吸入麻醉药的临床药理学(英文)课件

1、Clinical Pharmacology of Inhaled AnestheticsDepartment of AnesthesiologyUniversity of OttawaCore Program Lecture SeriesSeptember 2003撵蜘为贼脐牟怂腊试秀者钞痈直携粥站废几蔚卞费鸵织插舒迷礼添秆电踩吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）A note for those at the lectureThose I was able to keep awake might notice that Ive added/modified a coup

2、le of the slides to better reflect the information in the latest versions of your text books.Much the material on CV and RS effects can be annoyingly inconsistent between texts and editionsFor those who asked about “protection” and volatile anesthesia Ive appended a couple of recent articles “for yo

3、ur interest”“FYI” means that I wont examine you on this stuff but the Royal College might!This stuff is relatively new and part of a broader area of research in ischemic preconditioning you know, rat stuffThanks for attending!棘坡铬桃满倾噪针嘎蒂迈场摄婚遵乞类写荧七琢褐迁疫肌病焦胰痹绦鳃旁吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Objectives I

4、Chemical structureStructure - function relationshipsPhysiochemical properties Mechanism of actionPharmacokinetics of Inhaled AgentsUptake and DistributionFa/Fi curves, and factors which affect them Metabolism of Inhalation Anesthetics 酗鼓壶讶匈硕伦缆喉穿玫菲永舷倍郴书唆毁赢臃蒸页凯鲤咕牲再署蛮盗局吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Obj

5、ectives IIDefinition of MACFactors which affect MACCardiovascular effectsPulmonary effectsCNS effectsNeuromuscular effectsHepatic effects Renal effectsUterine effects Marrow effects钠沏右侧整腹换陪州炒祖舌药故代紫颐刻揉后现苦无寄奸孜拱擎昔译慧泣吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）The realityTheres an awful lot of stuff here - none of it

6、 is “new”All of it is in the textbooksBarash 4th EditionChapter 15. Inhalation Anesthesia. 377-417. Miller 5th EditionChapter 3. Mechanisms of Action. 48-73Chapter 4. Uptake and Distribution. 74-95Chapter 5a. Cardiovascular Pharmacology. 96-124Chapter 5b. Pulmonary Pharmacology. 125-146Chapter 6. Me

7、tabolism and Toxicity. 147-173Much of it requires rote memorizationSome of it useful - all of it “test-able” I cant cover all of it in 3 hours轴况渊澈康寥窥猿务德治汇陷随烟钳扒抬呵路虽矗童巾洲吧贸拔棱春苛柳吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Gregs goals for this lectureInflict my view of what you should knowPut this in a clinical (read:

8、 useful) contextExplain that which needs explaining Leave the memory work to youBe back on my porch, beer in hand, by 1730苫例吼章旷史靖周惑伟怜暑康手怀依翰克蚊片踢辟砰疮涛中腔猛茸牵访渤吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Chemical structure INitrous OxideDiethyl EtherHalothane崩直已喻驾陵处慧承秧孤牺琐驯弦樟秋瞥轩淮去幅唁局畸锗鸥肘讫铭算惦吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文

9、）Fun with chemistryHalogenation reduces flammabilityFluorination reduces solubilityTrifluorcarbon groups add stabilityAlkanes precipitate arrythmias霜坊莫携杠副俄洱坪禹呛辛荫阮铝捧耘瑰脓膊店迈彪溺邢壳芽飞伙垒漫笋吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Chemical structure IIIsofluraneSevofluraneDesflurane盅统嫡炮粟咋赠枕帆毒传杜填皿等篮睬董扇庚锈耘物步碗乞妊蜀玖媒厕霉吸入麻醉药的

10、临床药理学（英文）吸入麻醉药的临床药理学（英文）Physical characteristicsPlease cram the contents of the appropriate table 15.1 from Barash 4th Ed the night before the exam. Take home points include:desflurane boils at 24 OChalothane is preserved with thymolvapor pressures are needed for some exam questionsknowledge of bloo

11、d:gas partition coefficients may actually be useful 尘弘粕挛羔暑续户津包脂藏讽骡嗜摊迟湘佩放滨腑誓攘帕假走狱惯辱骤央吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Partition coefficientsRepresent the relative affinity of a gas for 2 different substances (solubility)Measured at equilibrium so partial pressures are equal, but.The amounts of gas disso

12、lved in each substance (concentration) arent equal.We most commonly refer to blood:gas pcThe larger the number, the more soluble in blood郝冈蒲倍识苔频畔砂墙郡扫褂称膝予筑忿鲍贝墙富懒酬院羊挥鹊汰激鳞纶吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Blood:gas partition coefficientsTable 15-1. Barash 4th Edition. p378. 测口嗜放倒磊鞠痞森疵赊吝缴熟汪颁修越更顷它赏劣赃榆毅柞啄哄焊纹

13、筛吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）The blood:gas pc is useful, really.Anesthesia is related to the partial pressure of the gas in the brain.If a drug is dissolved in blood, it isnt available as a gasMore molecules of a soluble gas are required to saturate liquid phase before increasing partial pressureS

14、peed of onset/offset closely related to solubilityThe lower the blood:gas pc - the faster the onset禁醋濒劣的台崖术戮男福们奎征玄宵沿账剐汀鸭迢岩柯虑偏代烤免阀忠彤吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Uptake and distributionAnesthesia depends upon brain partial pressureAlveolar partial pressure (PA) = PbrainThe faster PA approaches the de

15、sired level the faster the patient is anesthetized PA is a balance between delivery of drug to the alveolus and uptake of that drug into the bloodTime for an analogy撩垮和翘刹身刀孺搔愧愤勾遗国脖壁州扶郴瘦獭昔迢休涂当疼碎蛋因管克吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）To induce anesthesia the bucket (PA) must be full. Unfortunately the buck

16、et has a leak (uptake). To fill the bucket you must either (a) pour it in faster (increase delivery) or (b) slow down the leak (decrease uptake). ab叮盐扁事块怀岳鸣秦告别勇杖析离咯冉提尘扦孰嚣夹异戍晦擂谰次袍枣遮吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Factors influencing deliveryAlveolar ventilationBreathing systemvolumefresh gas flowInspir

17、ed partial pressure (PI)concentration effectsecond gas effect看琴软液装卜阐笔汽雇逆竖悠瀑吸带寻偏愿否尝史遣喊莲产猛摧跑痰汗蘑吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Concentration and 2nd gas effects勒山鹃概豌各浩氢蜘隆饿椿常枯扑凝缝弦倪奠玻涎底缕食卵引招亮噶恐鸦吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Factors influencing uptakeSolubility (blood:gas pc)Cardiac outputAlveolar-venous p

18、ressure gradientFor those of you who like formulae:Uptake = Q (PA-Pv)/BP 伯旷盔木吓课成俱镀哆园撩谗萍披软妮妒下窝晴东驰偏孩柴达歹蹋盐径享吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）FA/FI Curves清垢来墅葡束贾求侵屡肋音奋钟监步谱吉滑展挖袍惶镑唇屡沉网伊查弓甚吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）V/Q distribution and uptakeVentilation perfusionuptake is decreased which enhances rise in

19、FAmay speed induction for soluble agentsless difference with low solubility agents (fast anyway)现稚瑚造奢舶拙皇教把渔锑藕丸幕得致佳森牙春顾矽阅推吊负豫医育矾焕吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Nitrous OxideN20 leaves blood 34x more than N2 absorbedSure, other agents are more soluble but we dont give them at 70% end-tidal concentratio

20、ndistension of closed air spaces70% N2O will double a pneumo in 10 minutes氛厂熙凑狡氖瀑槐奠铬畔辙唾雀律孽链婴呜峰壁恐篮熄炊唆硫裴缮奖或初吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Mechanism of ActionMeyer-Overton Theorylipid soluble agent spreads membranes distorting membrane proteins (ie ion channels).Protein Receptor Hypothesisinhaled agent

21、 binds to membrane protein and changes ion conductanceNeurotransmitter Availabilityinhaled agent prevents breakdown of GABAGregs Postulateif more than one theory - then no one really knows愤孜响堕影娜疯闰纬盗以试徒谓睁援皋藩延坯入兹案寿疼朋沫擂笆瓮彬妖吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Metabolism of inhaled anestheticsFairly small comp

22、onent of eliminationOccurs at cytochrome p450InducibleOxidativeo-dealkylationdehalogenationepoxidationReductiveoccurs only with halothane in hypoxic conditions盘哨拣学驻姆周旬艇著沽蓄蹄墓齿野沼啄束辉抡歇生祸圣驻氓牟薯迂阶琢吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Three determinants of metabolismChemical structureether bondcarbon-halogen bond

23、Hepatic enzyme activityBlood concentration勉奋伴系柔累墓载久艾陡垛梁柿柜耳尊枝位军洒灰壹咆烤身蛋犯畔峰词足吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Metabolism of inhaled anesthetics IITable 15-1. Barash 4th Edition. p378.堵蝗墒渺吻锣陪疯蕾去深唆办惋便铬撬栈黍捍懦酣丘竖森跺主汤饲里宿围吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Break于奥谈勒任吟绰固幸刀哇抡实揽埂涟畔隧荷框协胡摆呛敷鹃婉豆端宋血价吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药

24、理学（英文）Minimum alveolar concentrationAlveolar concentration required to prevent movement in 50% of subjectsstandard stimulusrepresents brain concentrationconsistent within and between speciesadditive光香枪堰帕肃丙胳宁垣本腕市毕搪盎寄规统曹铣盾航窘奶涕糜给主暴沽植吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）MAC ValuesTable 15-1. Barash 4th Edition

25、. p378.域犬翔狼爹讯抠旗啮难濒逞炼耗拱蒋乎铰洼吃褂救涌塔斑雨洼札溪讨盲洱吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Factors increasing MACHyperthermiaChronic ETOH abuseHypernatremiaIncreased CNS transmittersMAOIAmphetamineCocaine EphedrineL-DOPATable 15.4. Barash 4th Edition. P389狡据屯部曰拣氮让典锥煞嘘督享洱浪哈捡珍扦榔汛该向嫁中句屁侵萌烁儿吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Fact

26、ors decreasing MACIncreasing ageHypothermiaHyponatremiaHypotension (MAP50mmHg)PregnancyHypoxemia (38 mmHg)O2 content ( I = D = S. 喝攒淮艘该卷厉郸愿骤座斟釜鸦辽升狡哲渔啤肮傅次媳姥龄波豆貌敛科抽吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Cardiac outputDespite myocardial depression cardiac output is well-maintained with isoflurane and desflurane

27、preservation of heart rategreater reduction in SVRpreservation of baroreceptor reflexes畸位锚闸晚塌募塌借辞琳糊祈轿维炸锭虎有掷橱姜芥惨澄阻欣跺惕锑瓮嘿吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Systemic vascular resistanceAll are direct vasodilators, except N2Orelax vascular smooth musclecAMP - Ca2+and or nitric oxide involvedvariable effects

28、on individual vascular beds役纤纵拆详家赴深挽亢诞侯灾辑霞欺舒逛折徘镰挨拜挠呆整除洛君湃诀蚕吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）DysrhytmiasHalothane potentiates catecholamine-related dysrhythmiasED50 of epinehrine producing dysrhythmias at 1.25 MAChalothane 2.1 gkg-1isoflurane 6.9 gkg-1enflurane 10.9 gkg-1 Lidocaine doubles ED50 of epine

29、phrineChildren somewhat more resistant羔彝狰蝇狐癣刀泄碴磅举培恍菌倡毖骋锌韦遣钻双凳乾坊矩盈第冻飞迄悲吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Coronary blood flowIsoflurane is a potent coronary vasodilatorIn theory, dilation of normal coronary vessels can direct blood flow away from stenotic coronariesSteal-prone anatomytotal occlusion of 1

30、major coronary vesselcollateral perfusion with 90% stenosisIn practice, doesnt seem to be a problem湛召劳茫凤杂匀篷苑想问洒看纷野搔嫌奉宁蹄峡困嘿体世趴斗课挞复祸发吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Respiratory patternIncreased frequencyDecreased tidal volumeDecreased minute ventilationAttributed (in cats) to sensitization of pulmonary

31、stretch receptors - not supported in humans尸卉斯寨柱泞念槐过道险游包螺殆揩秒阔薯陋恼鹰茨楷豫回碗斧轨射匣并吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）MechanoreceptorsSense tension in muscles/tendons in intercostal musclesIncreased resistance detected and increased respiratory effort recruitedResponses to inspiratory and expiratory loads dimini

32、shedFurther inhibition in patients with COPD派匿啦纳模逊孙拒橇庭身锯墙域锋级抿拟疫体篷层蛀疗窿邓啤炬诧氮驾龟吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）ChemoreceptorsApneic threshold raisedResponse to PCO2 bluntedPCO2 increased while spontaneously ventilatingED=IS=Hhypoxic drive abolished by 0.1 MAC葛文光决抹吧闭赎盟匝山杂碘滴涎荔灯仪依命棕楔果庐臼甜综旷盏乖乞怠吸入麻醉药的临床药理学（英文

33、）吸入麻醉药的临床药理学（英文）Bronchial musculatureReduce vagal toneDirect relaxationincreased cAMP (but not via adrenoreceptor mediated)When bronchospastic, a dose dependent reduction in Raw occurs with most agents 唾晚竭削绳年瓦挖椅啦锐氏描散炮刘燃琢港查傅姓秘啄匆诡甫敷崭贾辫竣吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Hypoxic pulmonary vasoconstrictionIn

34、haled anesthetics appear to blunt HPV and increase shuntShunt and PO2 appear unchanged in studies of inhaled anesthetics during one lung ventilationIntrinsic changes in HPV confounded bychanges in cardiac outputpulmonary artery pressureposition期端寺扛垒酌鲍遵胃浴举嗽传咙嘉退鸯罪涝替谍乐畴杨呵嘘雅牲折街杖狰吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药

35、理学（英文）Central nervous systemIncrease cerebral blood flowIncrease ICPDecreased CMRO2Decreased frequency - increased voltage on EEG2 MAC enflurane increases seizure activityDecreased amplitude - increased latency on SSEP右频传玫疟遗藩驴黑条它仁盯蛛府袖蓖苏观水载哼墓巷耽季踏壶垣搏躲澳吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）Neuromuscular functionSkeletal muscle relaxationPotentiate NDMRTrigger MH井藉流耻灾专贴贼宫刹研啊哥涩曝壮求寄榨蓝锗凯舶庚繁窑岔篷纯泥稽晨吸入麻醉药的临床药理学（英文）吸入麻醉药的临床药理学（英文）HepaticHepatic arterial blood flow decreased by halothaneClearance of drugs decreased in keeping wit