potassium-channel blockers

Effects on action potentials. The primary role of potassium channels in cardiac action potentials is cell repolarization. In non-nodal tissue (see figure), action potentials are initiated when a cell is depolarized to a threshold potential by an adjacent cell. This leads rapid opening of fast sodium channels and a slower opening of L-type calcium channels that permit calcium to enter the cell (phase 0 and 2, respectively). As these channels become inactivated, potassium channels open permitting potassium ions to leave the cell (Figure: K⁺ out), which causes repolarization of the membrane potential (phase 3). Potassium channels remain open until the next action potential is triggered. There are also different potassium channels that are responsible for the initial repolarization (phase 1) that occurs as the fast sodium channels become inactivated. Potassium channels are also responsible for repolarizing slow-response action potentials in the sinoatrial and atrioventricular nodes.

Potassium-channel blockers comprise the Class III antiarrhythmic compounds according to the Vaughan-Williams classification scheme. These drugs bind to and block the potassium channels that are responsible for phase 3 repolarization. Therefore, blocking these channels slows (delays) repolarization, which leads to an increase in action potential duration and an increase in the effective refractory period (ERP). On the electrocardiogram, this increases the Q-T interval. This is the common effect of all Class III antiarrhythmic drugs. The electrophysiological changes prolong the period of time that the cell is unexcitable (refractory) and therefore make the cell less excitable.

By increasing the ERP, these drugs are very useful in suppressing tachyarrhythmias caused by reentry mechanisms. Reentry occurs when an action potential reemerges into normal tissue when that tissue is no longer refractory. When this happens, a new action potential is generated prematurely (before normal activation) and a circular, repeating pattern of early activation can develop, which leads to a tachycardia. If the ERP of the normal tissue is lengthened, then the reemerging action potential may find the normal tissue refractory and premature activation will not occur.

Specific Drugs and Therapeutic Indications

The following table summarizes Class III compounds in terms of their therapeutic use and some special or distinguishing characteristics. More detailed information on specific drugs can be found at www.rxlist.com.

Drug Therapeutic Uses Comments

amiodarone severe supraventricular and ventricular arrhythmias very long half-life (25-60 days); Class I, II, III & IV actions and therefore decreases phase 4 slope and conduction velocity; potentially serious side effects (e.g., pulmonary fibrosis; hypothyroidism)

bretylium life-threatening ventricular tachycardia and fibrillation IV only; initial sympathomimetic effect (norepinephrine release) followed by inhibition, which can lead to hypotension

sotalol ventricular arrhythmias; atrial flutter and fibrillation also has Class II activity

ibutilide supraventricular arrhythmias; atrial flutter and fibrillation conversion

–slow inward Na⁺ activator, which delays repolarization; –inhibits Na⁺-channel inactivation, which increases ERP; IV only

dofetilide supraventricular arrhythmias; atrial flutter and fibrillation conversion very selective K⁺-channel blocker

Abbreviations: IV, intravenous.

Side Effects and Contraindications

All of these compounds, like Class I compounds, are proarrhythmic as well as being antiarrhythmic. For example, the increase in action potential duration can produce torsades de pointes (a type of ventricular tachycardia), especially in patients with long-QT syndrome. Amiodarone, because of its Class IV effects, can cause bradycardia and atrioventricular block, and therefore is contraindicated in patients with heart block, or sinoatrial node dysfunction.

Revised 12/28/07

DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.