药理学教学课件：Chapter 15 General Anesthetics

Chapter15GeneralAnesthetics

Generalanesthesiausuallyincludesanalgesia,amnesia,lossofconsciousness,inhibitionofsensoryandautonomicreflexes,and,inmanycases,skeletalmusclerelaxation.Theextentofgeneralanesthesiavarieswiththedrug,thedosage,andtheclinicalcircumstances.

ⅠGeneralanesthesiaAnidealanestheticdrug

---wouldinduceanesthesiasmoothlyandrapidlyandpermitrapidrecoveryassoonasadministrationceased.Thedrugwouldalsopossessawidemarginofsafetyandbedevoidofadverseeffects.Nosingleanestheticagentiscapableofachievingallofthesedesirableeffectswithoutsomedisadvantageswhenusedalone.Themodernpracticeofanesthesiamostcommonlyinvolvestheuseofcombinationsofdrugs.CombinationsofdrugsII.SIGNS&STAGESOFANESTHESIA

Fourstages:1.StageofAnalgesia(镇痛期):

Thepatientinitiallyexperiencesanalgesiawithoutamnesia.Laterinstagel,bothanalgesiaandamnesiaensue.

usedinsmalloperation.Duringthisstage,thepatientoftenappearstobedeliriousandexcitedbutdefinitelyisamnesic.RespirationisirregularNauseaandvomitingcanoccur.effortsaremadetolimitthedurationandseverityofthisstage,whichendswiththereestablishmentofregularbreathing.2.StageofExcitement:Thisstagebeginswiththerecurrenceofregularrespirationandextendstocompletecessationofspontaneousrespiration.Operationisinthisstage.3.StageofSurgicalAnesthesia:Whenspontaneousrespirationceases,stageIVispresent.Thisstageofanesthesiaincludesseveredepressionofthevasomotorcenterinthemedullaaswellastherespiratorycenter.Withoutfullcirculatoryandrespiratorysupport,deathrapidlyensues.4.StageofMedullaryDepression:III.

INHALEDANESTHETICSDepthofanesthesia---theconcentrationsofanestheticsintheCNS.Therateofinductionofanesthesiadependsonmultiplepharmacokineticfactorsthatdeterminethedifferenttransferratesoftheinhaledanestheticfromthelungtothebloodandfromthebloodtothebrainandothertissues.A.

Absorption＆DistributionAchievementofadequateconcentrationofananestheticinbrainrequirestransferofthatanestheticfromthealveolarairtobloodandthentobrain.“Minimumalveolarconcentration,MAC”最小肺泡浓度

---dependsonthesolubilityoftheanesthetic,itsconcentrationintheinspiredair,pulmonaryventilationrate(肺换气速度),pulmonarybloodflow,theconcentrationgradientoftheanestheticbetweenarterialandmixedvenousblood.TheconcentrationinthebrainSolubility:InfluencethetransferofananestheticfromthelungstothearterialTheblood:gaspartitioncoefficient血气分布系数---isausefulindexofsolubilityanddefinestherelativeaffinityofananestheticforthebloodcomparedtoair.Increasesintheinspiredanestheticconcentrationwillincreasetherateofinductionofanesthesiabyincreasingtherateoftransferintotheblood.AnestheticconcentrationintheinspiredAirB.

Elimination

Manyoftheprocessesofanesthetictransferduringrecoveryaresimilartothosethatoccurduringinductionofanesthesia.Veryfewwasmetabolizedbyliveroreliminatedbykidney.Mainlyeliminatedthroughtherespiratorytractbyprototype.Oneofthemostimportantfactorsgoverningrateofrecoveryistheblood:gaspartitioncoefficientoftheanestheticagent.Otherfactorscontrollingrateofrecoveryincludethepulmonarybloodflow,themagnitudeofventilation,andthesolubilityoftheanestheticinthetissues.

C.MechanismofAction

Siteofaction:CNS

Originalconceptsnonspecificinteractionsoftheseagentswithlipidrichnervecellmembrane

thatwerethoughttoleadtosecondarychangesinionflux.Thoughthemarkedstructuraldifferencesamonganesthetics,theanestheticpotencyweretheclosecorrelationwiththeirlipidsolubility.Morerecently,evidencehassuggestedthatthemodificationofioncurrentsbyanestheticsresultsfromspecificinteractionswithnervemembranecomponents.Thedifferentanestheticsappeartoinvolveinteractionswithmembersofthefastneurotransmitter-gatedchannel

family.Forexample,inhaledanestheticshavebeenreportedtocausemembranehyperpolarization(aninhibitoryaction)viatheiractivationofligand-gatedpotassiumchannels.MechanismofAction-review

Lipidtheory:Theeffectofinhalationanestheticsarepositivelyrelatedwithlipidsolubility,thehigherthelipidsolubility,thestrongertheanestheticeffect.Solubleinthecellmembranelipidlayer,makethedisorderedarrangementoflipidmolecules.MembraneproteinandNa+,K+channelsonthestructureandfunctionchange,inhibitthepolarizationofnervecells，widelyinhibittransmissionofnerveimpulses,leadtogeneralanesthesia.

Theoryofprotein--Newmechanisms:StrengthenthefunctionofinhibitoryneurotransmitterreceptororinhibitexcitatoryneurotransmitterreceptorfunctioninCNS.

-activatingGABAAreceptordirectlyoradjustthesensitivityofthereceptorforGABAindirectly,increasetheCl-internalflow;Theoryofprotein--Newmechanisms:--enhanceglycine甘氨酸receptorfunction,promoteCl-ionchannelsopen--inhibitexcitatoryneurotransmitterglutamatereceptors:ketamine氯胺酮--excitednervecellmembraneK+channels,promotingK+outflows.D.Toxicity

1.Hepatotoxicity(Halothane氟烷):averysmallsubsetofindividualsexposedtohalothanemaydevelopapotentiallysevereandlife-threateninghepatitis.2.Nephrotoxicity:

Thenephrotoxicpotentialofmethoxyflurane甲氧氟烷haslimiteditsclinicaluseinanesthesia.3.MalignantHyperthermia:

isanautosomal(常染色体)dominantgeneticdisorderofskeletalmusclethatoccursinsusceptibleindividuals.Themalignanthyperthermiasyndromeincludestachycardiaandhypertension,severemusclerigidity,hyperkalemia(高钾血症),andacidosis(酸中毒).4.ChronicToxicity:

Mutagenicity,Carcinogenicity,Effectsonreproduction,Hematotoxicity.Ⅳ.TYPESOFGENERALANESTHETICS

Generalanestheticsareusuallygivenbyinhalation

orbyintravenousinjection.ThechemicalstructuresofsomeinhaledanestheticsareshowninFig.10-1.A.InhaledAnestheticsVolatile(易挥发)liquids:1.Halothane氟烷:Cardiovasculareffect,Hepatotoxicity.

2.Enfluraneandisoflurane:themostcommonlyused，rapidonsetandrecovery，isusedforbothinductionandmaintenanceofanesthesia.3.Desflurane:rapidonsetandrecovery4.Sevoflurane:nostimulationonrespiratorytract5.nitrousoxide(N2O,laughinggas):

agas,thebetteranalgesia,usedforcombinedanaesthesia,Inductioninanesthesia.Theolderinhaledanesthetics

：suchasether,cyclopropane环丙烷,andchloroformarenolongerusedindevelopedcountriesforreasonsthatincludepotentialflammability易燃的(ether,cyclopropane)andorgantoxicity(chloroform).IV.INTRAVENOUSANESTHETICSDonotrequirespecializedequipment,haveanfasteronsetofanestheticaction,arecommonlyusedforinductionofanesthesia.1.Propofol丙泊酚

isanextremelyimportantintravenousanesthetic.Itproducesanesthesiaataratesimilartothatoftheintravenousbarbiturates,andrecoveryismorerapid.

Propofolisusedforbothinductionandmaintenanceofanesthesia.Thedrugdoesnotappeartocausecumulativeeffectsordelayedarousal(唤醒)followingprolongedinfusion.2.Ultra-short-actingbarbiturates：thiopentalsodium硫喷妥钠:

thiopentalisthemostcommonlyusedforinductionofanesthesia,oftenincombinationwithinhaledanesthetics.

3.Benzodiazepines苯二氮卓类:diazepam地西泮,midazolam咪哒唑仑,andlorazepam劳拉西泮,areusedinanestheticprocedures,produceasloweronsetofCNSeffectsandinduceaplateauofcentraldepressionthatappearstobebelowthatofatrueanestheticstate.4.Ketamine:

anphencyclidine苯环己哌啶

derivative;

thatproducesastatecalleddissociativeanesthesia;whichischaracterizedbyamnesia,andanalgesia,withoutactuallossofconsciousness.

ThemechanismofketaminemayinvolveblockadeofthemembraneeffectsoftheexcitatoryneurotransmitterglutamicacidattheNMDA(N-methyl-D-aspartate)receptorsubtype.Mechanismofaction5.Etomidate依托咪酯:

rapidonset,actionpotentis12timeshigherthanthiopental.useforinductionofanesthesiaItsmajoradvantageoverotheragentsisthatitcausesminimalcardiovascularandrespiratorydepr