Gender Differences: New Perspectives in Pharmacokinetics and Pharmacodynamics
Raymond L. Woosley, M.D., Ph.D., Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007
Conventional medical education teaches that there are hormonally responsive tissues with specific hormone receptors. For sex hormones these tissues are usually considered to be those responsible for sexual differentiation and/or reproduction. Cardiac muscle has generally been considered, like many tissues, unresponsive to sex hormone. However, we now know that cardiac tissue contains both estrogen and androgen receptors, although their function has been unknown until recently. Although, it has been known for over 70 years that the QT interval on the electrocardiogram is longer in adult females than males, only recently has it been observed that this difference develops at puberty. Another recent observation is that sex hormones, perhaps acting through their receptors (although this is not clear), can alter myocardial function. This research demonstrated that sex hormones can alter the expression of drug targets (ion channels) in cardiac tissue and their response to drugs. These results explain prior clinical and experimental observations. For example, after the local anesthetic bupivacaine, previously considered to be safe, began to be associated with cardiorespiratory arrest in pregnant patients, experiments in animals demonstrated that pretreatment with progesterone markedly increased the sensitivity of cardiac ion channels to block by bupivacaine. Furthermore, the far greater incidence of life-threatening ventricular arrhythmias in women than men treated with drugs such as quinidine, sotalol, terfenadine, erythromycin and halofantrine (all potassium channel blockers) can be at least partially understood with recent data indicating that sex hormones and gender influence the expression and drug sensitivity of potassium channels in the heart. Males have a smaller degree of change in the cardiac QT interval at the exact same plasma concentration of quinidine. Physicians caring for women and scientists developing new drugs should be aware of the potential physiologic and pharmacologic effects of sex hormones on cardiac and other tissues that could alter response to the actions of drugs.