Pharmacokinetic and electroencephalographic study of intravenous diazepam, midazolam, and placebo.
Eleven healthy volunteers received a single intravenous dose of diazepam (0.15 mg/kg), midazolam (0.1 mg/kg), and placebo by 1-minute infusion in a double-blind, three-way crossover study. Plasma concentrations were measured during 24 hours after dosage, and the electroencephalographic (EEG) power spectrum was simultaneously computed by fast-Fourier transform to determine the percentage of total EEG amplitude occurring in the 13 to 30 Hz range. Both diazepam and midazolam had large volumes of distribution (1.2 and 2.3 L/kg, respectively), but diazepam's half-life was considerably longer (33 versus 2.8 hours) and its metabolic clearance lower (0.5 versus 11.0 ml/min kg) than those of midazolam. EEG changes were maximal at the end of the diazepam infusion and 5 to 10 minutes after midazolam infusion. Percent 13 to 30 Hz activity remained significantly above baseline until 5 hours for diazepam but only until 2 hours for midazolam. For both drugs, EEG effects were indistinguishable from baseline by 6 to 8 hours, suggesting that distribution contributes importantly to terminating pharmacodynamic action. The relationship of EEG change to plasma drug concentration indicated an apparent EC50 value of 269 ng/ml for diazepam as opposed to 35 ng/ml for midazolam. However, Emax values were similar for both drugs (+19.4% and +21.3%, respectively).
Greenblatt
D J
DJ
Department of Psychiatry and Medicine, Tufts University School of Medicine, Boston, MA.
Ehrenberg
B L
BL
Gunderman
J
J
Locniskar
A
A
Scavone
J M
JM
Harmatz
J S
JS
Shader
R I
RI
D000328:Adult; D003975:Diazepam / Q000097:blood / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D004569:Electroencephalography; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics*; D010919:Placebos; D012044:Regression Analysis
D010919:Placebos; D003975:Diazepam; D008874:Midazolam