J Vuyk1. 1. Department of Anaesthesiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. j.vuyk@lumc.nl
Abstract
This manuscript describes the pharmacokinetic and pharmacodynamic interactions between propofol and the opioids. PHARMACOKINETIC INTERACTIONS: In vitro studies describe the reduced clearance of opioids in the presence of propofol, midazolam and etomidate due to interaction at the cytochrome P450 enzyme system. In vivo, however, pharmacokinetic interaction studies by mixed effects modelling predominantly focus on haemodynamic factors affecting distribution and elimination of concomitantly administered agents. In the presence of propofol the elimination clearance and rapid and slow distribution clearance of alfentanil is decreased. Consequently, plasma alfentanil concentrations are increased in the presence of propofol. Vice versa alfentanil reduces propofol elimination clearance and increases the deep volume of distribution. PHARMACODYNAMIC INTERACTIONS: Propofol and the opioids interact in a synergistic manner for various clinical end points. The magnitude of interaction is similar between the various opioids and hypnotic agents, taken into consideration the differences in potency between the opioids. CLINICAL INTERPRETATION OF PK/PD INTERACTIONS: A. Speed of induction. Using PK/PD interaction data speed of induction can be optimised. Of importance are the magnitude of PD interaction between propofol and the various opioids, the rate of administration and the time to peak effect of the agents involved. B. Haemodynamic stability. In ASA 1-2 patients the opioid induced hypnotic dose reduction is not associated with an increased haemodynamic stability of induction of loss of consciousness. In elderly patients or patients known with cardiovascular instability high opioid-low propofol anaesthesia may be associated with improved haemodynamic stability during induction of anaesthesia, however, no data are available regarding this yet. C. Speed of recovery. Time to return of consciousness after termination of propofol-opioid infusions of various duration can be reduced using optimal propofol-opioid concentrations. In general, optimal propofol target concentrations to assure this are 5 micrograms/ml in the presence of fentanyl, 3.5 micrograms/ml in the presence of alfentanil and sufentanil and 2.5 micrograms/ml in the presence of remifentanil. D. Spontaneous respiration. For single agents some data allow proper targeting of a drug concentration that is associated with adequate intraoperative respiration. However, no data exist on drug interactions regarding the respiratory depressant effects of hypnotic-opioid combinations. CONCLUSION: The proper exploration and use of published pharmacokinetic and pharmacodynamic interaction data allows the clinical anaesthesiologist to optimise the clinical administration of propofol and the various opioids when given alone or in combination.
This manuscript describes the pharmacokinetic and pharmacodynamic interactions between propofol and the opioids. PHARMACOKINETIC INTERACTIONS: In vitro studies describe the reduced clearance of opioids in the presence of propofol, midazolam and etomidate due to interaction at the cytochrome P450 enzyme system. In vivo, however, pharmacokinetic interaction studies by mixed effects modelling predominantly focus on haemodynamic factors affecting distribution and elimination of concomitantly administered agents. In the presence of propofol the elimination clearance and rapid and slow distribution clearance of alfentanil is decreased. Consequently, plasma alfentanil concentrations are increased in the presence of propofol. Vice versa alfentanil reduces propofol elimination clearance and increases the deep volume of distribution. PHARMACODYNAMIC INTERACTIONS: Propofol and the opioids interact in a synergistic manner for various clinical end points. The magnitude of interaction is similar between the various opioids and hypnotic agents, taken into consideration the differences in potency between the opioids. CLINICAL INTERPRETATION OF PK/PD INTERACTIONS: A. Speed of induction. Using PK/PD interaction data speed of induction can be optimised. Of importance are the magnitude of PD interaction between propofol and the various opioids, the rate of administration and the time to peak effect of the agents involved. B. Haemodynamic stability. In ASA 1-2 patients the opioid induced hypnotic dose reduction is not associated with an increased haemodynamic stability of induction of loss of consciousness. In elderly patients or patients known with cardiovascular instability high opioid-low propofol anaesthesia may be associated with improved haemodynamic stability during induction of anaesthesia, however, no data are available regarding this yet. C. Speed of recovery. Time to return of consciousness after termination of propofol-opioid infusions of various duration can be reduced using optimal propofol-opioid concentrations. In general, optimal propofol target concentrations to assure this are 5 micrograms/ml in the presence of fentanyl, 3.5 micrograms/ml in the presence of alfentanil and sufentanil and 2.5 micrograms/ml in the presence of remifentanil. D. Spontaneous respiration. For single agents some data allow proper targeting of a drug concentration that is associated with adequate intraoperative respiration. However, no data exist on drug interactions regarding the respiratory depressant effects of hypnotic-opioid combinations. CONCLUSION: The proper exploration and use of published pharmacokinetic and pharmacodynamic interaction data allows the clinical anaesthesiologist to optimise the clinical administration of propofol and the various opioids when given alone or in combination.