Cytochrome P450-2D6 Genotype Definition May Improve Therapy for Paroxysmal Atrial Fibrillation A Case of Syncope Following "Pill-in-the-Pocket" Quinidine plus Propafenone.

Abstract

Classes 1A, 1C and III anti-arrhythmics may be ineffective or induce adverse events including potentially fatal arrhythmias when administered in recommended doses. Serum levels of these medications vary widely during conventional dosing due in large part to variations in cytochrome P450-2D6 isoenzyme activity which metabolizes most antiarrhythmics in addition to over 25% of other commonly prescribed medications. 2D6 activity is also profoundly inhibited by some antiarrhythmics and other commonly used medications and varies widely between the individuals of all populations, a pattern which has resulted in separation of subjects into 4 phenotypes and genotypes consisting of poor metabolizers (PM), intermediate metabolizers (IM), efficient metabolizers (EM), and ultra-rapid metabolizers (UM). Patients with a phenotype PM classification almost universally are also genotype PM due to the possession of two inactive 2D6 alleles, with this PM pattern often inducing supratherapeutic and toxic antiarrhythmic blood levels during conventional antiarrhythmic therapy. UM individuals have supranormal levels of 2D6 activity often created by the presence of 3 or more active alleles which often induce subtherapeutic and ineffective drug levels during antiarrhythmic administration in conventional doses. We searched for evidence relating Cytochrome P450-2D6 phenotypes or genotypes to antiarrhythmic metabolism in order to judge whether this analysis might contribute to improved safety and effectiveness of antiarrhythmic medications commonly utilized in the treatment of atrial fibrillation. The available evidence strongly supported these possibilities. We also describe a patient in whom knowledge of his IM/PM CYP2D6 genotype might have prevented the only episode of syncope and myocardial stunning which developed during his 28 years of "Pill-in-a-Pocket" therapy.