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

Ropivacaine (RP) is a new, long-acting, pure S-enantiomer amide local anesthetic. The physicochemical properties of ropivacaine and bupivacaine are similar. Ropivacaine is slightly less potent compared with bupivacaine. The onset time is short and the duration of action is long. The central nervous system toxicity and cardiotoxicity of ropivacaine is lower than that of bupivacaine. Because of the high pka and low lipid solubility of RP, it blocks nerve fibres responsible for pain transmission (A § and C fibres) rather than motor function (Aβ fibres) and produces markedly the separation of sensory and motor block , Ropivacaine has an intrinsic vasoconstricting property when used in low concentration. RP is metabolized by cytochrome P450 in the liver and metabolites are excreted by the kidneys. The condition of hepatic or renal function will affect the metabolism and excretion of RP. The pharmacodynamics and pharmacokinetics of ropivacaine used for epidural anesthesia in patients with renal dysfunction had been studied. This study is to investigate the pharmacodynamics and pharmacokinetics of ropivacaine used for epidural anesthesia in patients with hepatic dysfunction, and provide theoretical bases for rational administration of RP during clinical anesthesia. 1. Material and Method1.1 Material This study included 20 patients scheduled to undergo upper abdominal surgery under the combined anesthesia(ASA â… ^â…¢,aged 20⁵8 years). They were divided into two groups: hepatic dysfunction group ( group â…  , n=10)and normal hepatic function group (group â…¡, n=10). Epidural block was performed at the T_8⁹ interspace, all patients received 7.5mg · L^-1 RP 2mg · kg^-1 plus adrenaline 5 μg · kg^-1epidurally in 2min. After 30min, general anesthesia was induced with sodium hydroxybutyrate (60⁸0mg ? kg"1)> remifentanil Qug'kg"1) andatracurium (0.5 mg "kg"1), the trachea was intubated after muscular relaxation and was maintained with inhalation of nitrous oxide (1:1) -. a continuous iv infusion of remifentanil and intermittent iv boluses of atracurium.1.2 Monitoring of pharmacodynamics1.2.1 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 of total dose, and thereafter at 3 min intervals until fixation of sensory dermatomal level, motor block was assessed by using a modified Bromage scale, Assessments of motor block were performed at 3 min intervals after injection of total dose until 30min.1.2.2 Determination of hemodynamics during anesthesia SBP, DBP, MAP, HR, SpC>2 and ECG were monitored continuously during anesthesia and recorded at before injection, 10,20,30,60,90,120,150,180min after injection of RP, The adverse reactions were recorded during anesthesia.1.3 Determination of pharmacokinetics1.3.1 The concentration of RP in plasma was determined by high-performance liquid chromatography (HPLC).Chromatographic conditions: The chromatographic column of Hypersil Cig was used. The column temperature was 40 °C. the column pressure was 100-llOkg/cm. The mobile phase consisted of acetonitrile-water(17:83)(v/v) and the flow rate was 2.0 mL ? min"1. The detection wavelength was 210 nm. The sensitivity was 0.08AUFS. Internal standard method was used and internal standard was bupivacaine. quantitation was detected by peak areas with internal standard. The retention time of RP and bupivacaine were 7.8 and 16.1min,respectively.1.3.2 Collection of blood samplesApproximately 4ml blood samples were drawn into heparinized tubes at0,10,20,30,45,60,90,120,150,180,240,360,480,720min after injection. The blood samples were centrifuged at 3500 rpm for 10 min, plasma was separated and kept frozenat -20°C until further analysis. 1.3.3 Data analysisEstimation and calculation of pharmacokinetic parameters were performed using 3P97 software. The peak plasma concentration (Cmax) and the time needed to reach this maximum concentration (Tmax) were directly obtained from observed values. 1.4 Statistics analysisThe data were expressed as *.±s ,Statistical package (SPSS 10.0) was used for processing data, a =0.05 was considered that the difference has statistical significant. 2.Resultsl.Comparison of pharmacodynamic index between groups:two groups were similar with respect to epidural block characteristics. No significant difference in onset time of sensory and motor block ,time to maximum spead of sensory block ,the segment of spinal nerve block and degree of motor block at 30min after injection (p>0.05) . 2.Changes of index for hemodynamics: SBP, DBP, MAP at each time-points after injection decreased markedly in group I ,which was significantly different from the baseline (P<0.05). At 10,20,30 ,60,90min after injection, SBP. DBP and MAP decreased markedly in group II ,which was significantly different from the baseline (P<0.05), SBP, DBP, MAP at 120. 150, 180min after injection increase a bit in group II , there was no significant difference compared with the baseline (p>0.05) .Compared with group I , SBP, MAP at 120, 150min and DBP at 120min after injection increase significantly in group II (p<0.05 or p<0.01) . At each time-points after 20min, HR decreased markedly in group I ,which was significantly different from the baseline (P<0.05). At each time-points after 60min, HR decreased markedly in group II ,which was significantly different from the baseline (P<0.05).The incidence of hypotension was higher and Ephedrine dose used was larger than that in group I ,which had significant differences between two groups(P<0.05). 3. The study of the pharmacokinetics in anesthetized patients: The results were as follows: 1) the plasma concentrations of RP at 10¹50min relative time-point in two groups was similar and had no significant difference in two groups (p>0.05 ) ; at 180⁷20min relative time-point, the plasma concentrations of RP in group I was higher than that in group II and had significant difference (p<0.05 or p<0.01) . 2) The concentration-time curve in two groups were adequately fitted to two- compartment open model. 3) The pharmacokinetics parameters such as ti/2Ka, h/2°, hn?, Tmax, Qnax, AUQh,, CL, V, Kio, K12, K2i were 0.09+0.18 and 0.04±0.04h; 0.55±0.77and 0.30± 0.38h; 7.39+2.18 and 3.42±0.43h; 0.65±1.20 and 0.23+0.08h; 1.07+0.44 and 0.95 ±0.29 mg-L"1;5.85 + 4.06 and 3.22 ±1.06 mg-h-L1; 0.29 + 0.12 and 0.61 ±0.18 ^^^^±0.95 and 2.01 ±0.71 L-kg^O.H+O.W and 0.33±0.14 ^^^±2.28 and 2.04 ±2.91 h"1;1.87+1.00 and 3.15 ±2.35 h"\ respectively, in Group I and II of patients. The t^pof Group I were longer than that of Group II, AUCo^t were larger than that of Group II, CL/F and Kio were smaller than that of Group Hand had significant difference (p<0.05 or p<0.01). Conclusion1. Ropivacaine 7.5mg ? mL"1 used for epidural anesthesia in patients with hepatic dysfunction and normal hepatic function, two groups are similar with respect to sensory and motor block efficacy within 30 min after injection and have no significant difference(p>0.05).2. Ropivacaine 7.5mg ? mL"1 used for epidural anesthesia in patients with hepatic dysfunction, the hemodynamic stability is worse than that in patients with normal hepatic function. The incidence of hypotension is higher than that in patients with normal hepatic function., RP should be administered by small and divided doses . The monitoring of circulatory function should be more attention.3.Ropivacaine 7.5mg ? mL'1 used for 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 plasma concentrations of RP in patients with hepatic dysfunction increase markedly, the t^e prolongs markedly,CL reduces markedly, the metabolism of RP in patients with hepatic dysfunction slows markedly. During clinical anesthesia, the dose of RP should be reduced and the interval time of administration should be prolonged, the cumulative intoxication of RP should beprevented.