarco@virginia.edu

Key Words: Cardiovascular Drugs • dofetilide • arrhythmia • antiarrhythmia agents • fibrillation • cardioversion

	Introduction

 
Dofetilide is a new antiarrhythmic drug that recently was recommended for approval by an advisory committee to the Food and Drug Administration (FDA) for treatment of patients with persistent atrial fibrillation. Dofetilide is a specific blocker of the rapid component of the outward delayed rectifier potassium current I_Kr and will represent the first drug with relatively pure class III antiarrhythmic properties to be widely released.

	Basic Electrophysiology

 
Cardiac depolarization results principally from the flow of inward Na⁺ and Ca²⁺ ions as the rapid and slow inward currents. Repolarization results from a balance between inactivation of the slow inward current and activation of repolarizing predominantly K⁺ currents. Early repolarization results from a transient outward current, I_TO, which is activated rapidly by membrane depolarization. Terminal repolarization is mediated by outward delayed rectifier K⁺ currents, I_K, which are activated slowly (over a period of 200 to 300 ms) on membrane depolarization and turn off, or deactivate, relatively slowly on membrane repolarization.

I_K can be separated pharmacologically into 2 components: a rapidly activating component, I_Kr, and a slower component, I_Ks, each carried by a separate ion channel molecule.^{1 2} HERG channels are responsible for I_Kr, whereas I_Ks flows through KvLQT1 channels. Specific blockers of I_Kr are therefore classified as pure class III antiarrhythmic agents because they produce only prolongation of action potential duration (and hence of QT interval). These actions may result in arrhythmia termination or suppression but can also lead to excess QT prolongation and polymorphic ventricular tachycardia. Examples of specific . . . [Full Text of this Article]

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