Pharmacokinetics of pethidine during anaesthesia and patient-controlled analgesic therapy

The pharmacokinetics of pethidine has been studied in 12 patients subjected to major intraabdominal surgery. Pethidine and norpethine were analyzed in plasma samples collected during anesthesia and during patient-controlled administration of small intravenous doses of pethidine in the early postoperative period. A second study on the pharmacokinetics of pethidine was performed on the 3-5th postoperative day. The plasma clearance of pethidine was significantly lower in the preoperative study (8.9 +/- 1.8 ml x kg x min-1) compared with the postoperative study (12.0 +/- 3.1 ml x kg x min-1). Volume of distribution (Vd) was not significantly influenced, being 4.25 +/- 1.72 l x kg-1 peroperatively and 3.14 +/- 0.84 l x kg-1 postoperatively. Elimination half-life decreased from 5.91 +/- 3.57 h peroperatively to 3.25 +/- 1.40 h postoperatively. The kinetics of pethidine in the postoperative study agreed with pethidine kinetics reported for healthy volunteers. The fraction of unbound pethidine decreased from 0.26 +/- 0.1 peroperatively to 0.18 +/- 0.1 postoperatively. Norpethidine, a metabolite of pethidine, has been claimed to be responsible for several side effects like respiratory depression and convulsions during pethidine therapy. No side effect attributable to norpethidine was observed in the self-administration period. Norpethidine plasma concentrations did not exceed 500 ng/ml. The altered pethidine pharmacokinetics during anesthesia and the ensuing postoperative hours and the interindividual differences of the disposition of the drug strongly suggest that pethidine should be given by individualized regimens in surgical patients.