Pharmacodynamics And Pharmacokinetics Of Levobupivacaine Used For Epidural Anesthesia In Patients With Hepatic Dysfunction

Levobupivacaine is another pure enantiomers structure that its chemical name is S-(-)-1-Metabolites-butyl - N - (2, 6-methylphenyl) - piperidine - 2-carboxamide hydrochloride salt. It have been shown that levobupivacaine widely distributed, eliminating slowly In vivo studies, and its cardiovascular system (Cardiovascular system. CVS) and central nervous system toxicity (Central nervous system. CNS) is less than that of bupivacaine; inherently vasoactive contraction, when epidural injecting, LEVO's plasma concentration-time curve coincide with the two-compartment open model. LEVO's elimination according to first-order rate process. In vivo , its protein binding rate is 97%, principal binding protein is a ₁-acid glycoprotein. LEVO is principly metabolized by cytochrome P450 ( CYP1A2 and CYP3A4) in the liver and most of metabolites are excreted by the kidneys. metabolism of LEVO can be influenced by the condition of hepatic or renal function and the application of the liver enzyme inducers and inhibitors. pharmacokinetics and pharmacodynamics of the LEVO have been reported in patients with renal dysfunction abroad and have been not reported in patients with hepatic dysfunction. This study is to investigate the pharmacodynamics and pharmacokinetics of LEVO used for epidural anesthesia in patients with hepatic dysfunction, and provide theoretical bases for rational administration of LEVO during clinical anesthesia.1 Material and Method1.1 MaterialThis study included 20 patients scheduled to undergo upper abdominal surgery under the combined anesthesia(ASA I～III, aged 20～60 years). They were divided into two groups: hepatic dysfunction group ( group I, n=10)and normal hepatic function group (group II, n=10). Preoperative blood clotting tests were normal, liver metabolism is not obviously affected by the use of drugs. The operation time is more than four hours or the need for blood transfusion, is not included. Surgical operation for common bile duct stones, cholecystectomy, ampulla space tumour laparotomy, hepatic hemangioma resection, gastric cancer radical resection or other. The subclavian vein puncture was done under local anesthesia tube for blood samples before anesthesia. Anesthesia method was epidural anesthesia compounding general anesthesia, epidural block was performed at the T_8-9 interspace, all patients received 7.5mg·L^-1 LEVO 1.8mg·kg^-1 plus adrenaline 5μg·kg^-1 epidurally in 1.5min. After 30min, sodium hydroxybutyrate (60～80 mg·kg^-1) , remifentanil (2μg·kg^-1) and succinylcholine (1～1.5 mg·kg^-1) were iv infusion, the trachea was intubated after muscular relaxation and was maintained with iv infusion of remifentanil and intermittent iv boluses of atracurium and sodium hydroxybutyrate when necessary.1.2 Monitoring of pharmacodynamics12.1 Sensory and motor block Sensory block was determined using a blunt point needle to test for loss of sensation to pin-prick. Assessments of sensory were performed at 1 min intervals in first 10 min after injection, and thereafter at 3 min intervals until fixation of sensory dermatomal level. It were recorded that onset time of sensory block(min), the maximum cephalic spread, time to maximum block (min), segmental of spinal never blocked (seg) . Motor block was assessed by using a modified Bromage scale, assessments of motor block were performed at 3 min intervals after injection until 30min, onset time of motor block(min) and bromage score at 30min after injection were recorded.1.2.2 Determination of hemodynamics during anesthesia SBP, DBP, MAP, HR, SPO₂ and ECG were monitored continuously during anesthesia and recorded before injection and at time points 5,10, 20, 30, 45, 60, 90,120,180, 240min after injection of LEVO. The adverse reactions, the quantity of bleeding, fluid infusion and urine were recorded during anesthesia.1.3 Determination of pharmacokinetics 1.3.1 The concentration of LEVO in plasma was determined by high-performance liquid chromatography (HPLC). Chromatographic conditions: The chromatographic column of Hypersil C18 was used. The column temperature was 40℃, the column pressure was 100-110kg/cm. The mobile phase consisted of methanor-water- ethylamine- glacial acetic acid (300:100:0.4:0.2)(v/v) and the flow rate was 1.2 ml·min^-1. The detection wavelength was 210 nm. The sensitivity was 0.08AUFS. Eexternal standard method was used, quantitation was detected by peak areas. Determination of plasma endogenous substances did not interfere with the assay, the retention time of LEVO is 10.3min.13.2 Collection of blood samples Approximately 3ml blood samples were drawn into heparinized tubes at time points 0, 5, 10, 20, 30, 45, 60, 90,120,180, 240, 360, 600, 840min after injection. The time point 1440min was added in group I. The blood samples were centrifuged at 3500 rpm for 10 min, plasma was separated and kept frozen at -20℃until further analysis.1.3.3 Data analysis Drawing concentration-time curve and calculation of pharmacokinetic parameters were performed using 3P97 software Compiled by Pharmacological Institute of Mathematics in China, choosing the best-compartment model. The peak plasma concentration (Cmax) and the time needed to reach this maximum concentration (Tmax) were directly obtained from observed values, plasma concentration-time curve area (Area under the curve AUC_0→t) was calculated by trapezoidal method.1.4 Statistics analysisStatistical package (SPSS 10.0) was used for processing data, the numerical data variables expressed as x|-±s, using two independent samples t-test (or t 'test), rank sum test and analysis of variance; the classified variables was used chi square test, Fisher's exact test of probabilities and rank sum test; bilateral a =0.05 was considered that the difference was statistical significant.2 Results2.1 general stateThere were no significant differences about patient characteristics and surgical details between two groups(P>0.05). Total serum bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, glutamyl transferase enzyme alkaline phosphatase in group I increased significantly compared with group II, the difference was statistically significant (P<0.05).2.2 pharmacodynamic index2.2.1 Sensory block and motor block Two groups were similar with respect to epidural block characteristics. There were no significant difference in onset time of sensory block (4.26±1.71 vs 4.42±1.8) min, the maximum cephalic spread, (T_3.70±1.20 vs T _3.90±1.45), time to maximum block (15.47±2.80 vs 15.46±3.03)min, segmental of spina never blocked(13.30±2.19 vs 12.80±1.93)seg, onset time of motor block(17.50±3.94 vs 18.13±3.48)min and bromage score at 30min after injection (P>0.05) .2.2.2 Changes of index for hemodynamics: HR: HR changes in the two groups were at first accelerate soon after slow down, which were significantly faster at 5, 10min after injection, the difference was statistically significant compared with pre-injection (P <0.05), HR began to decline at other time points In Group I. But difference was not significant compared with pre-injection (P> 0.05). HR from 45 min to 180 min after injection in group II slow down significantly, the difference was statistically significant compared with pre-injection (P <0.05). From 10 to 90min after injection, SBP, DBP and MAP decreased markedly in group I, which was significantly different from the baseline (P<0.05), from 10 to 60min after injection SBP, DBP and MAP decreased markedly in group II, which was significantly different from the baseline (P<0.05), SBP, DBP and MAP at other time points after injection increase a bit in both group, there was no significant difference compared with the baseline (p>0.05) . Compared with group II, DBP, MAP from 10 min after injection were lower in group I, but there was no significantly different (P>0.05).2.2.3 Adverse reactions During Anesthesia The incidence of hypotension and bradycardia was higher, ephedrine and atropine dose used was larger in group I than that in group II, but there were no significant differences between two groups (P>0.05). 2.3 The study of the pharmacokinetics in anesthetized patients:The results were as follows: the plasma concentrations of LEVO at 5～90min relative time-point in group I was lower than that in group II, the plasma concentrations of LEVO at 120～240min relative time-point in group I was higher than that in group II, but there was no significant difference in two groups (P>0.05) ; at 360～840min relative time-point, the plasma concentrations of LEVO in group I was higher than that in group II and there was significant difference (P<0.05 or P<0.01) . The plasma concentrations of LEVO of halves of the patients in group I could be still measured 1440 min after epidural injection.The concentration-time curve in two groups were adequately fitted to two-compartment open model. The pharmacokinetics parameters such as t_1/2ka, t_1/2a, t_1/2β, T_max,C_max, AUC_0→t, Cl/F, V/F, K₁₀, K₁₂, K₂₁ were (0.05±0.06 and 0.09±0.05 )h; (0.41±0.27 and 0.22±0.13 )h; (7.79±2.68 and 4.63±1.11)h; (0.33±0.24 and 0.34±0.22 )h; (0.72±0.26 and 0.79±0.19) mg·L^-1; (4.02±1.84 and 2.79±0.65)mg·h·L^-1; (0.46±0.24 and 0.58±0.16) L·h^-1; (3.07±1.54 and 1.72±0.96) L/kg^-1; (0.17±0.10 and 0.40±0.20 ) h^-1; (0.08±1.85 and 2.64±3.32) h^-1; (3.08±6.22 and 2.63±2.83 ) h^-1, respectively, in Group I and II of patients. The V/F and t_1/2β of Group I were larger than that of Group II, K₁₂ and K₁₀ were smaller than that of Group II and there was significant difference (P<0.05 or P<0.01). AUC_0→t of Group I were larger than that of Group II, the CL of group I were smaller than that of Group II, but there was no significant difference (P>0.05).3 Conclusion1. Levobupivacaine 7.5mg·ml^-1 used for thoracic epidural anesthesia in patients with hepatic dysfunction and normal hepatic function, two groups are similar with respect to sensory and motor block efficacy and there were no significant difference.2. Levobupivacaine 7.5mg·ml^-1 and 1.8 mg·mkg^-1 used for thoracic epidural anesthesia in patients with hepatic dysfunction, the hemodynamic stability is worse than that in patients with normal hepatic function. The monitoring and administration of circulatory function should be more attention.3. Levobupivacaine 7.5mg·mL^-1 used for thoracic epidural anesthesia in patients with hepatic dysfunction and normal hepatic function, the concentration-time curve are all adequately fitted to two-compartment open model.The terminal plasma concentrations of LEVO increase markedly and the metabolism of LEVO slows markedly in patients with hepatic dysfunction. During clinical anesthesia, the dose of LEVO should be reduced and the interval time of administration should be prolonged, the cumulative intoxication of should be prevented.