右美托咪啶的基礎(chǔ)與臨床

1、右美托咪啶的基礎(chǔ)與臨床,天津醫(yī)科大學(xué)總醫(yī)院王國林2013-6,內(nèi)容,一般介紹作用機(jī)制、藥代學(xué)、用藥方法文獻(xiàn)借鑒我們的研究,一、一般介紹、作用機(jī)制,背景,臨床工作中鎮(zhèn)靜非常重要，但近年新藥很少一些常用藥物特點Opiate/benzodiazepine – tolerance, efficacyPentobarbital – agitation, durationPropofol – limited access in s

2、ome jurisdictionsKetamine – emergence reactions, tolerance?2-adrenoreceptor agonism,背景（?2 受體激動劑）,Prototype agent is clonidineMore recent applications in clinical practiceSedationBehavior disorders Drug withdrawal

3、HypertensionProblem – hypotensionSolution – 2nd generation - ? ?2 specificity,右美托嘧啶,Pharmacologically active D- isomer of medetomidine1st synthesized in late 1980’s, Phase 1 studies in early 1990’s, clinical trials la

4、te 1990’s~ 8-fold greater ?2:?1 selectivity than clonidine1620:1 vs 200:1清除半衰期較可樂定短：2-3 vs 8-12 hrFDA approved for ICU sedation in adults,中樞作用機(jī)制,Locus ceruleus（藍(lán)斑）: Brainstem center - modulates wakefulnessMajor sit

5、e for hypnotic actions (sedation, anxiolysis)Mediated via various efferent pathways:Thalamus and subthalamus ? cortexNociceptive transmission via descending spinal tractsVasomotor center and reticular formationSpina

6、l cord: Binding to ?2 receptors ? analgesia via ? release of substance P,中樞作用機(jī)制,,,Sedation – central, G-proteins (inhibition) Analgesia – spinal cord, Substance P,機(jī)制 – CENTRAL ?2,Presynaptic receptors:Location:Sympat

7、hetic nerve endingsNoradrenergic CNS neuronsMechanism/action:Transmembrane receptorsCoupled to Go- and Gi- type G-proteins? adenylate cyclase and cAMP formationHyperpolarization (K+-channels)? Ca++ conductance ? N

8、E release,CELLULAR MECHANISM,中樞外效應(yīng),高血壓:peripheral ?1-agonism 心動過緩/低血壓:交感抑制- medullary VMC? 寒戰(zhàn):Diuresis:? renin, vasopressin; ? ANP,,,,,,,呼吸系統(tǒng)影響,Promoted as having minimal respiratory depressing effects0.17% incide

9、nce on monogram Most data suggests SaO2 and PaCO2 unaffected Numerous reports during spontaneous ventilation,二、藥代動力學(xué),藥代參數(shù),起效時間鎮(zhèn)靜10min,鎮(zhèn)痛20min達(dá)峰時間 60 ~ 90min作用時間 2.5 ~ 4h生物利用度 肌注：73%蛋白結(jié)合94%

10、代謝肝酶 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,國外研究資料顯示：在健康志愿者的研究中，當(dāng)靜脈輸注劑量范圍為0.2-0.7?g /kg·h 時，呼吸率和氧飽和度保持在正常范圍內(nèi)，未見呼吸抑制。靜脈輸注后：快速分布相的分布半衰期(t1/2)大約為6分鐘；終末清除半衰期(t1/2)大約為2小時；穩(wěn)態(tài)分布容積(Vss)大約為118升。清除率大約為3

11、9L/h。,藥代參數(shù),靜脈輸注本品0.2-0.7 ?g /kg﹒h直到24小時右美托咪定呈現(xiàn)線性動力學(xué),老年患者：右美托咪定的藥代動力學(xué)特性不隨年齡而改變。年輕(18-40歲)、中年(41-65歲)和老年(?65歲)受試者中右美托咪定的藥代動力學(xué)無差異。兒科患者：右美托咪定在兒科患者的藥代動力學(xué)特性未見詳細(xì)數(shù)據(jù)，但在歐美已廣泛使用。腎功能損傷：嚴(yán)重腎功能損傷受試者(肌酐清除率：?30mL/min)右美托咪定的藥代動力學(xué)(Cma

12、x、Tmax、AUC、t1/2、CL和Vss) 與健康受試者相比無明顯差異,特殊患者應(yīng)用,肝功能損傷,在不同程度肝功能損傷受試者(Child-Pugh分類A、B或C)，右美托咪定的清除率值比健康受試者低，肝功能損傷患者或許需要考慮減少給藥劑量,藥物用法,負(fù)荷量1 μg/kg iv 10 min繼而0.2 - 0.7 μg/kg/hr使用輸注泵, 不要推注 ！滴定藥效肝腎功能不全、老年人適當(dāng)減量,Dex 圍術(shù)期給藥方案,Examp

13、le: 70 kg patient. Assess BP, HR, volume status,2 mL Dex in 48 mL 0.9% saline= 200 ug/50 mL, or 4 ug/ml,Hypovolemic,Start at 40 mL/hr,,Stop load if ? HR,Usual load: 25 to 35 ug or 6 to 9 mL over 10-15 min,Monitor BP/HR

14、throughoutIf bradycardia, ? infusion,Maintenance: 0.2 to 0.7 ug/kg/hr [4 to 12 mL/hr],Volume preload500 to 1000 cc LR,Normovolemic,,,,,,,,,,,Dex=dexmedetomidine.,,三、相關(guān)文獻(xiàn),“自然睡眠” BIS,Kasuya Yet al. The correla

15、tion between bispectral index and observational sedation scale in volunteers sedated with dexmedetomidine and propofol. Anesth Analg 2009; 109:1811–1815.,DEX對ICU鎮(zhèn)靜死亡率影響,Pandharipande PP, et al. Effect of sedation with de

16、xmedetomidinevs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007; 298:2644–2653.,膿毒癥患者的預(yù)后（Sepsis vs no Sepsis）,,DEX與術(shù)后譫妄、POCD,DEX鎮(zhèn)靜機(jī)制不同，類似“自然”睡眠的鎮(zhèn)

17、靜是否與術(shù)后譫妄、POCD有關(guān),ICU鎮(zhèn)靜后譫妄發(fā)生率比較,Pandharipande PP, et al. Effect of sedation with dexmedetomidinevs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA

18、2007;298:2644–2653.,Riker RR,et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA 2009;301:489–499,右美或咪啶安定對ICU鎮(zhèn)靜患譫妄的比較,ANESTHESIOLOGY. 2009 NOV;111(5):1075-84.,306例患者

19、隨機(jī)分成 右美 0.1-0.7 µg /（ kg-1 ? h-1) 或嗎啡 10-70 µg /（ kg-1 ? h-1) 觀察指標(biāo)：譫妄Dexmedetomidine reduced the duration but not the incidence of delirium after cardiac surgery with effective analgesia/sedation, less hypote

20、nsion, less vasopressor requirement, and more bradycardia versus morphine regimen.,心臟手術(shù)后給右美或嗎啡鎮(zhèn)痛對老年患者譫妄的影響,AIRWAY CATASTROPHES CURR OPIN ANAESTHESIOL. 2009 , 6,Modern anesthetic medications such as dexmedetomidine and p

21、roven techniques such as awake fiberoptic intubation can be used to safely treat these difficult patients.,MINERVA ANESTESIOL. 2009;75(11):668-71.,This article describes the case of a patient with severe chronic obstruct

22、ive 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 successf

23、ully treated with glycopyrrolate.,右美托咪啶用于合并嚴(yán)重慢阻肺行頸動脈支架術(shù)患者的鎮(zhèn)靜,.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.

24、Dexmedetomidine was administered intravenously, total dose 1.84μg/kg over 38 minutes, followed by fiberoptic endotracheal intubation. Dexmedetomidine was then discontinued and general anesthesia was induced. The baby w

25、as 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 and 5 min were 6 and 8.,

26、右美用于合并脊髓性肌萎縮Ⅲ型患者剖宮產(chǎn)清醒氣管插管,ANESTH 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 t

27、he patient's native airway. The need 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

28、 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VS丙泊酚用于小兒對M

29、RI對睡眠的研究,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

30、 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 s

31、afety, although bradycardia and hypotension are the most predictable and frequent side effects.,CURR DRUG TARGETS. 2009 AUG;10(8):687-95,全麻中右美的應(yīng)用,ANESTHESIOLOGY. 2009 ;111(5):1111-9.,This is the first study showing that

32、dexmedetomidine added to ropivacaine increases the duration of sensory blockade in a dose-dependent fashion in rats. The findings are an essential first step encouraging future efficacy studies in humans.,右美加入羅哌卡因劑量依賴性延

33、長對大鼠坐骨神經(jīng)阻滯作用時間,延長局部麻醉藥對外周神經(jīng)阻滯的時間抑制外周神經(jīng)興奮性傳導(dǎo),Brummett C, et al. Perineural dexmedetomidine added to ropivacaine causes a dose-dependent increase in the duration of thermal antinociception in sciatic nerve block in rat. A

34、nesthesiology 2009;111:1111–1119.,Abdllah FW,et al:A &A,2013,,Blaudszun G,et al:Anesthesiology,2012,112:1316,與嗎啡劑量進(jìn)行換算,ACTA ANAESTHESIOL SCAND. 2009 ,26,The combination of dexmedetomidine and hypothermia improved sho

35、rt-term neurologic outcome compared with the control groupwhereas the combination therapy provided comparable neuroprotection with either of the two therapies alone.,右美加低溫在大鼠腦缺血再灌損傷的保護(hù)作用,MASUI. 2009;58(8):987-9.,A 64-ye

36、ar-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 main

37、tained with nitrous oxide in oxygen, propofol and remifentanil. After the operation, the patient was admitted to the intensive care unit under general anesthesia with propofol and remifentanil. In addition, dexmedetomid

38、ine was given without loading dose. The EKG changed from first degree AV block to second degree AV block followed by complete AV block and finally cardiac arrest. As soon as we performed heart massage, sinus rhythm app

39、eared. We should be careful in giving dexmedetomidine to a patient with AV block.,心跳驟停一例報告（發(fā)生于ICU）,四、我們的研究,,分組：A.假手術(shù)組 B.假手術(shù)+右美托咪啶10μg組C.膿毒癥組 D.膿毒癥+右美托咪啶2.5μg組 E.膿毒癥+右美托咪啶5μg組 F.膿毒癥+右美托咪啶10μg組,,觀察指標(biāo)：不同時間點動物的生存率、心率

40、、動脈血壓、動脈血pH（pHa）、動脈血氧分壓（PaO2）、動脈血二氧化碳分壓（PaCO2）、乳酸及心肺肝腎等組織病理變化，及動物血清IL-6、IL-10、SOD及MDA水平。,右美托咪啶對膿毒癥大鼠的保護(hù)效應(yīng)及其機(jī)制探討,心肺肝腎病理——心、肺,Sham,Sham+Dex10,CLP,CLP+Dex2.5,CLP+Dex5,CLP+Dex10,心肺肝腎病理——肝、腎,Sham,Sham+Dex10,CLP,CLP+Dex2.5,CLP

41、+Dex5,CLP+Dex10,,,,細(xì)胞因子、抗氧化因子改變,右美托咪啶右美托咪啶可以改善膿毒癥大鼠的心率、血壓、血氣、乳酸及組織病理指標(biāo)，提高生存率。 這一作用是通過降低血清IL-6水平，增加血清SOD水平，降低血清MDA水平，從而減少組織損傷而實現(xiàn)的。,結(jié)論,右美托咪啶節(jié)約全麻及阿片類鎮(zhèn)痛藥,77例患者，45～65歲，全麻 腹部手術(shù)麻醉誘導(dǎo)：咪唑安定 0.05 - 0.1 mg/kg ， 蘇芬太尼0.3 - 0.5µ

42、;g/kg ，依托咪酯 0.2 - 0.3 mg/kg ，順卡 0.15 mg/kg 右美：誘導(dǎo)時開始給 0.5µg/kg 前半小時，然后維持 0.4µg/kg/hr，縫皮是停止麻醉維持丙泊酚、蘇芬太尼，順卡，BIS40~60,順卡用量、肌松恢復(fù)時間,,,蘇芬太尼用量、,,右旋美托咪定復(fù)合丙泊酚用于胃鏡檢查術(shù)的臨床觀察 （我們的研究）,60例患者隨機(jī)分成右旋美托咪定復(fù)合丙泊酚與丙泊酚組泵注右旋美托咪定0.6μ

43、g/kg/hr10min，靜注丙泊酚直至睫毛反射消失,呼之不應(yīng)后停止泵注右美并置入內(nèi)鏡檢查單純注射丙泊酚視患者術(shù)中體動，嗆咳情況追加丙泊酚,所有病例均能順利完成操作開始檢查時 BIS值下降幅度大于P組(43.6 vs 49.7)MAP、HR、SpO2下降幅度小于P組兩組手術(shù)時間及蘇醒時間無差異丙泊酚總量、不良反應(yīng)發(fā)生率均少于P 組（75.1 vs 132.3）,右旋美托咪定復(fù)合丙泊酚用于胃鏡檢查術(shù)的臨床觀察 (我們的研究）

44、,不同劑量右美托咪啶對下腹部手術(shù)患者七氟醚MACBAR影響,研究右美對七氟醚抑制50%下腹部手術(shù)切皮誘發(fā)應(yīng)急反應(yīng)的MAC60例患者，置入喉罩，分別給0.4μg·kg-1·h-1至1.2μg·kg-1·h-1結(jié)果：隨右美劑量增加，可減少七氟醚MAC,但從0.8μg·kg-1·h-1增加到1.2μg·kg-1·h-1時，MAC不再降低，提示有封頂效應(yīng),

45、83;,付志強 等，中華麻醉學(xué)雜志，2011，31:677~679,小結(jié),Goal is to establish + maintain adequate drug conc at effect site to produce desired effect Dex can help optimize anesthesia via:Sedation, analgesia + ?? sympathetic activityAttenu

46、ation of stress response + ? HRSmooth emergence + tracheal extubationUnique mechanism of action on natural sleep pathway permits sedation + analgesia w/o respiratory depressionAdjunct agent of choice for many surgerie