Classification of antiarrhythmic drugs in relation to mechanisms of arrhythmias

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For more than 20 years, the classification of antiarrhythmic drugs proposed by Vaughan Williams [1] has held the field. In essence, it is based on the effects of antiarrhythmic agents on the transmembrane potentials of normal, isolated cardiac tissue. In 1972, Singh and Vaughan Williams modified the classification by introducing the calcium entry blocking effect as a fourth class of antiarrhythmic action [2], and in 1992, Vaughan Williams proposed that specific bradycardic agents constitute a fifth class [3]. A modification of the classification of Na+ channel blocking agents was provided by Harrison et al. [4], who subdivided class I actions into the classes a, b and c, mainly on the basis of the effects on action potential duration. Thus, class la agents prolonged the action potential duration, class Ib drugs shortened it, and class Ic components had little effect. Later, more sophisticated subclassifications of drugs that blocked inward currents, either carried by Na+ or Ca2+ ions, were made on the basis of the kinetics of ion channel blockade and by defining the state of the channel (i.e. resting, activated or inactivated) to which drugs bind and unbind [5–7]. An important consequence of these later modifications was the recognition of use or frequency-dependent channel blockade. Drugs with use-dependent action bind to the activated and/or inactivated channel and slowly dissociate from the channel during diastole. They therefore exert their greatest effect at rapid heart rates. The time constants for unbinding are short for class Ib drugs and long for class Ia and Ic drugs. Class Ic drugs, which have the slowest kinetics, can further be subdivided into three groups according to their saturation behaviour at rapid rates [7].