The effect of age on the pharmacokinetics and pharmacodynamics of midazolam

Clin Pharmacol Ther. 1999 Jun;65(6):630-9. doi: 10.1016/S0009-9236(99)90084-X.


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 Emax 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 in 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aging / metabolism*
  • Blood Pressure / drug effects
  • Dose-Response Relationship, Drug
  • Electroencephalography / drug effects*
  • Female
  • Heart Rate / drug effects
  • Humans
  • Hypnotics and Sedatives / administration & dosage
  • Hypnotics and Sedatives / blood
  • Hypnotics and Sedatives / pharmacokinetics*
  • Hypnotics and Sedatives / pharmacology*
  • Infusions, Intravenous
  • Male
  • Midazolam / administration & dosage
  • Midazolam / blood
  • Midazolam / pharmacokinetics*
  • Midazolam / pharmacology*
  • Respiration / drug effects
  • Volunteers


  • Hypnotics and Sedatives
  • Midazolam