Class+I+antiarrhythmics

Class I antiarrhythmics
 * Background:** The publication of the results of the Cardiac Arrhythmia Suppression Trial in 1989[296] and 1992[297] and other studies suggesting increased mortality associated with the use of antiarrhythmic drugs caused the medical community to reevaluate the choice and use of pharmacologic agents for the management of many serious arrhythmias. As a result, antiarrhythmic agents have been replaced in some cases (e.g., life-threatening ventricular arrhythmias) by implantable defibrillator devices. Antiarrhythmic drugs are still used as primary therapy for many supraventricular arrhythmias, but their use as primary therapy for 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]


 * 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 binding to the sodium channel ("on kinetics"). "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 Ia agents exhibit intermediate "on-off" sodium-channel receptor kinetics and correspondingly result in moderate effects on depolarization. The Ia agents include quinidine, procainamide, and disopyramide. The class Ib agents, lidocaine and its oral congeners mexiletine and tocainide, exhibit rapid "on-off" sodium-channel receptor kinetics and therefore minimal effects on depolarization. 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 significant changes in phase 0 of the action potential.


 * Distinguishing Features:** The class Ia drugs all seem relatively similar in electrophysiology, with each agent minimally increasing sinus rate and QT and His-ventricular intervals. Quinidine and disopyramide, however, seem to be particularly useful in managing supraventricular arrhythmias. All drugs of this group are effective in suppressing ventricular ectopy, and many cases of ventricular tachycardia are adequately controlled with a class Ia agent. This group of drugs seems to be less effective in preventing recurrences of severe or life-threatening ventricular tachycardias or fibrillation, and can even induce proarrhythmic events in these patients. A recent meta-analysis implied that the Ia drug quinidine, although effective at maintaining sinus rhythm at 1 year, was also linked to a significant increase in mortality, primarily as a result of proarrhythmia (i.e., torsade de pointes).[300]

Quinidine is available as various salts (sulfate, polygalacturonate, and gluconate) and in multiple dosage forms (capsules, tablets, and injection), allowing for the most versatility in drug administration, and it is considered the prototypical agent of this class, although procainamide is increasing in use. Procainamide is metabolized to an active metabolite (N-acetylprocainamide or NAPA), which possesses class III properties. Procainamide's rate of metabolism varies according to the hepatic acetylator status of the patient. In many cases, procainamide is the first-line agent for electrophysiologic drug testing. Of the drugs in the Ia class, disopyramide has the longest half-life, is the most negatively inotropic, and causes the most anticholinergic side effects.

Lidocaine is the prototypical class Ib agent and is the only drug in this class not administered orally. However, orally effective derivatives of lidocaine have been developed including tocainide (1984) and mexiletine (1986). The class Ib drugs tend to be the least effective of all the subclasses in treating potentially lethal arrhythmias, and they do not seem to favorably alter mortality compared with placebo.[295] Of the agents in this class, lidocaine is preferred for managing nonsustained ventricular tachycardia and frequent premature ventricular beats (>6/minute), and for use as an adjunct to defibrillation and CPR in patients with ventricular tachycardia and/or fibrillation. In these conditions, the drug appears to possess superior efficacy due to the ease of attaining and sustaining therapeutic serum drug concentrations with relatively few adverse effects. Lidocaine has relatively few adverse circulatory effects, presumably because the clearance of lidocaine is rapid in comparison to that of other class I antiarrhythmic agents. Lidocaine may be helpful for prophylaxis against ventricular fibrillation in the presence of myocardial ischemia or infarction, but, as with many antiarrhythmic drugs, re-analysis of previous trials has indicated that mortality may not be favorably altered and may, in fact, be increased.[301]

Initially, expectations were high for the class Ic agents (e.g., encainide, flecainide, moricizine, and propafenone) because they were extremely effective (80—90% success rates) in suppressing potentially lethal arrhythmias and had relatively minor side effects. Despite their efficacy in suppressing ventricular ectopy, however, these drugs appear to be prone to inducing proarrhythmias. 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 some to question the use of all class I agents, particularly in patients with compromised left ventricular function.[302]


 * Adverse Reactions:** Adverse GI effects are common during administration of class I agents and include: anorexia, diarrhea, bitter taste, abdominal pain, esophagitis, nausea/vomiting, and colic. These effects are a frequent reason for discontinuing antiarrhythmic therapy. Hepatotoxicity has also been reported with the use of these agents.

Class I antiarrhythmic drugs paradoxically can cause other cardiac arrhythmias, especially if serum concentrations are excessive or if other drugs are used concomitantly. When used in the treatment of atrial flutter or fibrillation, quinidine can slow the atrial rate enough to allow for 1:1 conduction through the AV node, thus causing a paradoxical increase in heart rate. Ventricular tachycardia is a serious and life-threatening adverse reaction that can occur early or late following initiation of antiarrhythmic therapy. Excessive amounts of these agents also can provoke polymorphic ventricular tachycardia or torsade de pointes.

Class I drugs can cause syncope in therapeutic doses. Although these episodes can subside spontaneously, occasionally they are fatal. If syncope occurs during therapy, the drug should be discontinued. Bradycardia also can occur, even at therapeutic serum drug concentrations. Overdose or intravenous administration of drugs in this class can cause dizziness, severe hypotension, respiratory arrest, or vascular collapse.

Tinnitus can be a sign of quinidine toxicity. This can be due to an excessive dosage, an acute reduction in renal function, or a change in urine pH.

Various hematologic effects have been reported with class I antiarrhythmic therapy. These include: hemolytic anemia (especially in patients with G6PD deficiency), aplastic anemia, leukopenia, agranulocytosis, and thrombocytopenic purpura.

Various dermatologic effects have been rarely reported with class I drug therapy. Types of reactions include rash, pruritus, exfoliative dermatitis, and urticaria.

Quinidine and procainamide have been reported to cause a lupus-like syndrome. In addition to developing a positive ANA, patients can exhibit symptoms such as polyarthritis, fever, and pleuritic chest pain.