Edward Miles Vaughan Williams' classification of antiarrhythmic drugs: then and now

This historical review provides a short biographical overview of the British pharmacologist Edward Miles Vaughan Williams (1918-2016) and summarises the experimental findings which form the basis for his original definition of three classes of antiarrhythmic drug (AAD) action, i.e. class I action: Na⁺ channel block; class II action: suppression of sympathetic activity; class III action: prolongation of action potential duration. As a putative class IV action, central nervous system modulation was discussed. The development and approval of novel antiarrhythmic compounds subsequently required more refined subdivision of class I action and a fourth class of action, i.e. 'Ca²⁺ antagonism' as exemplified by verapamil. For half a century, this simple and easy to remember classification has served as an orientation for students and clinicians alike. Nevertheless, it has also been criticised for not being sufficiently systematic and for failing to predict the increased mortality when applied post-myocardial infarction for prevention of sudden cardiac death as published in the Cardiac Arrhythmia Suppression Trial. To overcome this seeming shortcoming, the consensus of the European task force led to a more extensive classification ('The Sicilian Gambit'), with complete listing of multiple actions of the individual antiarrhythmic drugs known at that time. The resulting classification was never widely embraced by cardiologists, most likely due to its inherent complexity. Recently, the original Vaughan Williams classification of AAD action has been expanded in order to reflect today's improved knowledge about arrhythmia mechanisms and to include novel targets for AAD actions, but at the same time, the basic concept that proved so useful in the clinical management remained conserved.