PHARMACOKINETICS OF DROPERIDOL IN SURGICAL PATIENTS UNDER DIFFERENT CONDITIONS OF ANAESTHESIA

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1 Br. J. Anaesth. (),, -0 PHARACOKINETICS O DROPERIDOL IN SURGICAL PATIENTS UNDER DIERENT CONDITIONS O ANAESTHESIA K. A. LEHANN, A. VAN PEER,. IKONOAKIS, R. GASPARINI AND J. HEYKANTS Droperidol is a butyrophenone with neuroleptic properties used to supplement anaesthesia. It has pronounced antiemetic effects. Droperidol is often combined with volatile anaesthetics during balanced anaesthesia, or with the potent narcotic analgesics fentanyl or alfentanil in neuroleptanalgesia. Data on the pharmacokinetics of droperidol in man are scarce. Cressman, Plostnieks and Johnson [], performed a preliminary pharmacokinetic study in healthy, non-anaesthetized volunteers after an i.v. dose of mg of H-labelled droperidol. They determined the concentrations of droperidol by a radioassay after thin-layer chromatographic separation of droperidol. An elimination half-life of min was obtained but no values of the clearance or the volumes of distribution were reported. ore recently, ischler and colleagues [] studied the kinetics of droperidol using a specific radioimmunoassay method after an i.v. bolus injection of 0 (ig kg" in 0 anaesthetized patients. In the present study, the knowledge on the pharmacokinetics of droperidol was extended. The linearity of the kinetics of droperidol i.v. was determined using doses of, 0 and mg, and the possibility that volatile anaesthetics alter the kinetics of droperidol was also investigated. Because of the large patient population included, age and body weight were studied as possible factors influencing the variation in droperidol disposition. KLAUS A. LEHANN, PH.D.,.D. ; ICHAEL IKONOAKIS,.D.; Department of Anaesthesiology, University of Koln, Joseph-Stelzmann-Strasse, D-000 Koln, Germany. ROLAND GASPARINI, CHE.ENG. ; ACHIEL VAN PEER, PH.D. ; Jos HEYKANTS, PH.D.; Department of Drug etabolism and Pharmacokinetics, Janssen Pharmaceutica, Turnhoutseweg 0, B-0 Beerse, Belgium. Accepted for Publication: December,. SUARY The pharmacokinetics of droperidol were studied in surgical patients using doses of, 0 and mg i.v.. in association with neuroleptanalgesia or volatile anaesthetics. Plasma concentrations of droperidol were measured by radioimmunoassay. During neuroleptanalgesia, droperidol kinetics were linear over the dose range tested: the overall mean elimination ha/flife was min, \ld ss 0 litre and the plasma clearance ml min''. The kinetics of droperidol were similar under neuroleptanalgesia and under anaesthesia with halothane or enflurane. There was no significant correlation between the volume of distribution or clearance with age (- yr) or body weight (-0 kg). PATIENTS AND ETHODS orty-two patients (ASA grades III) scheduled to undergo elective abdominal, gynaecological or orthopaedic surgery participated after giving informed consent. Duration of surgery was at least 0 min. None of the patients had any significant hepatic or renal impairment. Individuals addicted to alcohol or drugs were excluded. All patients were premedicated with diazepam 0 mg by mouth on the evening before surgery and 0 mg i.m. h before surgery. Atropine 0. mg i.v. was followed by alcuronium mg, diazepam mg, hexobarbitone mg kg" and 0 % nitrous oxide in oxygen for min. Suxamethonium mg kg" was used to facilitate tracheal intubation. s were randomly assigned tofive groups. s of groups, and received a single dose of droperidol, 0 and mg i.v. respectively,

2 BRITISH JOURNAL O ANAESTHESIA TABLE I. Values of C, and X, in the bi- and triexponential equations fitting the individual droperidol plasma concentrations No. (ng ml-') C (ng ml- ) c (ng ml l ) (min" ) ;. (min- ) ;- (min- ) Droperidol mg 0 Droperidol 0 mg 0 Droperidol mg 0 Halothane Enflurane together with fentanyl ng kg" i.v. Artificial ventilation with a mixture of 0 % nitrous oxide in oxygen was used. Supplementary doses of fentanyl mg and alcuronium mg were added when necessary. groups and received droperidol 0 mg i.v. only but, initially, ventilation was with volatile anaesthetics:. vol % halothane or vol % enflurane in nitrous oxideoxygen. Ten minutes later, the halothane and enflurane concentrations were reduced to and. vol %, respectively. Heparinized -ml venous blood samples were drawn from the

3 DROPERIDOL PHARACOKINETICS contralateral arm in all patients, before administration of drugs and at,,, 0,, 0, 0,, 0, 0, 0, 0, 0, 00 and 0 min after administration. Blood samples were centrifuged and plasma was stored at 0 C until required for assay. Radioimmunoassay Droperidol plasma concentrations were measured by a radioimmunoassay kit for benperidol (Janssen Life Sciences Products, Beerse, Belgium), because of the better radiochemical stability of H-benperidol. The assay can be used for the determination of droperidol because of the favourable cross-reaction between both analogues, and metabolites of droperidol do not interfere. The method has been described in detail in the Appendix of the paper by ischler and colleagues []. All plasma samples were measured in duplicate. Intra-assay variability between duplicates was. (0.)%. Inter-assay variation was.% and. % for droperidol concentrations of 0 ng ml" and ng ml", respectively. Specific and nonspecific binding were. (0.) % and. (0.) %, respectively. Pharmacokinetic and statistical analysis Plasma concentration-time data were fitted to a bi- or triexponential equation (table I): C = Cfi-* Initial estimates of the parameters C, and { were obtained with the method of residuals []. inal estimates were calculated by the non-linear leastsquares regression program of SAS [] with the arquardt algorithm and weighting by the inverse square of the plasma concentration. The goodness of fit was judged by the ratio test [], standard deviations on parameters and scatter diagrams of the residuals between measured and predicted plasma concentrations. Plasma clearance (C), volumes of distribution (d ss, d area ), half-lives (J) and mean residence times (RT) were calculated by standard methods []. Analysis of variance [] was applied to d ss, Kd area, Cl, RT andtj to test for differences in these parameters over the studied dose range and effects of anaesthetics. The least significant difference test was used to compare pairs of means. All tests were two-tailed. Statistical significance was Time 00 0 IG.. (SE) droperidol plasma concentrations after i.v. administration of, 0 and mg to surgical patients under neuroleptanalgesia. Expressions describing the time courses of the mean droperidol plasma concentrations were: c = e- - ' +.e- OO ' +.e- 000 " ( mg); c = e- ' +.e- O ' +.e- 00 ' (0 mg); c = e- - l +.e- 00 " +.0e- 000 ' ( mg). declared at P < 0.0. Linear regression was performed to determine if there was any relationship between the pharmacokinetic parameters of droperidol and the factors age and body weight. All results are expressed as mean (). RESULTS After i.v. administration of droperidol its plasma concentrations decreased rapidly during the first min (fig. ). ollowing the distribution phase, concentrations decreased in parallel for the three doses. Plasma concentration-time profiles in some individuals were best characterized by a biexponential equation, whereas a triexponential model fitted the data more closely in others. The modelindependent kinetic parameters in the neuroleptanalgesia groups are shown in table II. There

4 00 BRITISH JOURNAL O ANAESTHESIA TABLE II. odel-independent pharmacokinetic parameters of droperidol, 0 and mg i.v. under neuroleplanalgesia Droperidol mg 0 Droperidol 0 mg 0 Droperidol mg 0 Sex Age (yr) 0. 0 Weight (kg) Kd" re» a (ml min" ) RT 0 0 n were no significant differences between the pharmacokinetic parameters at the different doses. Combination of the -, 0- and -mg data (n = 0) produced a pooled mean elimination half-life of + min, a plasma clearance of () ml min" and volumes of distribution of (0) litre (d ss ) and () litre (Kd area ). Volumes of distribution and clearance values were not dependent on age or body weight, as indicated by the low correlation coefficients (r < 0.). Concomitant use of volatile anaesthetics did not significantly alter droperidol volumes of distribution and clearance (table III). DISCUSSION The present study demonstrated the linearity, or dose-independence, of the kinetics of droperidol after single i.v. administration of, 0 and mgthree droperidol doses in the therapeutic range. The similarity of the mean droperidol plasma concentration-time curves at each of the doses suggests that the kinetics do not change as the dose increases. The insignificant differences in volumes of distribution and clearance confirm this independence of dose. urthermore, the half-life did not change as a function of dose. The kinetic

5 DROPERIDOL PHARACOKINETICS 0 TABLE III. odel-independent pharmacokinetic parameters of droperidol 0 mg under volatile anaesthesia Sex Age (yr) Weight (kg) Kd yd*"* a (ml min" ) RT T i Halothane Enflurane parameters obtained in this study were very similar to those previously reported by ischler and colleagues []. In contrast to the present study, they determined the kinetics of droperidol at only one dose0 ig kg", corresponding to a 0-mg total dose. The volatile anaesthetics halothane and enflurane did not significantly affect the kinetics of droperidol, probably because interindividual variability existed under each condition of anaesthesia. The clearance of droperidol 0 mg ranged from 00 to ml min" in neuroleptanalgesia, from 0 to ml min" in the halothane group and from to ml min" in the enflurane group. Thus the ranges of clearances do not appear to differ. The same considerations are relevant to the volumes of distribution and halflives. Normalizing the clearance and volumes of distribution for body weight did not decrease the interindividual variability. Coefficients of variation on weight-normalized parameters were as large as for the uncorrected parameters. Clearance and volumes of distribution were also not influenced by age, at least in the range - yr. In conclusion, droperidol i.v. in three therapeutic doses exhibited dose-linear kinetics under neuroleptanalgesia, and the kinetics were not greatly influenced by volatile anaesthetics. urther, the present study indicated that age and body weight of the normal population of adult surgical patients had no clinically relevant influence on the kinetics of droperidol. REERENCES. Cressman WA, Plostnieks J, Johnson PC. Absorption, metabolism and excretion of droperidol by human subjects following intramuscular and intravenous administration. Anesthesiology ; : -.. ischler, Bonnet, Trang H, Jacob L, Levron JC, laisler B, Vourc'h G. The pharmacokinetics of droperidol in anesthetized patients. Anesthesiology ; : -.. Gibaldi, Perrier D. Pharmacokinetics. nd Edn. New York: arcel Dekker, ; 0-, -.. SAS User's Guide Statistics. Cary: SAS Institute Inc.,.. Boxenbaum HG, Riegelman S, Elashoff R. Statistical estimations in pharmacokinetics. Journal of Pharmacokinetics and Biopharmaceutics ; : -.