Class+IV+antiarrhythmics

Class IV 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 re-evaluate 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:** The class IV antiarrhythmic, calcium-channel blocking agents inhibit the intracellular entry of calcium through the slow channels of the calcium-dependent tissues of the myocardium, which are concentrated in the sinoatrial (SA) and atrioventricular (AV) nodes. Of the calcium-channel antagonists available, only verapamil and diltiazem possess significant antiarrhythmic activity, unlike the dihydropyridine type of CCBs, which are ineffective in controlling arrhythmias. Blockade of the calcium channel will slow conduction, decrease automaticity, and prolong the refractory period within both the SA and AV nodes. As a result, SA nodal firing is depressed, the PR interval is prolonged on the surface electrocardiogram, and the ventricular response rate to atrial impulses is decreased. As one may predict given this mechanism of action, verapamil and diltiazem are useful in managing and treating supraventricular tachycardias including paroxysmal supraventricular tachycardia, atrial fibrillation and/or flutter, and re-entrant tachycardias involving the AV node.[295]'[302]


 * Distinguishing Features:** Unlike beta-blockers, calcium-channel blockers are not all chemically related. Verapamil, the prototype calcium-channel blocking agent, is a diphenylalkylamine, while diltiazem is related to the benzodiazepines. Although unrelated structurally, verapamil and diltiazem are similar in efficacy and hemodynamic effect, and are considered by many clinicians to be the drugs of first choice for PSVT. Adenosine, however, which is not a CCB, is highly effective in treating PSVT, and it is extremely helpful in differentiating wide complex tachycardia from PSVT and in treating patients with impaired left ventricular function or hypotension.[302]'[304] The primary differences between verapamil and diltiazem are the method of drug administration and cost. Verapamil is administered as a slow IV push over 3-5 minutes, whereas diltiazem is given as a bolus followed by a continuous infusion of 24 hours maximal duration.


 * Adverse Effects:** The most serious adverse effects associated with verapamil or diltiazem therapy are extensions of their pharmacodynamic and electrophysiologic effects on the AV node and the vasculature. These effects include bradycardia, AV block of any degree, which may require atropine therapy when severe, and excessive hypotension. Although the drugs possess negative inotropic characteristics, the risk of developing congestive heart failure or pulmonary edema due to verapamil or diltiazem is somewhat offset by afterload reduction.

Proarrhythmias, which range from benign heart block to life-threatening ventricular fibrillation, can occur during verapamil therapy, particularly in patients with accessory AV pathways. The vasodilatory action of the calcium-channel blockers result in many adverse effects, including dizziness, flushing, and peripheral edema, and tend to occur more often with diltiazem. Lethargy, headache, and fatigue have also been reported. About 1—3% of patients report adverse GI effects such as nausea/vomiting, anorexia, constipation, weight gain, thirst, dyspepsia, and dysgeusia. Moderate to marked transient elevations in liver-function tests and hepatocellular injury have been reported, usually occurring within 1—8 weeks following initiation of therapy. These changes resolve after discontinuation of therapy.