Effects of Aging

Many changes in the pharmacodynamics and pharmacokinetics of drug treatment occur with aging, yet some may be relatively unimportant (Greenblatt et al. 1998). The ratio of fat to lean body mass increases, and cardiac output and hepatic blood flow decrease. There may be further changes associated with medical illness. But the clinical importance of these changes is usually relatively minor because of the dramatic variability of hepatic metabolism. Age-related changes in metabolism vary with the isoenzymes involved. The activity of the CYP3A4 pathway does slow with age (von Moltke et al. 1995). Most studies of the tertiary amines, such as imipramine, suggest that concentrations of these drugs are increased somewhat in older individuals (Abernathy et al. 1985; Benetello et al. 1990; Furlanut and Benetello 1990). Alternatively, most studies of nortriptyline (Bertilsson 1979; Katz et al. 1989; Smith et al. 1980; Young et al. 1984; Ziegler and Biggs 1977) and desipramine (Abernathy et al. 1985; Nelson et al. 1985, 1995) indicate that ratios of blood level to dosage of these drugs are relatively unaffected by aging, suggesting that the 2D6 isoenzyme is not similarly affected. In addition, the relationship of nortriptyline and desipramine plasma concentrations to therapeutic effects appears to be relatively similar in younger and older adults (Katz et al. 1989; Nelson et al. 1985, 1995; Young et al. 1988). Renal clearance of the hydroxy metabolites does decrease with age (Nelson et al. 1988a; Young et al. 1984). As a result, concentrations of hydroxynortriptyline may be substantially elevated in older patients.

In children, the clearance of tricyclic compounds is increased. Half-lives of imipramine are shorter and ratios of desmethylimipramine to imipramine are higher, consistent with more rapid metabolism

(Geller 1991; Rapoport and Potter 1981). Alternatively, a study of desipramine in children found that the clearance of both desipramine and hydroxydesipramine was increased so that hydroxy metabolite-parent compound ratios were not elevated (Wilens et al. 1992).

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