ALPRAZOLAM IN YOUNG AND ELDERLY MEN - SENSITIVITY AND TOLERANCE TO PSYCHOMOTOR, SEDATIVE AND MEMORY EFFECTS

This study was designed to determine whether age influences sensitivit y to alprazolam and/or rate of acute tolerance development to the effe cts of alprazolam. Three treatments were each separated by 4 weeks. Tw enty-five young (ages 22-35) and 13 elderly (ages 65-75) men received 2 mg of alprazolam/2 min i.v. Blood samples were obtained over 48 hr, and sedative, psychomotor and memory effects were assessed serially fo r 12 hr. Clearance was lower (P = .05) and elimination t([1/2]) was lo nger (P = .005) in the elderly, but area under the concentration curve to 12 hr and maximum concentration did not differ by age group. Maxim um impairment was greater in the elderly for all assessments. Mean EC5 0 values differed between the elderly (25.3 and 25.0 ng/ml) and the yo ung (39.8 and 36.5 ng/ml) on card sorting and digit symbol substitutio n, respectively (P < .001). Bolus treatment data were used to individu alize doses for the crossover of placebo and alprazolam; infusions wer e designed to maintain a plateau alprazolam concentration between 1 an d 9 hr. Alprazolam concentrations through 12 hr did not differ between the young and elderly. Median t([1/2]) for offset of effect for digit symbol substitution was 2.8 hr in the young and 4.9 hr in the elderly (P = .05). Therefore, aging decreases alprazolam clearance and increa ses sensitivity to effects of alprazolam through a mechanism other tha n pharmacokinetics; aging also decreases the rate of offset of effect of alprazolam. In addition, the data provide insight into the intensit y of initial effect as a determinant of rate of tolerance development.