The pharmacology of intravenous infusions of lorazepam differs significantly from that of midazolam in critically ill patients. This results in significant delays in emergence from sedation with lorazepam as compared with midazolam when administered for ICU sedation.
Emergence time from sedation with propofol in ICU patients varies with the depth of sedation, the duration of sedation, and the patient's body habitus. Maintaining a light level of sedation ensures a rapid emergence from sedation with long-term propofol administration.
Despite previous reports of high interindividual variability in midazolam pharmacodynamics in patients in the surgical intensive care unit, these cross-validation results suggest that, when midazolam is administered using a target-controlled infusion device, the level of sedation can be predicted within 1 sedation score in 88% of patients based on the target midazolam concentration and the time since the conclusion of the anesthetic.
The intersubject variability and predictability of the three-compartment pharmacokinetic model are similar to those of other intravenous anesthetic drugs. This multicenter study did not confirm previous studies of exceptionally large variability of midazolam pharmacokinetics when used for sedation in intensive care settings.
1. The rates of diazepam (DZ) metabolism to the primary metabolites 3-hydroxydiazepam, 4'-hydroxydiazepam and nordiazepam were studied in vitro using rat hepatic microsomes and hepatocytes. 4'-hydroxydiazepam had the largest intrinsic clearance (Vmax/Km ratio, CL(int)) in both microsomes and hepatocytes representing 49 and 70% of total metabolism respectively. Whereas the contribution of 3-hydroxydiazepam was similar in both systems (21-24%), the N-demethylation pathway was greater in microsomes (27%) than hepatocytes (9%). 2. The pharmacokinetics of DZ were determined in vivo using the intraportal route to avoid blood flow limitations due to the high clearance of DZ. No dose dependency was observed in either clearance or steady state volume of distribution, which were estimated to be 38 ml/min/SRW (where SRW is a standard rat weight of 250 g) and 1.3 L/SRW respectively. Blood binding of DZ was concentration independent, the unbound fraction being 0.22. 3. Scaling factors were used to relate the in vitro CL(int) to the in vivo unbound clearance. Hepatocytes (123 ml/min/SRW) produced a more realistic prediction for the in vivo value (174 ml/min/SRW) than microsomes (41 ml/min/SRW). This situation is believed to arise from the quantitative differences in the three metabolic pathways in the two in vitro systems. It is speculated that end product inhibition is responsible for reduced total metabolism in microsomes whereas hepatocytes operate kinetically in a manner close to in vivo.
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