Class+IC+antiarrhythmics

Class IC antiarrhythmics


 * Background and History:** The first Class IC agent, flecainide, was approved by the FDA in 1985, with subsequent approvals for encainide and moricizine in 1986 and 1990. Initially, expectations were high for the Class IC agents (e.g., encainide, flecainide, moricizine, and propafenone) because they were extremely effective in suppressing potentially lethal arrhythmias, and appeared to exhibit relatively minor side effects. Despite their efficacy in suppressing ventricular ectopy, however, these drugs are prone to induce or exacerbate arrhythmias. Flecainide, encainide, and moricizine were evaluated in post-MI patients in the Cardiac Arrhythmia Suppression Trial (CAST), published in 1989.[296] The increased mortality results from the original CAST study[296] for encainide and flecainide published in 1989 led to the withdrawal of encainide from the U.S. market in 1991. The number of patients receiving moricizine were too few for meaningful analysis. Subsequently, a second CAST study (CAST II) compared moricizine to placebo in patients with asymptomatic or mildly symptomatic ventricular arrhythmias post myocardial infarction. Because lack of benefit was demonstrated early, CAST II was terminated prematurely.[297] The results of both CAST studies indicated that Class IC agents should be reserved for treatment of ventricular arrhythmias that are considered life-threatening. These studies have resulted in re-evaluation of the choice and use of pharmacologic agents for the management of arrhythmias (e.g., life-threatening ventricular arrhythmias). As a result, antiarrhythmic agents have been replaced in some cases by implantable defibrillator devices. Antiarrhythmic drugs are still used as primary therapy for many supraventricular arrhythmias, but their use as primary therapy for prevention of ventricular arrhythmias has declined since the publication of the trials mentioned above.

The Vaughan-Williams (V-W) classification system traditionally has been used to classify antiarrhythmic drugs.[298] This scheme places the available agents into one of four classes: I, II, III, or IV. The V-W system, however, has two limitations. First, although all drugs within a single class might possess a similar electrophysiologic action, they do not necessarily exert all of the same actions. The second limitation of the V-W classification system is that some agents have multiple electrophysiologic activities that complicate the placement of a drug into a single (e.g., amiodarone) or any (e.g., adenosine) category.[299]

Class IC antiarrhythmic agents include: encainide, flecainide, moricizine, and propafenone. Propafenone is a Class IC drug which also has weak beta-antagonist activity.[304]


 * Mechanism of Action:** Class I agents are membrane-active drugs that act on the sodium channel and slow the maximal rate of depolarization or Vmax as measured by phase 0 of the action potential. Blockade of the sodium channel results in reduced automaticity, delayed conduction, and prolonged refractory periods. The class I agents have been further classified into three subcategories; IA, IB, and IC. The differences among these subgroups lie in the nature of their inhibition of the sodium ion channel. 'On-off' receptor kinetics refers to the affinity of drug dissociation of the drug from the sodium channel. 'Off kinetics' describes the rapidity of dissociation of the drug from the sodium channel. The Class I agents also may be characterized by the mechanism by which they inhibit the sodium channel.[295]

The Class IC agents, encainide, flecainide, moricizine, and propafenone, possess extremely slow 'on-off' kinetics on the sodium-channel receptors and therefore have marked effects on depolarization, as demonstrated by a significant reduction in phase 0 of the action potential. Class IC agents as a whole markedly depress cardiac conduction, which might explain their proarrhythmic effects.


 * Distinguishing Features:** Class IC agents are indicated to treat documented life-threatening ventricular arrhythmias. Flecainide and propafenone are also used for conversion to and/or maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation and/or atrial flutter associated with disabling symptoms and without structural heart disease.[4224] Experience with moricizine in the treatment of supraventricular arrhythmias is limited.[4224]

Flecainide is eliminated by renal and hepatic routes, and drug dosage may require dosage adjustment in patients with renal or hepatic impairment. Propafenone and moricizine are extensively metabolized by the liver. Moricizine is transformed to several active, long-acting metabolites. Propafenone, encainide, and flecainide are CYP2D6 substrates, with potential for drug accumulation and toxicity when co-administered with CYP2D6 inhibitors (e.g., ritonavir, quinidine, amiodarone).


 * Adverse Effects:** Class IC agents share a propensity for proarrhythmic effects. As demonstrated in the CAST trial, use of Class IC agents in post-MI patients was associated with a threefold increase in mortality compared with placebo.[296] The cause of death in many cases was late proarrhythmia, which has led to limited use of Class IC agents,[302] and contraindications for use in patients with compromised left ventricular function.

Class IC agents should not be used in patients with left ventricular dysfunction or recent acute myocardial infarction due to the increased risk of serious arrhythmias. Propafenone and flecainide exhibit a mild to moderate negative inotropic effect, and can cause or worsen congestive heart failure. These effects occur especially in patients with cardiomyopathy, pre-existing severe heart failure, or decreased left ventricular ejection fractions.

In addition to proarrhythmic effects, the most typical adverse reactions to Class IC agents include neurological effects (eg., visual impairment, dizziness, headache, tremor, tinnitus and gastrointestinal complaints (e.g., nausea/vomiting, constipation or diarrhea, dyspepsia). Many of these side effects are dose-related. Dysgeusia occurs in about 20% of patients receiving propafenone.

Class IC agents generally have a narrow therapeutic range, and the toxicity risk can be increased in the presence of higher dosage, impaired drug elimination, or enhanced pharmacodynamic effects. Factors which impair drug elimination of Class IC agents include hepatic impairment (all agents), renal impairment (flecainide), and cytochrome P-450 drug interactions (e.g., CYP2D6 inhibitors). Toxicity risk may also be increased by pharmacodynamic interactions with co-existing disease states (e.g., structural heart disease, heart failure) or other antiarrhythmic drugs (e.g., diltiazem, verapamil, beta-blockers).