CLASSIFICATION OF ANTIARRHYTHMIC DRUGS
Antiarrhythmic drugs have historically been segre-gated by the Vaughn Williams classification system into four main groups, based on their predominant mecha-nism of action. This is a good starting point for organ-izing one’s thinking about the various antiarrhythmic drugs, but it is a great oversimplification and does not address several drugs that have electrophysiological effects characteristic of more than one group. Thus, although the grouping of antiarrhythmic agents into four classes is convenient, such a classification falls short of explaining the underlying mechanisms by which many drugs ultimately exert their therapeutic antiarrhythmic effect. Also, certain agents do not fall neatly into the four classes;.
Class I antiarrhythmic drugs are characterized by their ability to block the voltage-gated sodium channel. The class I agents may block the channel when it is in either the open or the inactivated state. Inhibition of the sodium channel results in a decrease in the rate of rise of phase 0 of the cardiac membrane action potential and a slowing of the conduction velocity. Additionally, class I drugs, through inhibition of the sodium channel, require that a more hyperpolarized membrane poten-tial (more negative) be achieved before the membrane becomes excitable and can propagate an excitatory stimulus. As a result, the ERP of fast-response fibers is prolonged. Although many class I antiarrhythmic drugs possess local anesthetic actions and can depress myo-cardial contractile force, these effects are usually ob-served only at higher plasma concentrations.
The antiarrhythmic drugs in class I suppress both normal Purkinje fiber and His bundle automaticity in addition to abnormal automaticity resulting from myo-cardial damage. Suppression of abnormal automaticity permits the sinoatrial node again to assume the role of the dominant pacemaker.
The antiarrhythmic agents that belong to class I are divided into three subgroups (Table 16.1) with slightly different properties. Class IA drugs slow the rate of rise of phase 0 (Vmax>) of the action potential and prolong the ventricular ERP. Members of this class impair the function of the membrane sodium channel, thereby de-creasing the number of channels available for mem-brane depolarization. Class IA drugs do not alter the resting membrane potential. Because they decrease Vmax>, class IA drugs slow conduction velocity. Members of this class directly decrease the slope of phase 4 depo-larization in pacemaker cells, especially those that arise outside of the sinoatrial node.
Members of class IB have a minimal effect on the rate of depolarization and are characterized by their ability to decrease the duration of action potential and ERP of Purkinje fibers. Members of this class have a minimal effect on conduction velocity in ventricular myocardium and are without apparent effect on refrac-toriness.
The drugs in class IC produce a marked depression in the rate of rise of the membrane action potential and have minimal effects on the duration of membrane ac-tion potential and ERP of ventricular myocardial cells.
Class II antiarrhythmic drugs competitively inhibit β- adrenoceptors and inhibit catecholamine-induced stimu-lation of cardiac β-receptors. In addition, some members of the group (e.g., propranolol and acebutolol) cause electrophysiological alterations in Purkinje fibers that resemble those produced by class I antiarrhythmic drugs. The latter actions have been called membrane-stabilizing effects.
Class III antiarrhythmic drugs prolong the membrane action potential by delaying repolarization without alter-ing phase 0 of depolarization or the resting membrane potential. Class III drugs have a significant risk of proar-rhythmia because of the prolongation of action poten-tial and the induction of torsades de pointes.
Class IV drugs block the slow inward Ca++ current (L-type calcium channel) in cardiac tissue. The most pro-nounced electrophysiological effects are exerted on car-diac cells that depend on the Ca++ channel for initiating the action potential, such as those found in the sinoatrial and A-V nodes. The administration of class IV drugs slows conduction velocity and increases refractoriness in the A-V node, thereby reducing the ability of the A-V node to conduct rapid impulses to the ventricle. This ac-tion may terminate supraventricular tachycardias and can slow conduction during atrial flutter or fibrillation.
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