The effect of age on the pharmacokinetics and pharmacodynamics of midazolam

Objective: We investigated the pharmacologic properties of midazolam with special regard to age using the electroencephalogram (EEG) as a measure of the hypnotic-sedative effect, Methods: Nine younger (24 to 28 years) and nine elderly (67 to 81 years) male volunteers received midazolam by a computer-controlled device, Two infusion cycles with linearly increasing target plasma levels (slope, 40 ng/mL/min for the younger subjects; 20 ng/mL/min for the elderly subjects) were administered until defined end points were attained (median EEG frequency <4 Hz and loss of responsiveness to acoustic stimuli), An EEG was recorded to quantitate the hypnotic effect, relating the: median frequency of the power spectrum to the plasma level by a sigmoid E-max model, including an effect compartment, Pharmacokinetic data were derived from arterial blood samples with use of a three-compartment model, Results: The total doses needed to reach the defined end points were 71 +/- 9 mg and 35 +/- 6 mg for the younger and elderly subjects, respectively (P < .001), Pharmacokinetic parameters were similar in both groups (clearance, 399 +/- 91 and 388 +/- 97 mL/min; steady-state volume of distribution, 85 +/- 22 and 104 +/- 11 L in young and elderly subjects, respectively). Pharmacodynamic data showed a large difference in half-maximum concentration (EC50; young subjects, 522 +/- 236 ng/mL; elderly subjects, 223 +/- 56 ng/mL; P < .05), a steep concentration-response curve, and distinct hysteresis, We found much interindividual variability iu the plasma concentrations necessary to achieve the clinical end points, regardless of age, Conclusions: These results suggest that the lower doses needed to reach sedation in the elderly subjects were attributable to a 50% decrease in EC50, not to changes in pharmacokinetics.