FEMALE GENDER AS A RISK FACTOR FOR DRUG-INDUCED CARDIAC-ARRHYTHMIAS -EVALUATION OF CLINICAL AND EXPERIMENTAL-EVIDENCE

One of the most pronounced gender-based differences in response to dru gs is women's far greater risk of developing the life-threatening vent ricular arrhythmia called torsades de pointes (TdP). A review of the l iterature and databases of the Food and Drug Administration reveals th at a much higher percentage of women than men develop TdP arrhythmias after taking a variety of drugs, such as antihistamines (terfenadine, astemizole), antibiotics (erythromycin), antimalarials (halofantrine), antiarrhythmics (quinidine, d-sotalol), and miscellaneous other drugs . All of these drugs have in common the ability to block potassium cur rents, thereby prolonging cardiac repolarization and the QT interval o n the EGG. The available experimental data support the hypothesis that gender differences in specific cardiac ion current densities are resp onsible, at least in part, for the greater susceptibility of females f or developing TdP arrhythmias. In isolated perfused rabbit hearts (Lan gendorff technique), female rabbit hearts display greater baseline and drug-induced (quinidine and d-sotalol) changes in QT intervals than m ale hearts, and at least two different repolarizing potassium current densities (I-Kr and I-Kl) are found to be significantly lower in ventr icular cardiomyocytes from female rabbits compared with those from mal es. Thus, it appears that as in humans, clear gender differences exist in the electrophysiologic characteristics governing cardiac repolariz ation in rabbits. This model and perhaps others should be examined as predictors of functional and pharmacologic differences between men and women. Understanding the potential mechanisms responsible for the gre ater risk of drug-induced arrhythmias in women could lead to screening methods for identification of individuals at risk for drug-induced ar rhythmias or to the development of drugs with reduced risk of inducing arrhythmia.