右美托咪啶的基础与临床课件.ppt

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1、右美托咪啶的基础与临床天津医科大学总医院王国林2013-6内容内容一般介绍一般介绍作用机制、药代学、用药方法作用机制、药代学、用药方法文献借鉴文献借鉴我们的研究我们的研究一、一般介绍、作用机制一、一般介绍、作用机制背景背景o临床工作中镇静非常重要，但近年新药很少临床工作中镇静非常重要，但近年新药很少o一些常用药物特点一些常用药物特点nOpiate/benzodiazepine tolerance,efficacynPentobarbital agitation,durationnPropofol limited access in some jurisdictionsnKetamine eme

2、rgence reactions,toleranceo2-adrenoreceptor agonism 背景（背景（2 受体激动剂）受体激动剂）oPrototype agent is clonidineoMore recent applications in clinical practiceoSedationoBehavior disorders oDrug withdrawal oHypertensionoProblem hypotensionoSolution 2nd generation-2 specificity右美托嘧啶右美托嘧啶oPharmacologically active

3、D-isomer of medetomidineo1st synthesized in late 1980s,Phase 1 studies in early 1990s,clinical trials late 1990so 8-fold greater 2:1 selectivity than clonidinen1620:1 vs 200:1n清除半衰期较可乐定短：2-3 vs 8-12 hroFDA approved for ICU sedation in adults中枢作用机制中枢作用机制oLocus ceruleus（蓝斑）:nBrainstem center-modulates

4、 wakefulnessnMajor site for hypnotic actions(sedation,anxiolysis)nMediated via various efferent pathways:oThalamus and subthalamus cortexoNociceptive transmission via descending spinal tractsoVasomotor center and reticular formationoSpinal cord:nBinding to 2 receptors analgesia via release of substa

5、nce P 中枢作用机制中枢作用机制Dexmedetomidine Sedation central,G-proteins(inhibition)Analgesia spinal cord,Substance P机制机制 CENTRAL 2oPresynaptic receptors:nLocation:oSympathetic nerve endingsoNoradrenergic CNS neuronsnMechanism/action:oTransmembrane receptorsoCoupled to Go-and Gi-type G-proteinsn adenylate cycl

6、ase and cAMP formationnHyperpolarization(K+-channels)n Ca+conductance NE releaseCELLULAR MECHANISMCaCa+CaCa+CaCa+Decrease in Decrease in influx of Cainflux of Ca+Decrease in actionDecrease in actionpotential due topotential due tohyperpolarizationhyperpolarization 2 2A A 2 2ARARG Go oG Gk kK K+K K+K

7、 K+中枢外效应中枢外效应o高血压:nperipheral 1-agonism o心动过缓/低血压:n交感抑制-medullary VMCo 寒战:oDiuresis:n renin,vasopressin;ANP 呼吸系统影响呼吸系统影响oPromoted as having minimal respiratory depressing effectsn0.17%incidence on monogram oMost data suggests SaO2 and PaCO2 unaffected oNumerous reports during spontaneous ventilation

8、 二、药代动力学二、药代动力学药代参数药代参数o起效起效时间镇静静10min,镇镇痛痛20mino达达峰时间峰时间 60 90mino作用作用时间 2.5 4ho生物利用度生物利用度 肌注肌注：73%o蛋白蛋白结合合94%o代代谢肝肝酶 P450 葡萄糖醛酸葡萄糖醛酸o排泄排泄尿尿：95%、大便、大便：4%o分布半衰期分布半衰期 5mino消除半衰期消除半衰期 2 5h国外研究资料显示：在健康志愿者的研究中，国外研究资料显示：在健康志愿者的研究中，当静脉输注剂量范围为当静脉输注剂量范围为0.2-0.70.2-0.7 g g/kgh /kgh 时，时，呼吸率和氧饱和度保持在正常范围内，未见呼吸呼

9、吸率和氧饱和度保持在正常范围内，未见呼吸抑制。抑制。静脉输注后：静脉输注后：快速分布相的分布半衰期快速分布相的分布半衰期(t(t1/21/2)大约为大约为6 6分钟；分钟；终末清除半衰期终末清除半衰期(t(t1/21/2)大约为大约为2 2小时；小时；稳态分布容积稳态分布容积(Vss)(Vss)大约为大约为118118升。升。清除率大约为清除率大约为39L/h39L/h。药代参数药代参数静脉输注本品静脉输注本品0.2-0.70.2-0.7 g g /kgh/kgh直直到到2424小时右美托咪定呈现线性动力学小时右美托咪定呈现线性动力学参数负荷输注(min)/总输注时间(hrs)10min/12

10、hrs 10min/24hrs 10min/24hrs 35min/24hrs右美托咪定的目标浓度(ng/mL)和剂量(g/kg/hr)0.3/0.170.3/0.170.6/0.331.25/0.70t1/2,h1.780.302.220.592.230.212.500.61CL,L/h46.38.343.16.535.36.836.57.5Vss,L88.722.9102.420.393.617.099.617.8Avg Css,ng/mL0.270.050.270.050.670.101.370.20老年患者老年患者：右美托咪定的药代动力学特性不随年龄而改变。年轻右美托咪定的药代动力学特

11、性不随年龄而改变。年轻(18-(18-4040岁岁)、中年、中年(41-65(41-65岁岁)和老年和老年(6565岁岁)受试者中右美托咪受试者中右美托咪定的药代动力学无差异。定的药代动力学无差异。儿科患者儿科患者：右美托咪定在儿科患者的药代动力学特性未见详细数据，右美托咪定在儿科患者的药代动力学特性未见详细数据，但在欧美已广泛使用。但在欧美已广泛使用。肾功能损伤：肾功能损伤：严重肾功能损伤受试者严重肾功能损伤受试者(肌酐清除率：肌酐清除率：30mL/min)30mL/min)右美托咪右美托咪定的药代动力学定的药代动力学(Cmax(Cmax、TmaxTmax、AUCAUC、t1/2t1/2、C

12、LCL和和Vss)Vss)与健与健康受试者相比无明显差异康受试者相比无明显差异特殊患者应用特殊患者应用肝功能损伤肝功能损伤o在不同程度肝功能损伤受试者(Child-Pugh分类A、B或C)，右美托咪定的清除率值比健康受试者低，肝功能损伤患者或许需要考虑减少给药剂量肝功能损伤肝功能损伤Child-PughChild-Pugh分类分类A AB BC C平均清除率（正常人的%）74%64%53%药物用法药物用法负荷量负荷量1 1 g/kg g/kg iviv 10 min 10 min继而继而0.2 0.2-0.7 0.7 g/kg/hrg/kg/hr使用输注泵使用输注泵,不要推注不要推注 ！滴定药

13、效滴定药效肝肾功能不全、老年人适当减量肝肾功能不全、老年人适当减量Dex Dex 围术期给药方案围术期给药方案Example:70 kg patient.Assess BP,HR,volume status2 mL Dex in 48 mL 0.9%saline=200 ug/50 mL,or 4 ug/mlHypovolemicStart at 40 mL/hrStop load if HRUsual load:25 to 35 ug or 6 to 9 mL over 10-15 minMonitor BP/HRthroughoutIf bradycardia,infusionMainte

14、nance:0.2 to 0.7 ug/kg/hr 4 to 12 mL/hrVolume preload500 to 1000 cc LRNormovolemicDex=dexmedetomidine.三、相关文献三、相关文献o“自然睡眠自然睡眠”BISKasuya Yet al.The correlation between bispectral index and Kasuya Yet al.The correlation between bispectral index and observational sedation scale in volunteers sedated wit

15、h observational sedation scale in volunteers sedated with dexmedetomidine and propofol.Anesth Analg 2009;109:1811dexmedetomidine and propofol.Anesth Analg 2009;109:18111815.1815.DEXDEX对对ICUICU镇镇静死静死亡率亡率影响影响Pandharipande PP,et al.Effect of sedation with dexmedetomidinevs Pandharipande PP,et al.Effect

16、 of sedation with dexmedetomidinevs lorazepam on lorazepam on acute brain dysfunction in mechanically ventilated patientsacute brain dysfunction in mechanically ventilated patients:the MENDS randomized controlled trial.JAMA 2007;298:26442653.the MENDS randomized controlled trial.JAMA 2007;298:264426

17、53.脓毒症患者的预后脓毒症患者的预后（Sepsis vs no SepsisSepsis vs no Sepsis）DEX与术后谵妄、与术后谵妄、POCDoDEX镇静机制不同，类似“自然”睡眠的镇静是否与术后谵妄、POCD有关ICUICU镇静后谵妄发生率比较镇静后谵妄发生率比较Pandharipande PP,et al.Effect of sedation with Pandharipande PP,et al.Effect of sedation with dexmedetomidinevs lorazepam on acute brain dysfunction in dexmedet

18、omidinevs lorazepam on acute brain dysfunction in mechanically ventilated patients:the MENDS randomized controlled mechanically ventilated patients:the MENDS randomized controlled trial.JAMA 2007;298:26442653.trial.JAMA 2007;298:26442653.Riker RR,et al.Dexmedetomidine vs midazolam for sedation of cr

19、itically ill patients:a randomized trial.JAMA 2009;301:489499右美右美或咪或咪啶安啶安定对定对ICUICU镇静镇静患谵患谵妄的妄的比较比较ANESTHESIOLOGY.2009 NOV;111(5):1075-84.1.306例患者随机分成例患者随机分成 右美右美 0.1-0.7 g/（kg-1 h-1)或吗啡或吗啡 10-70 g/（kg-1 h-1)2.观察指标：谵妄观察指标：谵妄3.Dexmedetomidine reduced the duration but not the incidence of delirium aft

20、er cardiac surgery with effective analgesia/sedation,less hypotension,less vasopressor requirement,and more bradycardia versus morphine regimen.心脏手术后给右美或吗啡镇痛对老年患者心脏手术后给右美或吗啡镇痛对老年患者谵妄的影响谵妄的影响 AIRWAY CATASTROPHES CURR OPIN ANAESTHESIOL.2009,6 1.Modern anesthetic medications such as dexmedetomidine and

21、 proven techniques such as awake fiberoptic intubation can be used to safely treat these difficult patients.MINERVA ANESTESIOL.2009;75(11):668-71.1.This article describes the case of a patient with severe chronic obstructive pulmonary disease and severe carotid stenosis,who underwent carotid stentin

22、g under monitored anesthesia care with dexmedetomidine.2.Only one episode of bradycardia and hypotension was observed,and this was successfully treated with glycopyrrolate.右美托咪啶用于合并严重慢阻肺行颈动脉右美托咪啶用于合并严重慢阻肺行颈动脉支架术患者的镇静支架术患者的镇静.INT J OBSTET ANESTH.2009;18(4):403-7.1.A 35-year-old,41-kg parturient at 35

23、 weeks of gestation with spinal muscular atrophy presented for cesarean section.2.Dexmedetomidine was administered intravenously,total dose 1.84g/kg over 38 minutes,followed by fiberoptic endotracheal intubation.Dexmedetomidine was then discontinued and general anesthesia was induced.3.The baby was

24、delivered 68 minutes after the dexmedetomidine infusion 4.During administration of dexmedetomidine,maternal heart rate,blood pressure and oxygen saturation remained stable.5.Apgar scores at 1 and 5 min were 6 and 8.右美用于合并脊髓性肌萎缩右美用于合并脊髓性肌萎缩型患者型患者剖剖宫产清宫产清醒醒气气管管插插管管ANESTH ANALG.2009 SEP;109(3):745-53.1

25、.Dexmedetomidine provided an acceptable level of anesthesia for MRI sleep studies in children with OSA,producing a high yield of interpretable studies of the patients native airway.2.The need for artificial airway support during the MRI sleep study was significantly less with dexmedetomidine than wi

26、th propofol.3.Dexmedetomidine may be the preferred drug for anesthesia during MRI sleep studies in children with a history of severe OSA and may offer benefits to children with sleep-disordered breathing requiring anesthesia or anesthesia for other diagnostic imaging studies.右美右美VSVS丙泊酚用于小儿对丙泊酚用于小儿对

27、MRIMRI对睡眠的研究对睡眠的研究In addition it posses sympatholytic and antinociceptive effects that allow hemodynamic stability during surgical stimulation.Different from most of clinically used anesthetics,dexmedetomidine brings about not only a sedative-hypnotic effect via an action on a single type of recepto

28、rs,but also an analgesic effect and an autonomic blockade that is beneficial in cardiac risk situations.Several studies have demonstrated its safety,although bradycardia and hypotension are the most predictable and frequent side effects.CURR DRUG TARGETS.2009 AUG;10(8):687-95CURR DRUG TARGETS.2009 A

29、UG;10(8):687-95全麻中右美的应用全麻中右美的应用ANESTHESIOLOGY.2009;111(5):1111-9.1.This is the first study showing that dexmedetomidine added to ropivacaine increases the duration of sensory blockade in a dose-dependent fashion in rats.2.The findings are an essential first step encouraging future efficacy studies i

30、n humans.右美加入罗哌卡因剂量依赖性延长对大鼠右美加入罗哌卡因剂量依赖性延长对大鼠坐骨神经阻滞作用时间坐骨神经阻滞作用时间o延长局部麻醉药对外周神经阻滞的时间延长局部麻醉药对外周神经阻滞的时间o抑制外周神经兴奋性传导抑制外周神经兴奋性传导Brummett C,et al.Perineural dexmedetomidine added to Brummett C,et al.Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increase in the duration of ropivac

31、aine causes a dose-dependent increase in the duration of thermal antinociception in sciatic nerve block in rat.thermal antinociception in sciatic nerve block in rat.Anesthesiology 2009;111:11111119.Anesthesiology 2009;111:11111119.Abdllah FW,et al:A&A,2013Abdllah FW,et al:A&A,2013Blaudszun G,et al:A

32、nesthesiology,2012,112:1316Blaudszun G,et al:Anesthesiology,2012,112:1316与吗啡剂量进行换算与吗啡剂量进行换算ACTA ANAESTHESIOL SCAND.2009,26 The combination of dexmedetomidine and hypothermia improved short-term neurologic outcome compared with the control groupwhereas the combination therapy provided comparable neur

33、oprotection with either of the two therapies alone.右美加低温在大鼠脑缺血再灌损伤的保护作右美加低温在大鼠脑缺血再灌损伤的保护作用用MASUI.2009;58(8):987-9.1.A 64-year-old woman with hypertension,diabetes mellitus and asymptomatic first degree AV block underwent low anterior resection of the rectum.2.Anesthesia was induced with propofol,vec

34、uronium bromide and remifentanil and maintained with nitrous oxide in oxygen,propofol and remifentanil.3.After the operation,the patient was admitted to the intensive care unit under general anesthesia with propofol and remifentanil.In addition,dexmedetomidine was given without loading dose.4.The EK

35、G changed from first degree AV block to second degree AV block followed by complete AV block and finally cardiac arrest.5.As soon as we performed heart massage,sinus rhythm appeared.6.We should be careful in giving dexmedetomidine to a patient with AV block.心跳骤停一例报告（发生于心跳骤停一例报告（发生于ICUICU）四、我们的研究四、我们

36、的研究分组：分组：A.A.假手术组假手术组 B.B.假手术假手术+右美托咪啶右美托咪啶10g10g组组C.C.脓毒症组脓毒症组 D.D.脓毒症脓毒症+右美托咪啶右美托咪啶2.5g2.5g组组 E.E.脓毒症脓毒症+右美托咪啶右美托咪啶5g5g组组 F.F.脓毒症脓毒症+右美托咪啶右美托咪啶10g10g组组 观察指标：观察指标：不同时间点动物的生存率、心率、不同时间点动物的生存率、心率、动脉血压、动脉血动脉血压、动脉血pHpH（pHapHa）、）、动脉血氧分压（动脉血氧分压（PaOPaO2 2）、动脉血）、动脉血二氧化碳分压（二氧化碳分压（PaCOPaCO2 2）、乳酸）、乳酸及心肺肝肾等组织病

37、理变化，及及心肺肝肾等组织病理变化，及动物血清动物血清IL-6IL-6、IL-10IL-10、SODSOD及及MDAMDA水平。水平。右美托咪啶对脓毒症大鼠的保护效应及右美托咪啶对脓毒症大鼠的保护效应及其机制探讨其机制探讨心肺肝肾病理心肺肝肾病理心、肺心、肺ShamShamSham+Dex10Sham+Dex10CLPCLPCLP+Dex2.5CLP+Dex2.5CLP+Dex5CLP+Dex5CLP+Dex10CLP+Dex10心肺肝肾病理心肺肝肾病理肝、肾肝、肾ShamShamSham+Dex10Sham+Dex10CLPCLPCLP+Dex2.5CLP+Dex2.5CLP+Dex5CLP

38、+Dex5CLP+Dex10CLP+Dex10细胞因子、抗氧化因子改变细胞因子、抗氧化因子改变o右美托咪啶右美托咪啶可以改善脓毒症大鼠的心右美托咪啶右美托咪啶可以改善脓毒症大鼠的心率、血压、血气、乳酸及组织病理指标，提高生率、血压、血气、乳酸及组织病理指标，提高生存率。存率。o这一作用是通过降低血清这一作用是通过降低血清IL-6水平，增加血清水平，增加血清SOD水平，降低血清水平，降低血清MDA水平，从而减少组织水平，从而减少组织损伤而实现的。损伤而实现的。结论结论右美托咪啶节约全麻及阿片类镇痛药右美托咪啶节约全麻及阿片类镇痛药o77例患者，4565岁，全麻 腹部手术o麻醉诱导：咪唑安定 0.

39、05-0.1 mg/kg，苏芬太尼0.3-0.5g/kg，依托咪酯 0.2-0.3 mg/kg，顺卡 0.15 mg/kg o右美：诱导时开始给 0.5g/kg 前半小时，然后维持 0.4g/kg/hr，缝皮是停止o麻醉维持丙泊酚、苏芬太尼，顺卡，BIS4060顺卡用量、肌松恢复时间顺卡用量、肌松恢复时间苏芬太尼用量、苏芬太尼用量、右旋美托咪定复合丙泊酚用于胃镜检查术的临床观察右旋美托咪定复合丙泊酚用于胃镜检查术的临床观察（我们的研究）（我们的研究）o60例患者随机分成右旋美托咪定复合丙泊酚与丙泊酚组o泵注右旋美托咪定0.6g/kg/hr10min，静注丙泊酚直至睫毛反射消失,呼之不应后停止泵

40、注右美并置入内镜检查o单纯注射丙泊酚o视患者术中体动，呛咳情况追加丙泊酚 o所有病例均能顺利完成操作o开始检查时 BIS值下降幅度大于P组(43.6 vs 49.7)oMAP、HR、SpO2下降幅度小于P组o两组手术时间及苏醒时间无差异o丙泊酚总量、不良反应发生率均少于P 组（75.1 vs 132.3）右旋美托咪定复合丙泊酚用于胃镜检查术的临床观察右旋美托咪定复合丙泊酚用于胃镜检查术的临床观察 (我们的研究）我们的研究）不同剂量右美托咪啶对下腹部手术患者七氟醚不同剂量右美托咪啶对下腹部手术患者七氟醚MACBAR影响影响o研究右美对七氟醚抑制50%下腹部手术切皮诱发应急反应的MACo60例患者

41、，置入喉罩，分别给0.4gkg-1h-1至1.2gkg-1h-1o结果：随右美剂量增加，可减少七氟醚MAC,但从0.8gkg-1h-1增加到1.2gkg-1h-1时，MAC不再降低，提示有封顶效应付志强付志强 等，中华麻醉学杂志，等，中华麻醉学杂志，20112011，31:67767931:677679小结小结oGoal is to establish+maintain adequate drug conc at effect site to produce desired effect oDex can help optimize anesthesia via:nSedation,analgesia+sympathetic activitynAttenuation of stress response+HRnSmooth emergence+tracheal extubationoUnique mechanism of action on natural sleep pathway permits sedation+analgesia w/o respiratory depressionoAdjunct agent of choice for many surgeries谢谢！谢谢！