Clinical implications of variable antiarrhythmic drug metabolism

Due to their narrow therapeutic indices, antiarrhythmic drugs have a great potential for adverse outcome. This is amplified by extreme inter-individual variability in their disposition and their pharmacological actions. Genetically determined inter-individual differences in metabolism account for a great deal of this variability. However, because of active metabolites, chirally-specific actions and chirally-specific metabolism, it is not possible to generalize about the outcome of phenotypic differences in the metabolism of a given drug. Careful study of these factors can enable physicians to understand the spectrum of potential responses to a drug. Newly developed molecular biology techniques now make it possible to determine the genotype for the CYP2D6 gene that controls metabolism of many antiarrhythmic drugs. This information, combined with a full understanding of the drugs' clinical pharmacology now makes it possible to predict the clinical outcome for drugs such as encainide, flecainide, mexiletine, propafenone and combinations of these drugs with quinidine.