Effect Of Clonidine On Bupivacaine Clearance In Tunisian Patients: Population Pharmacokinetic Investigation.
H. Eljebari, N. Jebabli, S. Trabelssi, I. Salouage , E. Gaies, M. Lakhal, A. Klouz
Service de Pharmacologie Clinique Centre National de Pharmacovigilance, Tunis, Tunisia
Objectives: Combined lumbar and sciatic nerve blocks is associated with an increased plasmatic concentrations of bupivacaine, reaching sometimes toxic concentrations, with a large inter and intraindividual variability. Our team aimed to study the effects of clonidine, an α-2 mimetic known to affect systemic clearance, on bupivacaine pharmacokinetics when given as an adjuvant.
Methods: 62 patients with ASA scores I-II and aged between 18-102 years old were included in our study. Exclusion criteria were patients under 18 years and those contraindicated for plexus or nerve blocks. A dose of 120 mg of bupivacaine (for each nerve) was administered with 1 mcg/kg of clonidine (19 patients, group 1) or without clonidine (43 patients, group 2). We collected plasma samples, for each patient, before the blocks and 5, 10, 30, 45, 60, 120 and 240 minutes post-second injection. Time between both injection (lag time) was recorded. We used non linear mixed effects model (NONMEM) to analyse population pharmacokinetics of bupivacaine and determine the effect of clonidine association on bupivacaine absorption and systemic clearance.
Results: Time-concentration profiles were analyzed using a two compartments model with first order absorption, two input compartment, a central elimination and a flip-flop kinetic. We obtained a significant correlation between Bayesian-estimated and experimental observation (R² =0.7561, p< 0, 01). The most important covariates included body weight and age which affect respectively the volume of distribution and clearance. Moreover, our results show that clearance in the first group was significantly less than in group 2 (32.6 l/h and 60.74 l/h, respectively. p= 0.0429). No disparity in bupivacaine absorption was observed between two groups.
Conclusion: We have shown that bupivacaine absorption is fast in the two sites of injection, despite clonidine administration. Moreover, clonidine decreases bupivacaine clearance only. In fact, several studies have previously shown the effect of clonidine on local anaesthetics: Kopacz J (2001) reported that clonidine decrease lidocaine clearance in vivo, Mazoit JX (1996) demonstrated how clonidine decrases lignocaine peak plasma concentration when used as an adjuvant and Bruguerolle B (1996) detailed the decreasing effect of clonidine pre-treatment on bupivacaine metabolism in mice. Altogether, these data along with our results, shall allow us to better predict bupivacaine concentrations to administer in the presence or not of clonidine. Furthermore, our pharmacokinetic model will be used to determine an individual dosage for each patient and insure a better risk/benefit ratio.
References:
[1] Bernard Bruguerolle, Laurence Attolini, Anne Marie Lorec, Manon Gantenbein. Kinetics of Bupivacaïne After Clonidine Pretreatment in Mice. Can. J. Anesth. (1995) 4(5): 434-7.
[2] Jean Xavier Mazoit, Dan Benhamou, Yves Veillette and Kamran Samii. Clonidine and/or Adrenaline Decrease Lignocaine Plasma Peak Concentration After Epidural Injection. Br J Clin Pharmacol (1996) 42:242-5.
[3] Dan J. Kopacz, Chritopher M. Bernards. Effect of Clonidine on Lidocaine Clearance in Vivo. Anesthesiology (2001) 95:1371-6.
