Antiarrhythmic agents
Valenzuela, C.; Tamargo, J.; Delpón, E. and Pérez, O.
Ars Pharm.36;(4);507-526, (1995)
Key words: Sodium current, Action potential, Antiarrhythmic drugs, ArrhythmiasAbstract
Antiarrhythmic agents are a very heterogeneus group of drugs which, together with programmed electrical stimulation, pacemaker implantation, ablation and surgery, constitute the basis of the antiarrhythmic therapy. Most clinical arrhythmias are due to reentry , which represents an alteration of the cardiac impulse. The basis for reentry are: a)an anatomical or functional abstacle which defines the circus movement, b) an area of unidirectinal block, and c) the lenght of path must exceed the wave length determined 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. Antiarrhythmic drugs acting by this mechanism include those that decrease the fast inward sodium current (INal), the so-called class I antiarrythmic drugs. 2) Lengthening of the effective refractory period, in such a way that the wavefront encroaches in its own refractary period and the cardiac impulse cannot be propagated anymore. Drugs that selectively prolonged the effective refractory period are included as class III antiarrhytmics. Recent clinical studies (CAST, 1989) have warned the scientific community about the effectiveness and safety of class I antiarrhytmic drugs, since two of them (flecainide and encainide) did not decrease, but increased mortality in patients which previous myocardial infarction and asymptomatic ventricular extrasystoles. These results led numerous work groups and pharmaceutical companies to develop new class III antiarrhythmic drugs. The "ideal" class III antiarrhythmic drug would be that which produced minimal effect in sinus rhythm but produced a marked prolongation of the effective refractory period when the heart rate increased (i.e. during tachycardia). However, none of the available class III antiarrhythmic drugs exhibit this pharmacological profile. On the conttrary, they prolonged cardiac refractoriness more at low frequencies of stimulation (bradycardia) than a higher stimulation rates. Only amiodarone, the first class III antiarrhythmic drug, which exhibits class I, II (beta-adrenoceptor blockade) and IV (calcium 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 polarization 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.
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