Review Question - QID 216563

This patient with palpitations, fatigue, a history of hypertension and obstructive sleep apnea (OSA), tachycardia, and an ECG with absent P waves and irregularly irregular tachycardia likely has atrial fibrillation (AF) with rapid ventricular response. Pharmacological cardioversion may be performed for AF with dofetilide, a class III antiarrhythmic that blocks potassium channels responsible for phase 3 repolarization in the ventricular action potential (label 4 in Figure A).

Potassium channels in cardiac action potentials facilitate the movement of positively charged potassium from the intracellular to the extracellular space. More specifically, in phase 3 of the ventricular action potential, slow-response potassium channels facilitate repolarization of the membrane potential. Class III antiarrhythmics such as dofetilide block slow-response potassium channels, thus increasing action potential duration. By delaying repolarization, the same cell cannot be activated again which increases the effective refractory period. This is useful for suppressing tachyarrhythmias, as diseased heart tissues cannot as effectively transmit aberrant early action potentials to the surrounding refractory normal cardiac tissue. Dofetilide specifically can be used for pharmacological cardioversion of atrial fibrillation and atrial flutter in patients without underlying structural heart disease or long-QT syndrome; however, rate controlled is preferred over rhythm control with dofetilide.

Figure/Illustration A shows the action potential of a ventricular cardiac myocyte. The influx and efflux of different ions including potassium, sodium, and calcium are also shown, as well as the effective refractory period (ERP). Label 1 corresponds with phase 0, label 2 corresponds with phase 1, label 3 corresponds with phase 2, label 4 corresponds with phase 3, and label 5 corresponds with phase 4 of the cardiac action potential.

Mounsey et al. review the mechanism of action, pharmacokinetics, and adverse effects of dofetilide. This article also reviews some older studies for indications for dofetilide.

Incorrect Answers:
Answer 1: Label 1 shows phase 0 of the cardiac action potential, which corresponds to rapid sodium influx and depolarization. Class Ic antiarrhythmics such as flecainide exhibit strong sodium channel blockade and prolong phase 0.

Answer 2: Label 2 shows phase 1 of the cardiac action potential, initial repolarization that is caused by the opening of a transient, fast-response K+ channel. Dofetilide and other class III antiarrhythmics only affect slow-response K+ channels and would not be expected to significantly affect the duration of this phase.

Answer 3: Label 3 shows phase 2 of the cardiac action potential, a plateau phase characterized by the influx of calcium through long-lasting calcium channels. Class IV antiarrhythmics that block these channels include verapamil and diltiazem.

Answer 5: Label 5 shows phase 4 of the cardiac action potential, a period of ventricular diastole. In this phase, a relatively negative resting membrane potential is maintained by the activity of potassium leak channels. No antiarrhythmics have significant action in phase 4 of non-pacemaker myocytes.

Bullet Summary:
Class III antiarrhythmics, such as dofetilide, are slow-response potassium channel blockers that increase the effective refractory period by prolonging phase 3 of the cardiac myocyte action potential.