PHARMACOKINETIC CHANGES IN THE ELDERLY - DO THEY CONTRIBUTE TO DRUG-ABUSE AND DEPENDENCE

The elderly frequently use psychoactive drugs including alcohol (ethan ol) benzodiazepines and opioid analgesics, which have a propensity to cause abuse and dependence, Theoretically, the changes in pharmacokine tics of these agents in the elderly may modify their abuse and depende nce potential, In the elderly. blood alcohol concentrations following an oral dose are higher, alcohol withdrawal syndrome follows a more se vere and protracted clinical course and requires treatment with higher doses of chlordiazepoxide than needed for younger adults. However, th ere is no direct evidence that supports an increased direct abuse and dependence potential of alcohol because of its altered kinetics in the elderly. In the case of oxidatively metabolised benzodiazepines, both age-related pharmacokinetic and pharmacodynamic changes may increase their clinical effects in the elderly. The hypothesis that benzodiazep ines have an increased abuse and dependence potential in the elderly h as not been tested. Many of the benzodiazepines (e.g. alprazolam, tria zolam and midazolam) are metabolised by the cytochrome P450 (CYP) 3A s ubfamily. The pharmacokinetics of these agents may be modified by inhi bition of CYP3A due to concurrently administered medications such as s elective serotonin reuptake inhibitors. Unfortunately, data on the dir ect measures of abuse and dependence potential of benzodiazepines are not available in the elderly. Thus, a conclusive statement on the cont ribution of age-related pharmacokinetic changes to benzodiazepine abus e and dependence cannot be made at the present time. The clinical effe cts of codeine do not appear to change with age. Codeine is O-demethyl ated to its active metabolite morphine by the genetically polymorphic CYP2D6 isozyme. The activity of this isozyme is unaltered by age, gend er or smoking habits; however, it is subject to potent inhibition by s ome of the frequently used medications in the elderly, such as the ant idepressants paroxetine and fluoxetine. This may result in an impairme nt in O-demethylation of codeine to morphine and may lead to a decreas e in the abuse and dependence potential of codeine. Conversely, those with a very rapid CYP2D6 catalytic activity may have an increased pote ntial for codeine abuse and dependence. The clinical significance of a ge-related pharmacokinetic changes should be evaluated within the cont ext of clinical practice. Most physicians are inclined to prescribe lo wer doses to the elderly, which may offset the potential impact of alt ered pharmacokinetics on the abuse and dependence potential of psychoa ctive agents. In summary, the available data are not sufficient for a definitive conclusion on whether the pharmacokinetic changes in the el derly translate to an increase in the abuse and dependence potential o f alcohol, benzodiazepines or opioids. In particular. the data on age- associated changes in direct measures of abuse potential of these agen ts are missing. Future comparative systematic pharmacokinetic-pharmaco dynamic studies assessing pertinent outcome measures on abuse and depe ndence potential of commonly used psychoactive drugs are required to r esolve the ongoing controversy on risk factors for drug abuse and depe ndence in the elderly.