To evaluate the kinetics and dynamics of lorazepam during administration as a bolus plus an infusion, using electroencephalography as a pharmacodynamic end point.
Nine volunteers received a 2-mg bolus loading dose of lorazepam, coincident with the start of a 2 μg/kg/hr zero-order infusion. The infusion was stopped after 4 hrs. Plasma lorazepam concentrations and electroencephalographic activity in the 13- to 30-Hz range were monitored for 24 hrs.
The bolus-plus-infusion scheme rapidly produced plasma lorazepam concentrations that were close to those predicted to be achieved at true steady state. Mean kinetic values for lorazepam were as follows: volume of distribution, 126 L; elimination half-life, 13.8 hrs; and clearance, 109 mL/min. Electroencephalographic effects were maximal 0.5 hr after the loading dose, were maintained essentially constant during infusion, and then declined in parallel with plasma concentrations after the infusion was terminated. There was no evidence of tolerance. Plots of pharmacodynamic electroencephalographic effect vs. plasma lorazepam concentration demonstrated counterclockwise hysteresis, consistent with an effect-site equilibration delay. This was incorporated into a kinetic-dynamic model in which hypothetical effect-site concentration was related to pharmacodynamic electroencephalographic effect via the sigmoid Emax model. The analysis yielded the following mean estimates: maximum electroencephalographic effect, 12.7% over baseline; 50% effective concentration, 13.1 ng/mL; and effect-site equilibration half-life, 8.8 mins.
Despite the delay in effect onset, continuous infusion of lorazepam, preceded by a bolus loading dose, produces a relatively constant sedative effect on the central nervous system, which can be utilized in the context of critical care medicine.
From the Departments of Pharmacology and Experimental Therapeutics (Drs. Greenblatt, von Moltke, and Shader and Mr. Harmatz) and Neurology (Dr. Ehrenberg and Ms. Corbett), Tufts University School of Medicine, Boston, MA; the Division of Clinical Pharmacology and the Department of Neurology (Dr. Ehrenberg and Ms. Corbett), New England Medical Center, Boston, MA; and Wyeth-Ayerst Research (Dr. Wallace), Radnor, PA .
Address requests for reprints to: David J. Greenblatt, MD, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111. E-mail: email@example.com
Supported, in part, by grants MH-34223, MH-01237, DA-05258, and RR-00054 from the Department of Health and Human Services and by a grant-in-aid from Wyeth-Ayerst Research, Radnor, PA.