Antiarrhythmic drugs can be divided into four Vaughan Williams classes (I-IV) 
according to defined electrophysiological effects on the myocardium. Thus, the 
Vaughan Williams classification also coincides with the main myocardial targets 
of the antiarrhythmics, i.e., myocardial sodium-, potassium-, and 
calcium-channels or beta-adrenergic receptors. A more detailed characterization 
which is also based on the myocardial targets of a drug is given by the 
"Sicilian Gambit" approach of classification. Nevertheless, the appropriate drug 
for the management of a given clinical arrhythmia has to be chosen according to 
the electrophysiological effects of the respective drug. A main determinant of 
the antiarrhythmic or proarrhythmic properties of a drug is the frequency 
dependence of its electrophysiological effects. The sodium-channel blockade 
induced by class-I substances is enhanced with increasing heart rates. Thus, 
class-I antiarrhythmics can be subclassified as substances showing a more 
exponential, an approximately linear, or rather saturated block-frequency 
relation. Class-III antiarrhythmics (potassium-channel blockade) can be further 
differentiated according to the component of the delayed rectifier potassium 
current (IK) which is inhibited by a drug. Class-III drugs inhibiting 
selectively the rapidly activating and deactivating IKr component exhibit a 
marked reverse rate dependence, i.e., the drug induced prolongation of the 
cardiac action potential is minimized at high rates. On the other hand, during 
bradycardia the pronounced action potential prolongation may cause early 
afterdepolarizations and triggered activity leading to torsades de pointes 
arrhythmias (acquired QT syndrome). Class-III substances inhibiting the slowly 
activating IKs component are currently under investigation and are expected to 
show a direct rate dependence. Experimental data available so far point to an 
action potential prolonging effect at least independent of rate. However, it is 
uncertain whether proarrhythmic effects can be thus avoided, especially in light 
of the fact that one form of congenital QT syndrome (LQT1) seems to be linked to 
dysfunction of the IKs-channel.