The Effect Of Adrenaline On Pharmacodynamics And Pharmacokinetics Of Levobupivacaine For Epidural Anesthesia

Levobupivacaine(LEVO) is a new,long-acting amide local anesthetic.It is a pure enantiomer that its chemical name is S-(-)-1-Butyl-N-(2,6-dimethylphenyl)-2-piperidinecarboxamide.Molecular biology research on drug action indicated that the absorption,distribution,metabolism,excretion and the binding with targets include receptor,enzyme,ion channel of drugs show stereoselectivity.So enantiomers of chiral drugs often show different characteristics of pharmacology and toxicology.The physicochemical properties and anaesthesia potence of LEVO and Bupivacaine(BUPI) appear similar.The central nervous system toxicity and cardiotoxicity of LEVO is less than that of BUPI.The pharmacodynamics of LEVO had been studied in some countries,while the study on the pharmacokinetic of LEVO was less.Until now the effect of adrenaline on the pharmacokinetic and pharmacodynamics of LEVO for epidural anesthesia has not been reported.Therefore,the aim of this study was to investigate the effects of adrenaline on the pharmacodynamics and pharmacokinetics for epidural anesthesia of LEVO 0.75%,and to provide theoretical bases for rational administration of LEVO during clinical anesthesia.1 Material and Method1.1 Subjects and ProceduresThis study included 60 patients scheduled to undergo elective popliteal vein valve replacement surgery and cleaning operation of knee jiont by arthroscope under epidural anesthesia(ASAⅠ～Ⅱ,aged30～61).They were randomly divided into three groups:Groupâ… (7.5mg·ml^-1LEVO group,n=20),Groupâ…¡(7.5mg·ml^-1 LEVO with 2.5μg·ml^-1 adrenaline group,n=20),Groupâ…¢(7.5mg·ml^-1 LEVO with 5μg·ml^-1 adrenaline group,n=20).36 of the 60 patients were eligible to be included into the pharmacokinetic analysis.Patients who had a history of known hypersensitivity to amide local anaesthetics,severe respiratory,renal,hepatic or cardiac disease, hematopathy,disturbance of blood coagulation or seizure disorders were excluded. Patients whose body mass index(BMI) was more than 30kg·m^-2 were also excluded.The epidural puncture was performed with the patient in the left-lateral position,at the L_1-2 interspace.Patients received LEVO 1.8mg·kg^-1 with 2.5μg·kg^-1 or 5μg·kg^-1 adrenaline or without adrenaline epidurally respectively.At first,with the bevel of a needle pointing caudalward,a test dose of 3ml 0.5%LEVO was injected.Three minutes later,if there was no sign of subarachniod or intravascular injection,other 7.5mg·ml^-1 LEVO was injected in 1.5 minutes.1.2 Assessments of pharmacodynamics1.2.1 Sensory and motor blockSensory block was assessed using a blunt point needle to test for loss of pain to pin-prick in the left anterior axillary line.Assessments were made every 1min during the first 10 minutes after the epidural injection,subsequently every 3 minutes until fixation of sensory dermatomal level and after that every 30 minutes until total recovery from analgesia.The onset time,time until maximal cephalad spread,the maximal cehpalad spread level and time until total recovery from analgesia were observed and recorded.Motor block was evaluated every 3 minutes after the epidural injection by using a modified Bromage scale.The onset time,maintenance time,and maximum degree of motor block were observed and recorded.The effect of anesthesia was assessed.1.2.2 Determination of hemodynamics during anesthesiaSBP,DBP and HR were monitored continuously and values before and at time points 5,10,20,30,45,60,90,120,180,240min after injection of LEVO were recorded. The adverse reactions,the quantity of bleeding and fluid infusion were recorded during anesthesia.1.3 Determination of pharmacokinetics1.3.1 Analysis of the concentrations of LEVO in plasma(high-performance liquid chromatography,HPLC)Chromatographic conditions:The chromatographic column of Kromasil C18 was used.The column temperature was 40℃,the column pressure was 100-110kg·cm^-1. The mobile phase consisted of methanol,water,ethylamine and glacial acetic acid (volume ratio 300:100:0.4:0.2) and the flow rate was 0.9ml·min^-1.The detection wavelength was 230nm.The sensitivity was 0.08AUFS.Internal standard method was used and internal standard was Lidocaine(LIDO).Quantitation was detected by peak areas.Determination of plasma endogenous substances did not interfere with the assay. The retention time of LEVO and LIDO were 9.6min and 4.5min respectively.1.3.2 Blood sampleVenous blood samples were collected at time points 0,5,10,20,30,45,60,90, 120,180,240,360,480,600,840,1440min after injection.The samples were stored on ice and centrifuged for 10 minutes at 3500rpm and 2℃within 4 hours.The plasma was transferred into tubes and stored at -40℃.1.3.3 Data analysisThe pharmacokinetic parameters were determined from plasma concentration -time data with 3P97 software package.The peak plasma concentration(Cmax) and the time to reach peak concentration(Tmax) were directly obtained from observed values.1.4 Statistics analysisStatistical package(SPSS 13.0) was used for processing data,the numerical data variables expressed as(?)+s,using ANOVA,LSD and rank sum test;the classified variables was used chi square test,Fisher's exact test of probabilities and rank sum test; bilateral P=0.05 was considered that the difference was statistical significant.2 Results2.1 General stateThere were no significant difference in age,height,weight,injection volume, surgery duration,blood loss,liquid infusion and index for hepatic and renal fuction among three groups(P＞0.05).2.2 Pharmacodynamic parameters2.2.1 Sensory block,motor block and effect of anesthesiaThere were no significant difference in the onset time of sensory block (6.69±0.95 vs 6.83±1.44 vs 6.64±0.85) min,the time until maximal cephalad spread (14.90±5.27 vs 15.71±4.64 vs 13.01±3.85) min,the maximal cehpalad spread level (T4.10±1.07 vs T4.25±0.85 vs T4.25±1.00),the time until total recovery from sensory block(461.80±88.68 vs 455.50±82.24 vs 452.50±72.00) min,the onset time of motor block(12.25±3.88 vs 12.57±2.98 vs 11.05±2.19)min,the time until complete recovery from motor block(285.50±64.83 vs 288.45±71.66 vs 240.31±57.29) min and the parameter characterizing the intensity of motor block(Bromage scores) among three groups(P＞0.05).There were no significant difference in the effect of anesthesia among three groups(P＞0.05).2.2.2 Changes of index for hemodynamicsIn three groups,SBP and DBP deceased gradually after injection.SBP at 30min,45min in Groupâ… and Groupâ…¢,and DBP at 30min in Groupâ…¡after injection decreased markedly,which was significantly different from the baseline(P＜0.05).HR at 10min in Groupâ…¡and 5min,10min in Groupâ…¢after injection were significantly different from those of pre-injection(P＜0.05).There were no significant difference in SBP,DBP and HR among three groups(P＞0.05).2.2.3 Adverse reactions during anesthesiaFew adverse reactions occurred in three groups.Hypotension,bradycardia,chill was common.There were no significant differences among three groups(P＞0.05).2.3 Pharmacokinetic parametersThe plasma concentrations of LEVO at time points from 10min to 240min in Groupâ… and Groupâ…¢were higher than that in Groupâ…¡.The plasma concentrations of LEVO at 20min,60min,120min in Groupâ… were higher than that in Groupâ…¢after epidural injection(P＜0.05).The concentration-time curves of three groups were adequately fitted to a two-compartment open model after the curve and model fitting by 3P97 software package.The pharmacokinetic parameters such as t_1/2Ka,t_1/2α,t_1/2β,T_max,C_max,AUC_0→t,CL,V,K₁₀,K₁₂,K₂₁ were(0.07±0.06 vs 0.05±0.07 vs 0.11±0.04)h,(0.27±0.29 vs 0.30±0.29 vs 0.28±0.25)h,(9.85±5.83 vs 9.95±5.03 vs 9.09±3.51)h,(0.20±0.18 vs 0.24±0.25 vs 0.24±0.09)h,(2.17±1.03 vs 1.07±0.40 vs 1.52±0.39) mg·L^-1,(10.76±1.92 vs 8.77±3.27 vs 10.74±5.16) mg·h·L^-1, (0.18±0.05 vs 0.24±0.09 vs 0.20±0.07)L·h^-1,(0.83±0.49 vs 1.63±0.68 vs 0.75±0.38)L·kg^-1,(0.32±0.23 vs 0.17±0.10 vs 0.30±0.15)h^-1,(1.20±1.51 vs 1.25±1.45 vs 2.77±1.84)h^-1,(0.54±0.40 vs 0.86±0.65 vs 1.20±0.96) h^-1 respectively in patients of three groups.C_max,K₁₀ in Groupâ… and Groupâ…¢were larger than that in Groupâ…¡,â…¤in Groupâ…¡was larger than that in Groupâ… and Groupâ…¢, K₁₂ in Groupâ…¢and Groupâ… was larger than that in Groupâ…¡(P＜0.05). 3 Conclusions3.1 7.5mg·ml^-1 LEVO used for lumber epidural anesthesia,the onset time of sensory block is short,the duration is long,the analgesia effect is satisfactory,while the onset time of motor block is slower and the duration of is short.The addition of adrenaline with different concentration dose not markedly improve the pharmacodynamic characteristics of 7.5mg·ml^-1 LEVO.3.2 During the epidural anesthesia of 7.5mg·ml^-1 LEVO with or without adrenaline,the hemodynamic is stable.The three treatment are well tolerated by patients.All the incidence of adverse reaction are low.And all the patients are safe.3.3 The addition of adrenaline with different concentration decreses the plasma concentration and C_max of LEVO and delays the elimination of LEVO.The addition of adrenaline 2.5μg·ml^-1 to 7.5mg·ml^-1 LEVO may cause marked decrease of the plasma concentration,therefore,it may be a useful strategy to reduce the risk of toxicity and adverse reaction,and increase the safety of epidural anesthesia.