Jaap Vuyk

Pharmacodynamics in the elderly

An overview is given of the influence of age on the pharmacodynamics of drugs used during general and locoregional anaesthesia. For some groups of agents a distinct separation into age-related changes in the pharmacokinetics and pharmacodynamics is possible, whereas for others the literature indicates only that responses in the elderly are enhanced. I start with an overview of the influence of age on cardiovascular and neuroendocrine function and include a short account of the state-of-the-art in pharmacodynamic modelling. The physiological changes that occur with age are associated with an increased sensitivity to the effects of anaesthetic agents. For most intravenous hypnotic agents, and inhalational anaesthetic agents, the increased sensitivity with age is, at least in part, explained by altered pharmacodynamics. For opioids and local anaesthetics applied for blockade of the central nervous system, the pharmacodynamic involvement is not always clear. For neuromuscular blocking agents, pharmacodynamic involvement appears to be nearly absent in the reduced dose requirements seen with age--so that the latter appear to be caused by altered pharmacokinetics. Future studies, using pharmacokinetic-pharmacodynamic (PK-PD) mixed-effects modelling, should further explore this area to obtain clinically applicable data for improving our insight into the delivery of anaesthetics to the elderly and improving the quality of anaesthesia in this fast-growing population.

Mixed-Effects Modeling of the Influence of Midazolam on Propofol Pharmacokinetics

BACKGROUND: The combined administration of anesthetics has been associated with pharmacokinetic interactions that induce concentration changes of up to 30%. Midazolam is often used as a preoperative sedative in advance of a propofol-based anesthetic. In this study, we identified the influence of midazolam on the pharmacokinetics of propofol. METHODS: Eight healthy male volunteers were studied on two occasions in a random crossover manner. During Session A, volunteers received propofol 1 mg/kg in 1 min followed by an infusion of 2.5 mg · kg−1 · h−1 for 59 min. During Session B, in addition to this propofol infusion scheme, a target-controlled infusion of midazolam (constant Ct: 125 ng/mL) was given from 15 min before the start until 6 h after termination of the propofol infusion. Arterial blood samples for blood propofol and plasma midazolam concentration analysis were taken until 6 h after termination of the propofol infusion. Nonlinear mixed-effects models examining the influence of midazolam and hemodynamic variables on propofol pharmacokinetics were constructed using Akaike criterion for model selection. RESULTS: In the presence of midazolam (Cblood: 224.8 ± 41.6 ng/mL), the blood propofol concentration increased by 25.1% ± 13.3% compared with when propofol was given as single drug. Midazolam (Cblood: 225 ng/mL) reduced propofol Cl1 from 1.94 to 1.61 L/min, Cl2 from 2.86 to 1.52 L/min, and Cl3 from 0.95 to 0.73 L/min. Inclusion of mean arterial blood pressure further improved the propofol pharmacokinetic model. CONCLUSIONS: Midazolam reduces the metabolic and rapid and slow distribution clearances of propofol. In addition, a reduction in mean arterial blood pressure is associated with propofol pharmacokinetic alterations that increase the blood propofol concentration.

Propofol reduces the distribution and clearance of midazolam.

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 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 CT: 0.6 or 1.0 &mgr;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 Akaikes information-theoretic criterion for model selection. RESULTS: In the presence of a mean blood propofol concentration of 1.2 &mgr;g · mL−1, the plasma midazolam concentration was increased by 26.9% ± 9.4% compared with midazolam given as a single drug. Propofol (Cblood: 1.2 &mgr;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.

Circulatory model of vascular and interstitial distribution kinetics of rocuronium: a population analysis in patients

The time-course of the neuromuscular blocking effect of rocuronium depends on circulatory mixing and the rate of distribution into the interstitial space. In order to quantitatively evaluate these processes, a physiologically meaningful model of distribution kinetics based on circulatory transport and interstitial diffusion, was fitted to rocuronium disposition data in 10 patients using a population approach. Information on cardiac output and circulatory mixing was obtained from the kinetics of indocyanine green (ICG), which was injected simultaneously with rocuronium. As a compromise between physiological reality and parameter identifiability, the organs of the systemic circulation were lumped into a heterogeneous subsystem, described by an axially distributed model of extravascular diffusion. Diffusion into the interstitial space determines the rate of rocuronium distribution in the body (diffusional time constant 89xa0min). The resulting whole body distribution kinetics depends both on cardiac output and on the apparent permeability surface area product (0.16xa0l/min). The analysis of the ICG data revealed that heterogeneity of blood transit time through the systemic circulation decreased and that cardiopulmonary volume increased, respectively, with cardiac output. The approach should be useful for studying the effect of disease states on distribution kinetics of drugs.

Erratum to: Prospective Clinical and Pharmacological Evaluation of the Delcath System’s Second-Generation (GEN2) Hemofiltration System in Patients Undergoing Percutaneous Hepatic Perfusion with Melphalan

Introduction nPercutaneous hepatic perfusion (PHP) with melphalan is an effective treatment for patients with hepatic metastases, but associated with high rates of bone marrow depression. To reduce systemic toxicity, improvements have been made to the filtration system. In pre-clinical studies, the Delcath System’s GEN2 filter was superior to the first-generation filters. In this clinical study, we analysed the pharmacokinetics and toxicity of PHP using the new GEN2 filter.