Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome

Drug-induced torsade de pointes is a rare life-threatening adverse drug rea ction (ADR) which is strongly influenced by gender. Drugs that prolong card iac repolarisation include antiarrhythmics, gastrokinetics, antipsychotics, antihistamines and antibacterials. Such drugs share the potential to block cardiac voltage-gated potassium channels, particularly the rapid component (I-Kr) of the delayed rectifier potassium current (I-K). By doing so, such drugs usually, but not always, prolong the QT interval. Even if the electr ocardiographic signs are subdued, the underlying blockade of I-Kr current m ay precipitate the occurrence of arrhythmia. Women are perceived to be more prone to ADRs than men. Such a propensity ma y result from gender-associated differences in drug exposure, in the number of drugs prescribed (polypharmacy), in drug pharmacology, as well as from possible differences in the way the adverse event is perceived. A prolonged QT interval on the electrocardiogram (time that elapses from the onset of the cardiac ventricular depolarisation to the completion of its repolarisat ion) is associated with the occurrence of torsade de pointes and related ve ntricular arrhythmias. The QT interval is influenced by heart rate, autonom ic nervous system, electrolyte disturbances and above all, drugs that block potassium channels. Two-thirds of the cases of drug-induced torsade de pointes occur in women. Therefore, this adverse effect represents a perfect example of gender diffe rences impairing women's health. Clinical and experimental studies show tha t female gender is associated with a longer corrected QT interval at baseli ne and a greater response to drugs that block I-Kr, both of which facilitat e the emergence of arrhythmia. This results most likely from a specific reg ulation of ionic channel expression (potassium, calcium, etc) by sex steroi ds, even though nongenomic effects may play a role as well. Estrogens facil itate bradycardia-induced prolongation of the QT interval and the emergence of arrhythmia whereas androgens shorten the QT interval and blunt the QT r esponse to drugs. Hence, underlying genetic defects of potassium channels t hat may be asymptomatic in normal conditions, may precipitate drug-induced arrhythmia in women more frequently than in men. Even in the presence of a drug that mildly blocks IKr and seldom prolongs the QT interval, women are still more prone to drug-induced torsade de pointes, due to their reduced c ardiac 'repolarisation reserve'. This is an important aspect of I-Kr blocka de to be aware of during the development of new drugs.