Pharmacokinetic and pharmacodynamic factors that can affect sensitivity to neurotoxic sequelae in elderly individuals

Early-life exposure to agents that modulate neurologic function can have long-lasting effects well into the geriatric period. Many other factors can affect neurologic function and susceptibility to neurotoxicants in elderly individuals. In this review we highlight pharmacokinetic and pharmacodynamic factors that may increase geriatric susceptibility to these agents. There is a decreasing trend in hepatic metabolizing capacity with advancing years that can affect the ability to dear therapeutic drugs and environmental chemicals. This factor combined with decreased renal clearance causes prolonged retention of numerous drugs in elderly individuals. A geriatric pharmacokinetic database was developed to analyze changes in drug clearance with advancing age. This analysis shows that the half-life of drugs processed by hepatic cytochrome P450 enzymes or via renal elimination is typically 50-75% longer in those older than 65 than in young adults. Liver and kidney diseases are more common in elderly individuals and can further decrease the clearance function of these organs. Polypharmacy, the administration of numerous drugs to a single patient, is very common in elderly individuals and increases the risks for drug interaction and side effects. With advancing age the nervous system undergoes a variety of changes, including neuronal loss, altered neurotransmitter and receptor levels, and decreased adaptability to changes induced by xenobiotics. These changes in the central nervous system can make elderly individuals more susceptible to neurologic dysfunction when confronted with single pharmacologic agents, polypharmacy, or environmental toxicants. The many factors that affect elderly responses to neuroactive agents make environmental risk assessment for this age group a special concern and present a unique challenge.