Antiarrhythmic agents

Abstract

Antiarchythmic agents are a very hoterogenous group of drugs wbich, together with

programmed electrical stimulation, pacemaker implantation, ablation and surgery, constitute

the basis of the antiarrhythmic therapy. Most clinical arrhythmias are due to reentry,

wbich represents an alteration of the cardiac impulse. The basis for reentry are: a) an

anatomical or functional obstacle wbich defines the circus movement, b) an area of

unidirectional block, and c) the length of path must exceed the wave length deterrnined

by effective refractoriness. Theoretically, reentrant arrhythmias can be suppressed by: 1)

decreasing the conduction velocity, so that the area of unidirectional block becomes an

area or bidirectional block. Antiaarrhythmic drugs acting by tbis mechanism include

those that decrease the fast inward sodiurn current (INal), the so-called class 1 antiarrythmic

drugs. 2) Lengthening of the effective refractory period, in such a way that the wavefront

encroaches in its own refractory period and the cardiac impulse cannot be propagated

anyrnore. Drugs that selectively prolonged the effective refractory period are included as

class ID antiarrhytrnics. Recent clinical studies (CAST, 1989) have warned the scientific

cornmunity about the effectiveness and safety of class 1 antiarrhythmic drugs, since two

of them (flecainide and encainide) did not decrease, but increased mortality in patients

wbich previous myocardial infarction and asyrnptomatic ventricular extrasystoles. These

results led numerous work groups and pharmaceutical companies to develop new class

ID antiarrhythmic drugs. The "ideal" class ID antiarrhythmic drug would be that which

produced minimal effect in sinus rhythm but produced a marked prolongationof the

effective refractory period when the heart rate increased (i.e. during tachycardia). However,

none of the available class ID antiarrhythmic drugs exhibit tbis pharmacological profIle.

On the contrary, they prolonged cardiac refractoriness more at low frequencies of stimulation

(bradycardia) than at bigher stimulation rates. Only arniodarone, the first class ID antiarrhythmic

drug, wbich exhibits class 1, TI (J3-adrenoceptor blockade) and IV (calciurn antagonist)

properties produced a prolongation of the effective refractory period at all cardiac rates,

i.e. its effect is frequency-independent. The use of Molecular Biology techniques which

allow us to determine the structure of the ionic channels involved in the repolarization

of the cardiac action potential, as well as the studies performed in isolated human cardiac

myocytes will afford the basis for a more rational design of new antiarrhythmic drugs.