Acquired Salivary Dysfunction: Drugs and Radiation

When considering the effects of drugs on salivary glands, a distinction should be drawn between the complaint of oral dryness (xerostomia), a symptom, and measurable secretory hypofunction, a sign. In general, the symptom of xerostomia is often not accompanied by objective reductions in salivary output, and xerostomia is not a reliable indicator of secretory hypofunction. Whereas therapeutic pharmaceutical side effects represent the most prominent cause of xerostomia, with over 500 drugs associated with this symptom, only a small number of drugs have been demonstrated to reduce salivary output substantially. There are examples in which drugs with a high prevalence of xerostomia complaints do not affect secretory function. The mechanisms responsible for this discrepancy between subjective and objective findings have not been fully identified. It is hypothesized that alterations in systemic or mucosal hydration may play a role. Of the drugs with true salivary hypofunctional actions, most have direct anticholinergic properties. In almost all cases, the salivary effects of pharmaceuticals are not permanent, and function returns to pretreatment levels when the medication is stopped. By contrast, the effects of irradiation on the salivary glands are permanent when exposures exceed 50 Gy. About 40,000 individuals per year receive irradiation that involves the salivary glands (by external beam or internal sources--radon implants and 1311) for treatment of cancers of the head and neck region. Although these radiation effects have been recognized as a significant clinical problem for more than 80 years, the specific mechanisms responsible for radiation-induced salivary gland dysfunction are still not understood. With the exception of studies documenting the secretory functional deficits following head and neck irradiation, limited studies have been done in humans. The majority of experimental work has been done in rodents. A variety of mechanisms, including mitotic and interphase cell death, direct DNA damage or effects of secondary metabolites, damage to progenitor cells, or altered gene expression, have all been proposed to explain the salivary epithelial cell death observed. Recent experimental studies with models of radiation-induced salivary damage in rats and a human salivary cell line suggest that the small percentage of surviving epithelial cells are capable of performing functions such as signal transduction and ion transport normally. Apoptotic cell death following irradiation has not been a prominent feature in these model systems. The effects of head and neck radiation on the salivary glands and oral cavity continue to present multiple significant clinical problems both during and after radiotherapy. In recent years, there has been some progress in minimizing these effects through more careful shielding and pretreatment planning. Additionally, there are preliminary results from a clinical trial suggesting that the use of a secretagogue, pilocarpine HCl, given during the course of radiotherapy, may reduce the secretory hypofunctional effects. A multicenter trial is now underway to test this hypothesis. There is still a real need to develop more effective treatments for this condition.