右美托咪啶的基础和临床讲解培训课件

1、内容一般介绍作用机制、药代学、用药方法文献借鉴我们的研究内容一般介绍一、一般介绍、作用机制一、一般介绍、作用机制背景临床工作中镇静非常重要，但近年新药很少一些常用药物特点Opiate/benzodiazepine tolerance, efficacyPentobarbital agitation, durationPropofol limited access in some jurisdictionsKetamine emergence reactions, tolerance2-adrenoreceptor agonism 背景临床工作中镇静非常重要，但近年新药很少背景（2 受体激动剂）

2、Prototype agent is clonidineMore recent applications in clinical practiceSedationBehavior disorders Drug withdrawal HypertensionProblem hypotensionSolution 2nd generation - 2 specificity背景（2 受体激动剂）Prototype agent is右美托嘧啶Pharmacologically active D- isomer of medetomidine1st synthesized in late 1980s,

3、 Phase 1 studies in early 1990s, clinical trials late 1990s 8-fold greater 2:1 selectivity than clonidine1620:1 vs 200:1清除半衰期较可乐定短：2-3 vs 8-12 hrFDA approved for ICU sedation in adults右美托嘧啶Pharmacologically active 中枢作用机制Locus ceruleus（蓝斑）: Brainstem center - modulates wakefulnessMajor site for hypno

4、tic actions (sedation, anxiolysis)Mediated via various efferent pathways:Thalamus and subthalamus cortexNociceptive transmission via descending spinal tractsVasomotor center and reticular formationSpinal cord: Binding to 2 receptors analgesia via release of substance P中枢作用机制Locus ceruleus（蓝斑）: 中枢作用机

5、制Dexmedetomidine Sedation central, G-proteins (inhibition) Analgesia spinal cord, Substance P 中枢作用机制Dexmedetomidine Sedatio机制 CENTRAL 2Presynaptic receptors:Location:Sympathetic nerve endingsNoradrenergic CNS neuronsMechanism/action:Transmembrane receptorsCoupled to Go- and Gi- type G-proteins adeny

6、late cyclase and cAMP formationHyperpolarization (K+-channels) Ca+ conductance NE release机制 CENTRAL 2Presynaptic recCELLULAR MECHANISMCa+Ca+Ca+Decrease in influx of Ca+Decrease in actionpotential due tohyperpolarizationa2Aa2ARGoGkK+K+K+CELLULAR MECHANISMCa+Ca+Ca+中枢外效应高血压:peripheral 1-agonism 心动过缓/低血

7、压:交感抑制- medullary VMC 寒战:Diuresis: renin, vasopressin; ANP 中枢外效应高血压:右美托咪啶的基础和临床讲解培训课件呼吸系统影响Promoted as having minimal respiratory depressing effects0.17% incidence on monogram Most data suggests SaO2 and PaCO2 unaffected Numerous reports during spontaneous ventilation 呼吸系统影响Promoted as having minim二

8、、药代动力学二、药代动力学药代参数起效时间镇静10min,镇痛20min达峰时间 60 90min作用时间 2.5 4h生物利用度 肌注：73%蛋白结合94%代谢肝酶 P450 葡萄糖醛酸排泄尿：95%、大便：4%分布半衰期 5min消除半衰期 2 5h药代参数起效时间镇静10min,镇痛20min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0.2-0.7g /kgh 时，呼吸率和氧饱和度保持在正常范围内，未见呼吸抑制。静脉输注后：快速分布相的分布半衰期(t1/2)大约为6分钟；终末清除半衰期(t1/2)大约为2小时；稳态分布容积(Vss)大约为118升。清除率大约为39L/h

9、。药代参数国外研究资料显示：在健康志愿者的研究中，当静脉输注剂量范围为静脉输注本品0.2-0.7 g /kgh直到24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/12hrs10min/24hrs10min/24hrs35min/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 , h1.780.302.220.500.61CL, L/h46.38.343.16.535.36.836.57.5Vss, L88.722.9102.420.39

10、3.617.099.617.8Avg Css, ng/mL0.270.050.270.050.670.101.370.20静脉输注本品0.2-0.7 g /kgh直到24小时右美老年患者：右美托咪定的药代动力学特性不随年龄而改变。年轻(18-40岁)、中年(41-65岁)和老年(65岁)受试者中右美托咪定的药代动力学无差异。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，但在欧美已广泛使用。肾功能损伤：严重肾功能损伤受试者(肌酐清除率：30mL/min)右美托咪定的药代动力学(Cmax、Tmax、AUC、t1/2、CL和Vss) 与健康受试者相比无明显差异特殊患者应用老年患者：特殊

11、患者应用肝功能损伤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Child-Pugh分类ABC平均清除率（正常人的%）74%64%53%肝功能损伤在不同程度肝功能损伤受试者(Child-Pugh分药物用法负荷量1 g/kg iv 10 min继而0.2 - 0.7 g/kg/hr使用输注泵, 不要推注 ！滴定药效肝肾功能不全、老年人适当减量药物用法负荷量1 g/kg iv 10 minDex 围术期给药方案Example: 70 kg patient. Assess BP, HR, volu

12、me 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, infusionMaintenance: 0.2 to 0.7 ug/kg/hr 4 to 12 mL/hrVolume preload500 to 1000 cc LRNormovolemicDex=de

13、xmedetomidine.Dex 围术期给药方案Example: 70 kg pati三、相关文献三、相关文献“自然睡眠” BISKasuya Yet al. The correlation between bispectral index and observational sedation scale in volunteers sedated with dexmedetomidine and propofol. Anesth Analg 2009; 109:18111815.“自然睡眠”Kasuya Yet al. The correDEX对ICU镇静死亡率影响Pandharipand

14、e PP, et al. Effect of sedation with dexmedetomidinevs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007; 298:26442653.DEX对ICU镇静死亡率影响Pandharipande PP脓毒症患者的预后（Sepsis vs no Sepsis）脓毒症患者的预后（Sepsis vs no Sepsis）DEX与术后谵妄、POCDDEX镇静机制

15、不同，类似“自然”睡眠的镇静是否与术后谵妄、POCD有关ICU镇静后谵妄发生率比较DEX与术后谵妄、POCDDEX镇静机制不同，类似“自然”睡Pandharipande PP, et al. Effect of sedation with dexmedetomidinevs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007;298:26442653.Pandharipande PP, et al. E

16、ffecRiker RR,et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009;301:489499右美或咪啶安定对ICU镇静患谵妄的比较Riker RR,et al. DexmedetomidinANESTHESIOLOGY. 2009 NOV;111(5):1075-84.306例患者随机分成 右美 0.1-0.7 g /（ kg-1 h-1) 或吗啡 10-70 g /（ kg-1 h-1) 观察指标：谵妄Dexmedetomid

17、ine reduced the duration but not the incidence of delirium after 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谵妄的影响ANESTHESIOLOGY. 2009 NOV;111(5 AIRWAY CATASTROPHES CURR OPIN ANAESTH

18、ESIOL. 2009 , 6 Modern anesthetic medications such as dexmedetomidine and proven techniques such as awake fiberoptic intubation can be used to safely treat these difficult patients. AIRWAY CATASTROPHES CURR OPMINERVA ANESTESIOL. 2009;75(11):668-71. This article describes the case of a patient with s

19、evere chronic obstructive pulmonary disease and severe carotid stenosis, who underwent carotid stenting under monitored anesthesia care with dexmedetomidine. 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支架术患者的镇静

20、MINERVA ANESTESIOL. 2009;75(11.INT J OBSTET ANESTH. 2009;18(4):403-7. A 35-year-old, 41-kg parturient at 35 weeks of gestation with spinal muscular atrophy presented for cesarean section. Dexmedetomidine was administered intravenously, total dose 1.84g/kg over 38 minutes, followed by fiberoptic endo

21、tracheal intubation. Dexmedetomidine was then discontinued and general anesthesia was induced. The baby was delivered 68 minutes after the dexmedetomidine infusion During administration of dexmedetomidine, maternal heart rate, blood pressure and oxygen saturation remained stable. Apgar scores at 1 a

22、nd 5 min were 6 and 8.右美用于合并脊髓性肌萎缩型患者剖宫产清醒气管插管.INT J OBSTET ANESTH. 2009;18ANESTH ANALG. 2009 SEP;109(3):745-53.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. The ne

23、ed for artificial airway support during the MRI sleep study was significantly less with dexmedetomidine than with propofol. 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-disorde

24、red breathing requiring anesthesia or anesthesia for other diagnostic imaging studies.右美VS丙泊酚用于小儿对MRI对睡眠的研究ANESTH ANALG. 2009 SEP;109(3):In addition it posses sympatholytic and antinociceptive effects that allow hemodynamic stability during surgical stimulation. Different from most of clinically use

25、d anesthetics, dexmedetomidine brings about not only a sedative-hypnotic effect via an action on a single type of receptors, 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 hy

26、potension are the most predictable and frequent side effects.CURR DRUG TARGETS. 2009 AUG;10(8):687-95全麻中右美的应用CURR DRUG TARGETS. 2009 AUG;10ANESTHESIOLOGY. 2009 ;111(5):1111-9. This is the first study showing that dexmedetomidine added to ropivacaine increases the duration of sensory blockade in a do

27、se-dependent fashion in rats. The findings are an essential first step encouraging future efficacy studies in humans.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ANESTHESIOLOGY. 2009 ;111(5):1延长局部麻醉药对外周神经阻滞的时间抑制外周神经兴奋性传导Brummett C, et al. Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increa

28、se in the duration of thermal antinociception in sciatic nerve block in rat. Anesthesiology 2009;111:11111119.延长局部麻醉药对外周神经阻滞的时间Brummett C, eAbdllah FW,et al:A &A,2013Abdllah FW,et al:A &A,2013Blaudszun G,et al:Anesthesiology,2012,112:1316与吗啡剂量进行换算Blaudszun G,et al:AnesthesioloACTA ANAESTHESIOL SCAND

29、. 2009 ,26 The combination of dexmedetomidine and hypothermia improved short-term neurologic outcome compared with the control groupwhereas the combination therapy provided comparable neuroprotection 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用ACTA ANAESTHESIOL SCAND. 2009 MASUI. 2009

30、;58(8):987-9.A 64-year-old woman with hypertension, diabetes mellitus and asymptomatic first degree AV block underwent low anterior resection of the rectum. Anesthesia was induced with propofol, vecuronium bromide and remifentanil and maintained with nitrous oxide in oxygen, propofol and remifentani

31、l. 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. The EKG changed from first degree AV block to second degree AV block followed by complete AV block and fin

32、ally cardiac arrest. As soon as we performed heart massage, sinus rhythm appeared. We should be careful in giving dexmedetomidine to a patient with AV block.心跳骤停一例报告（发生于ICU）MASUI. 2009;58(8):987-9.A 64-y四、我们的研究四、我们的研究分组：A.假手术组 B.假手术+右美托咪啶10g组C.脓毒症组 D.脓毒症+右美托咪啶2.5g组 E.脓毒症+右美托咪啶5g组 F.脓毒症+右美托咪啶10g组 观察指

33、标：不同时间点动物的生存率、心率、动脉血压、动脉血pH（pHa）、动脉血氧分压（PaO2）、动脉血二氧化碳分压（PaCO2）、乳酸及心肺肝肾等组织病理变化，及动物血清IL-6、IL-10、SOD及MDA水平。右美托咪啶对脓毒症大鼠的保护效应及其机制探讨分组：观察指标：右美托咪啶对脓毒症大鼠的保护效应及其机制探右美托咪啶的基础和临床讲解培训课件心肺肝肾病理心、肺ShamSham+Dex10CLPCLP+Dex2.5CLP+Dex5CLP+Dex10心肺肝肾病理心、肺ShamSham+Dex10CLPCL心肺肝肾病理肝、肾ShamSham+Dex10CLPCLP+Dex2.5CLP+Dex5CLP+Dex10心肺肝肾病理肝、肾ShamSham+Dex10CLPCL细胞因子、抗氧化因子改变细胞因子、抗氧化因子改变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，提高生存率。 这一作用是通过降低血清IL-6水平，增加血清SOD水平，降低血清MDA水平，从而减少组织损伤而实现的。结论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、乳右美托咪啶节约全麻及阿片类镇痛药77例患者，4565岁，全麻 腹部手术麻醉诱导：咪唑安定 0.05 - 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