This thesis describes the day to day interaction between propofol and midazolam as encountered in every day practice. The direct interaction of premedication given to patients before surgery has... Show moreThis thesis describes the day to day interaction between propofol and midazolam as encountered in every day practice. The direct interaction of premedication given to patients before surgery has profound implications. The propofol induction dose can be decreased with respect to the target BIS. Besides the interaction mechanisms of propofol and midazolam, the pharmacological backgrounds of propofol-opioid interactions are given. The future perspectives of PK-PD modeling and the use of additional informative techniques are given in the last chapter. Show less
BACKGROUND: Midazolam, at sedative levels, increases blood propofol concentrations by 25%. We evaluated the reverse interaction and determined the influence of propofol on the pharmacokinetics of... Show moreBACKGROUND: Midazolam, at sedative levels, increases blood propofol concentrations by 25%. We evaluated the reverse interaction and determined the influence of propofol on the pharmacokinetics of midazolam. METHODS: Eight healthy male volunteers were studied on 2 occasions in a random crossover manner. During session A, volunteers received midazolam 0.035 to 0.05 mg . kg(-1) IV for 1 minute followed by an infusion of 0.035 to 0.05 mg . kg(-1) . h(-1) for 59 minutes. During session B, in addition to this midazolam infusion scheme, a target-controlled infusion of propofol (constant C-T: 0.6 or 1.0 mu g . mL(-1)) was given from 15 minutes before the start until 6 hours after termination of the midazolam infusion. Arterial blood samples for propofol and midazolam concentration analysis were taken until 6 hours after termination of the midazolam infusion. Nonlinear mixed-effect models examining the influence of propofol and hemodynamic variables on midazolam pharmacokinetics were constructed using Akaike's information-theoretic criterion for model selection. RESULTS: In the presence of a mean blood propofol concentration of 1.2 mu g . mL(-1), the plasma midazolam concentration was increased by 26.9% +/- 9.4% compared with midazolam given as a single drug. Propofol (C-blood: 1.2 mu g . mL(-1)) reduced midazolam central volume of distribution from 5.37 to 2.98 L, elimination clearance from 0.39 to 0.31 L . min(-1), and rapid distribution clearance from 2.77 to 2.11 L . min(-1). Inclusion of heart rate further improved the pharmacokinetic model of midazolam. CONCLUSIONS: Propofol reduces the distribution and clearance of midazolam in a concentration-dependent manner. In addition, inclusion of heart rate as a covariate improved the pharmacokinetic model of midazolam predominantly through a reduction in the intraindividual variability. (Anesth Analg 2010; 110: 1597 -606) Show less
