The objective of these proposed studies is to assess pharmacodynamic contributions to side effects of psychopharmacological drugs as a fnction of aging by: (1) examination of pharmacodynamic changes in relation to pharmacokinetic changes, (2) comparison of de novo sensitivity in relation to acute adaptive tolerance, (3) comparison of three benzodiazepines, diazepam, lorazepam and alprazolam, with differing receptor binding and lipid solubility properties. In clinical settings, elderly patients with intercurrent illness and medications have been reported to be hypersensitive to the benzodiazepines to be examined; the proposed studies will focus on the healthy older adult. Assessment of side effects and impairment will include neuromotor, psychomotor, cognitive, sleep and cardiovascular measures. In particular, the neuromoto-cognitive task battery has been designed to test impairments (e.g., memory loss, ataxia, bradykinesia) known to occur with advanced age, as well as to be responsive to the above drugs. In the future, the more sensitive and reliable tasks can be utilized clinically to predict susceptibility to psychotropic drug side effects and impairment in older populations. Whenever possible an effect-concentration curve will be calculated for each task over successive time intervals after drug administration for both older and younger populations. Correlating the slope, intercept and variance of the curve with age should provide a basis for knowing whether predictable levels of impairment can be generalized for drugs across age. The contrast between young and old groups for acute peak effects, acute tolerance, and other pharmacodynamic characteristics may elucidate the altered mechanisms involved in age-related central nervous system hypersensitivity. Understanding these changes may contribute to more knowledgeable drug formulaton and prescribing of psychopharmacological drugs for the elderly, leading to a reduction in the more frequent adverse drug effects, including accidents, noted in the elderly.
| Nikaido, A M; Ellinwood Jr, E H; Heatherly, D G et al. (1990) Age-related increase in CNS sensitivity to benzodiazepines as assessed by task difficulty. Psychopharmacology (Berl) 100:90-7 |
