Pharmacokinetic And Pharmacodynamic Study Of Dexmedetomidine In The Elderly Patients During Spinal Anesthesia

OBJECTIVES(1) To compare the pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine between the elderly and young patients during spinal anesthesia;(2) Establish a population pharmacokinetics model for dexmedetomidine in adult patients with spinal anesthesia, to investigate the factors affecting the population pharmacokinetics preliminarily.METHODSFifteen elderly subjects and nineteen young subjects with spinal anesthesia were enrolled in the present study followed by the inclusion/exclusion criteria. Demographic data, vital sign and adverse events were collected after a intravenous infusion with a loading dose of0.5μg·kg-1for10min and a maintenance dose of0.5μg-kg-1·h-1for50min. Series blood samples were collected before intravenous infusion and at10min、20min、30min、45min、1h (end of the infusion) after the infusion, then10min、20min、30min、45min、1h、1.5h、2h、3h、8h、10h after the end of the infusion. Plasma concentrations of dexmedetomidine were detected by HPLC-MS/MS method. Pharmacokinetic parameters were calculated by WinNolin software. Analysis of these data in two ways:(1) To compare the pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine between the elderly and young patients, and to analyze the PK-PD correlation. All the statistical analysis was performed with SPSS18.0software;(2) We used nonlinear mixed effects model (NONMEM) to construct population pharmaclkinects model, and investigate the factors affecting the population pharmacokinetics.RESULTS(1) The results of the study of the difference of pharmacokinetic and pharmacodynamic characteristics of dexmedetomidine between the elderly and young patients:In this study, the main pharmacokinetic parameters of dexmedetomidine in elderly patients were as follows:t1/2was2.19±0.60h; Tmax was20.53±22.30min; Cmax was775.79±377.44ng-L-1; AUC(0�'t) was991.87±221.22ng-h-L-1; AUC(0�'∞) was1037.24±217.77ng-h-L-1; CLwas46.30±10.67L-h-1; V was140.74±28.94LThe main pharmacokinetic parameters of dexmedetomidine in young patients were as follows:t1/2was2.20±0.48h; Tmax was19.47±18.09min; Cmax was701.03±397.14ng-L-1; AUC(0�'t) was1189.10±443.03ng-h-L-1; AUC(0�'∞) was1270.60±422.89ng-h-L-1; CL was53.89±15.82L-h-1; V was169.02±52.16LThere were no significant difference between the elderly and young subjects in major pharmacokinetic parameters, while CL showed a decline trend in elderly patients; Tmax and Cmax were different significantly between genders in elderly subjects, the other PK parameters did not show significant difference; While all the PK parameters were no significant difference between genders in young subjects.After intravenous infusion for1hour, BISAUCO-t and BISmin both were approaching between the elderly and young subjects. There were no significant difference between groups in the three parameters, while Tmin-BIs during one, two, three hours after the infusion showed a decreased by28%,15%and15%in elderly patients.SBP, DBP, HR and SpO2showed a significant difference in time dependent; SBP was different significantly between groups, while no significant difference for the D-value and different significantly for the time to begin declining of SBP. The observed values, D-values of DBP and HR were both no significant difference between groups, while the observed value and D-value of SpO2showed a significant difference.There were14drug-related adverse events in the young group, while26drug-related adverse events in the elderly group who was elevated by46%than the young group; And the ratio of intervention in the elderly group was68.75%(11/16),while36.84%(7/19) was in young group, and there was no significant difference between the two groups. SBP, DBP and HR showed no difference between groups before intervention, while a significant difference existed in SpO2between groups.All pharmacodynamic indices were no significant correlation with the main pharmacokinetic parameters (Cmax, AUC(0�'t), AUC(0�'∞)) of dexmetomidine.(2)The results of population pharmacokinetics of dexmedetomidine in the adult patients during spinal anesthesia:We established a population pharmacokinetics model for dexmedetomidine, which showed the phannacokinetics of dexmedetomidine were fitted in a three-compartment open model, and the major typical values of the population were:CL was0.83L-min-1, V1was28.40L, Q2was2.11L-min-1, V2was47.10L, Q3was0.43L-min-1, V3was45.00L;Population pharmacokinetic study showed that body weight can partcially interpretated the individual varibilities of CL and Q3,gender and total cholesterol interpretated for V2and Q3. The individual varibilities of CL and Q2were decreased by2.3%and16.8%. Then males showed a greater Q2than female, Q2in females were0.51times compared to males.CONCLUSIONS(1) After intravenous infusion with a loading dose of0.5μg·kg-1for10min and a maintenance dose of0.5μg·kg-1·h-1for50min, the CL of dexmedetomidine in elderly patients showed a declined trend, the clinical effect of the elderly was obvious, while showed significant adverse cffects. So we suggested a loading dose decrease when elderly patients used the dexmedetomidine injection.(2) Population pharmacokinetic model showed that body weight can partcially interpretated the individual varibilities of CL and Q3, gender and total cholesterol interpretated for V2and Q3, Q2in females were0.51times compared to males.