Clinical pharmacokinetics of anxiolytics and hypnotics in the elderly. Therapeutic considerations (Part I).
Anxiolytic and hypnotic drugs are extensively prescribed for elderly individuals throughout Western society. Old age may be associated with an altered clinical response to this class of compounds, and there is a considerable ethical and economic stake in understanding these changes so that therapy may be approached with a maximum likelihood of therapeutic benefit and a minimum risk of side effects. Old age may lead to altered pharmacokinetics of sedative-anxiolytic drugs, causing higher plasma concentrations (relative to young individuals) after single or multiple doses. By far the majority of the available scientific data refer to the benzodiazepines, which have become the most widely prescribed class of sedative-anxiolytic drugs. Although there is not complete consistency in the available data, the weight of evidence indicates that old age is associated with impaired clearance of the benzodiazepines which are biotransformed by microsomal oxidation (such as diazepam, desmethyldiazepam, desalkylflurazepam, bromazepam, alprazolam, triazolam and others). For those benzodiazepines metabolised mainly by glucuronide conjugation (oxazepam, lorazepam, temazepam) or nitroreduction (nitrazepam), there are minimal, if any, age-related decrements in clearance. Only in the case of triazolam is there direct evidence linking impaired clearance to enhanced clinical effects in the elderly. The logical suggestion that benzodiazepines biotransformed by conjugation or by nitroreduction may be safer for the elderly than those biotransformed by oxidation has not yet been directly validated. Reasonable epidemiological evidence has linked the use of long (versus short) half-life benzodiazepines (regardless of the specific metabolic pathway) with an increased incidence of adverse reactions such as confusion, falls and hip fractures in elderly persons. However, the decreased clearance and increased accumulation of the benzodiazepines in question are not clearly validated as the cause of the increased frequency of adverse reactions. Old age may also be associated with an increased intrinsic sensitivity to benzodiazepines; that is, enhanced pharmacodynamic response, relative to young individuals, at any given plasma or target organ concentration. This change in sensitivity may coexist with, or be independent of, alterations in pharmacokinetics. Altered benzodiazepine sensitivity has been documented both in the course of clinical use of benzodiazepines prior to endoscopy or cardioversion, and in placebo-controlled laboratory trials. Animal models of aging have validated an enhanced response to benzodiazepines as a consequence of impaired clearance, increased intrinsic sensitivity or both. However, many studies directly assessing benzodiazepine receptor affinity, density and function in aging animals have failed to identify significant age-related changes.(ABSTRACT TRUNCATED AT 400 WORDS)
Greenblatt
D J
DJ
Department of Psychiatry, Tufts University School of Medicine, Boston, Massachusetts.
Harmatz
J S
JS
Shader
R I
RI
D000368:Aged; D000375:Aging / Q000378:metabolism*; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics*
D014151:Anti-Anxiety Agents; D006993:Hypnotics and Sedatives