The number and proportion of elderly (greater than 65 yr) within the U.S. continues to increse, along with the disproportionate use of drugs in this sub-population. The elderly often respond differently to drugs than younger patients, and this is reflected in a twofold greater incidence of adverse reactions. The overall goal of the proposed research is to gain insight into the role and importance of altered drug disposition/pharmacokinetics and pharmacodynamics in age-related changes in drug responsiveness in man. Such information should lead to more rational and safer drug use in the elderly. Aging leads to an increase in cerebral sensitivity to the benzodiazepines. Studies are planned using the brain uptake index technique in the rat to investigate, in this important class of psychoactive drugs, the role of lipid solubility and plasma binding upon the translocaton of drug to its site of action, and the effects of aging upon this process. Clinical studies are also proposed using a variety of psychomotor function tests to separate the contributions of altered disposition and central responsiveness to the increased effects of single doses of diazepam in the elderly. The effects of aging on the plasma accumulation of diazepam and its psychopharmacologically active metabolites following chronic drug administration will also be investigated in man. Of particular interest will be the relationship between the acute and chronic dosing situations, and the comparison of the results from chemically specific assays versus those from a """"""""receptor binding assay"""""""" reflecting total benzodiazepine-like activity. Drug interactions are more likely in the elderly since multiple drug therapy is common. Investigations will be performed using the model system propranolol:rifampin to determine whether in man the aging process lead to an alteration in the ability to induce drug metabolizing enzymes. The loss of adaptive responsiveness with aging may result in changes in the rates of induction and de-induction and/or the extent of induction. Similarly, the effects of aging on inhibition of the oxidative drug metabolizing enzymes will be evaluated using the model interacting drugs, propranolol:cimetidine. Age-related alterations in drug interactions may be partly responsible for the increase in adverse effects observed in elderly patients.
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