Pharmacologic causes of arrhythmogenic actions of antiarrhythmic drugs.

All currently known antiarrhythmic agents can induce or worsen arrhythmias. Inappropriate dosage selection, mistakenly based on pharmacokinetic data from "normal" subjects, may result in adverse reactions when an antiarrhythmic drug is given to patients. Unexpected variations in drug clearance can increase plasma concentration of antiarrhythmic agents and aggravate arrhythmias. Changes in the rate of drug metabolism by the liver, e.g., due to cessation of alcohol or drugs that induce hepatic metabolism, can reduce drug clearance, making a previously well-tolerated dose toxic. Another possible explanation for adverse drug reactions is nonlinear protein binding. Recently, genetic determinants of drug metabolism have been identified as explanations of interindividual variations in drug responsiveness. Finally, the interactions of antiarrhythmic agents may also lead to aggravation of arrhythmias. A better understanding of the pharmacology of antiarrhythmic agents can reduce, if not prevent, the occurrence of potentially lethal proarrhythmic events.