Class+IA+antiarrhythmics

Class IA antiarrhythmics
 * Background:** The publication of the results of the Cardiac Arrhythmia Suppression Trials 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 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 IA antiarrhythmic agents include: disopyramide, procainamide, and quinidine.


 * 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'd escribes 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.


 * Distinguishing Features:** The class IA drugs are relatively similar in electrophysiology, with each agent minimally increasing sinus rate, QT interval, and the His-ventricular interval. Quinidine is considered the prototypical agent of this class. Class IA drugs 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. 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 and disopyramide are also useful in managing supraventricular arrhythmias.

Quinidine is available as various salts and in multiple dosage forms (capsules, tablets, and injection), allowing for versatile drug administration.

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.

Relative to other Class IA antiarrhythmics, disopyramide has the longest half-life, and has significant negative inotropic and anticholinergic effects.


 * Adverse Reactions:** Adverse GI effects are common during administration of class IA 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 IA 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 IA 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 Ia antiarrhythmic therapy. These include: hemolytic anemia (especially in patients with G6PD deficiency), aplastic anemia, leukopenia, agranulocytosis, and thrombocytopenic purpura.

Dermatologic effects have been rarely reported with class IA 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.