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DepartmentofAnesthesiologyCivicCampusAnoteforthoseatthelecture•ThoseIwasabletokeepawakemightnoticethatI’veadded/mo

difiedacoupleoftheslidestobetterreflecttheinformationinthelatestversionsofyourtextbooks.•Muchthemate

rialonCVandRSeffectscanbeannoyinglyinconsistentbetweentextsandeditions•Forthosewhoaskedabout“protection”andvolatil

eanesthesiaI’veappendedacoupleofrecentarticles“foryourinterest”•“FYI”meansthatIwon’texamineyouonthisstuffbuttheRoyalCollegemight!•Thisstuffi

srelativelynewandpartofabroaderareaofresearchinischemicpreconditioning–youknow,ratstuff•Thanksforattending!DepartmentofAnesth

esiologyCivicCampusObjectivesI•Chemicalstructure•Structure-functionrelationships•Physiochemicalproperties•Mechanismofacti

on•PharmacokineticsofInhaledAgents•UptakeandDistribution•Fa/Ficurves,andfactorswhichaffectthem•MetabolismofIn

halationAnestheticsDepartmentofAnesthesiologyCivicCampusObjectivesII•DefinitionofMAC•Factorswhichaffe

ctMAC•Cardiovasculareffects•Pulmonaryeffects•CNSeffects•Neuromusculareffects•Hepaticeffects•Renaleffects•Uterineeffects

•MarroweffectsDepartmentofAnesthesiologyCivicCampusThereality•There’sanawfullotofstuffhere-noneofitis“new”

•Allofitisinthetextbooks•Barash4thEdition•Chapter15.InhalationAnesthesia.377-417.•Miller5thEdition•Chap

ter3.MechanismsofAction.48-73•Chapter4.UptakeandDistribution.74-95•Chapter5a.CardiovascularPharmacology.96-124•Chapter5b.PulmonaryPha

rmacology.125-146•Chapter6.MetabolismandToxicity.147-173•Muchofitrequiresrotememorization•Someofituseful-allofit“test-able”•Ican’tcov

erallofitin3hoursDepartmentofAnesthesiologyCivicCampusGreg’sgoalsforthislecture•Inflictmyviewofwhatyoushoul

dknow•Putthisinaclinical(read:useful)context•Explainthatwhichneedsexplaining•Leavethememoryworktoyou•B

ebackonmyporch,beerinhand,by1730DepartmentofAnesthesiologyCivicCampusChemicalstructureINitrousOxideDiethylEtherHalothan

eDepartmentofAnesthesiologyCivicCampusFunwithchemistry•Halogenationreducesflammability•Fluorinationreducessolubility•Trifluorcarbongroups

addstability•AlkanesprecipitatearrythmiasDepartmentofAnesthesiologyCivicCampusChemicalstructureIIIsofluraneSevoflur

aneDesfluraneDepartmentofAnesthesiologyCivicCampusPhysicalcharacteristics•Pleasecramthecontentsoftheappropriatet

able15.1fromBarash4thEdthenightbeforetheexam.Takehomepointsinclude:•desfluraneboilsat24OC•halothaneisp

reservedwiththymol•vaporpressuresareneededforsomeexamquestions•knowledgeofblood:gaspartitioncoefficientsmayactuallybeusefulDepartmentofAn

esthesiologyCivicCampusPartitioncoefficients•Representtherelativeaffinityofagasfor2differentsubstances(solubility)•Measuredatequilibriumsop

artialpressuresareequal,but...•Theamountsofgasdissolvedineachsubstance(concentration)aren’tequal.•Wemostcommonlyre

fertoblood:gaspc•Thelargerthenumber,themoresolubleinbloodDepartmentofAnesthesiologyCivicCampusBlood:gaspartitioncoefficientsAnestheticBlood:GasPCD

esflurane0.42Nitrousoxide0.46Sevoflurane0.65Isoflurane1.46Enflurane1.91Halothane2.50Table15-1.Barash4thEdition.p378.DepartmentofAnesthesiology

CivicCampusTheblood:gaspcisuseful,really.•Anesthesiaisrelatedtothepartialpressureofthegasinthebrain.•Ifadr

ugisdissolvedinblood,itisn’tavailableasagas•Moremoleculesofasolublegasarerequiredtosaturateliquidphasebeforeincreasingpartialpre

ssure•Speedofonset/offsetcloselyrelatedtosolubility•Thelowertheblood:gaspc-thefastertheonsetDepartmentofAnesthesiologyCivicCam

pusUptakeanddistribution•Anesthesiadependsuponbrainpartialpressure•Alveolarpartialpressure(PA)=Pbrain•Thefa

sterPAapproachesthedesiredlevelthefasterthepatientisanesthetized•PAisabalancebetweendeliveryofdrugtothealveolusanduptakeofth

atdrugintotheblood•TimeforananalogyDepartmentofAnesthesiologyCivicCampusToinduceanesthesiathebucket(PA)mustbefull.Unfor

tunatelythebuckethasaleak(uptake).Tofillthebucketyoumusteither(a)pouritinfaster(increasedelivery)or(b)slowdown

theleak(decreaseuptake).abDepartmentofAnesthesiologyCivicCampusFactorsinfluencingdelivery•Alveolarventilation•Breathingsystem•volume•freshgasflow•I

nspiredpartialpressure(PI)•concentrationeffect•secondgaseffectDepartmentofAnesthesiologyCivicCampusConcentrationand2ndgaseffects

DepartmentofAnesthesiologyCivicCampusFactorsinfluencinguptake•Solubility(blood:gaspc)•Cardiacoutput•Alveolar-venouspressu

regradient•Forthoseofyouwholikeformulae:Uptake=•Q•(PA-Pv)/BPDepartmentofAnesthesiologyCivicCampusFA/FICurvesDepartm

entofAnesthesiologyCivicCampusV/Qdistributionanduptake•Ventilation<perfusion•bloodleavingshuntdilutesPAfromnormallun

g•inductionwithlowsolubilityagentwillbedelayed•littledifferencewithsolubleagents(slowanyway)•Ventila

tion>perfusion•uptakeisdecreasedwhichenhancesriseinFA•mayspeedinductionforsolubleagents•lessdifferencewithlowsolubilityage

nts(fastanyway)DepartmentofAnesthesiologyCivicCampusNitrousOxide•N20leavesblood34xmorethanN2absorbed•Sure,otheragentsaremoresolublebutwedon’tgiv

ethemat70%end-tidalconcentration•distensionofclosedairspaces•70%N2Owilldoubleapneumoin10minutesAgentBlood:GasPCNitrousOxide0.47Nitrogen

0.014DepartmentofAnesthesiologyCivicCampusMechanismofAction•Meyer-OvertonTheory•lipidsolubleagentspreadsmembran

esdistortingmembraneproteins(ieionchannels).•ProteinReceptorHypothesis•inhaledagentbindstomembraneproteinandchangesionconductance•Neurotransmit

terAvailability•inhaledagentpreventsbreakdownofGABA•Greg’sPostulate•ifmorethanonetheory-thennoonereallyknowsDep

artmentofAnesthesiologyCivicCampusMetabolismofinhaledanesthetics•Fairlysmallcomponentofelimination•Occursatcytochromep450•Inducible•Oxidative•o

-dealkylation•dehalogenation•epoxidation•Reductive•occursonlywithhalothaneinhypoxicconditionsDepartmentofAnesth

esiologyCivicCampusThreedeterminantsofmetabolism•Chemicalstructure•etherbond•carbon-halogenbond•Hepaticenzy

meactivity•BloodconcentrationDepartmentofAnesthesiologyCivicCampusMetabolismofinhaledanestheticsIIAgent%metabolizedHalothane20Sevoflurane2-5Enflurane

2.4Isoflurane0.2Desflurane0.02NitrousOxide0.004Table15-1.Barash4thEdition.p378.DepartmentofAnesthesiologyCiv

icCampusBreakDepartmentofAnesthesiologyCivicCampusMinimumalveolarconcentration•Alveolarconcentrationrequiredtopreventmovementin50%ofsubjects•st

andardstimulus•representsbrainconcentration•consistentwithinandbetweenspecies•additiveDepartmentofAnest

hesiologyCivicCampusMACValuesAgentMACNitrousoxide104Desflurane6.6Sevoflurane1.8Enflurane1.63Isoflurane1.17Halothane

0.75Table15-1.Barash4thEdition.p378.DepartmentofAnesthesiologyCivicCampusFactorsincreasingMAC•Hypert

hermia•ChronicETOHabuse•Hypernatremia•IncreasedCNStransmitters•MAOI•Amphetamine•Cocaine•Ephedrine•L-DOPATable15.4.Barash4thEdition.P389Depar

tmentofAnesthesiologyCivicCampusFactorsdecreasingMAC•Increasingage•Hypothermia•Hyponatremia•Hypotension(MAP<50mmHg)•Pregnancy•Hypoxemia(<

38mmHg)•O2content(<4.3mlO2/dl)•Metabolicacidosis•Narcotics•Ketamine•Benzodiazepines•2agonists•LiCO3•Localanesthetics•ETOH(acute)•Andmanymore...Table

15.5.Barash4thEdition.P390DepartmentofAnesthesiologyCivicCampusFactorswithnoinfluenceonMAC•Durationofanesthesia•Sex•Alkalosis•PCO2•Hypertension•Anem

ia•Potassium•Magnseium•AndothersDepartmentofAnesthesiologyCivicCampusEffectsonorgansystems•Cardiovascular•Pulmonary•CNS•N

euromuscular•Hepatic•Renal•Uterine•MiscellaneousDepartmentofAnesthesiologyCivicCampusInhaledanestheticsandt

heCVsystem•Effectcanbehardtoquantify•Invitroandinvivoeffectscanbequitedifferent•Sympatheticstimulation•Baroreceptorreflexes•Animalmodelvshumansubj

ect•Informationprovidedinthislectureisabroadoverview.•PleaserefertoMillerforadetaileddiscussionofthetopicDepartmentofAnesthesiology

CivicCampusBloodpressure•AlldecreaseBP,exceptN2O•Effectcausedbyacombinationof•Vasodilation•Myocardialdepression’•DecreasedCNStone•Rela

tivecontributionofeachisdrugdependentDepartmentofAnesthesiologyCivicCampusHeartrate•Effectsvariableandagent-specific•halothanedecreasesHR•S

evofluraneandenfluraneneutral•Desfluraneassociatedwithtransienttachycardia•occurswithrapidincreasesinM

AC•associatedwithincreasesinserumcatecholamines•similareffectmaybeseenwithisofluraneDepartmentofAnesthes

iologyCivicCampusMyocardialcontractility•Allvolatileanestheticsaredirectmyocardialdepressantsinvitro,includingN2O.•Effectoncirculationi

nvivomodifiedbyeffectsonpulmonarycirculationandsympatheticstimulation.•Asbestaswecantell,at1MACanestheticsdepresscontractilityinthefollowingorder•H=

E>I=D=S.DepartmentofAnesthesiologyCivicCampusCardiacoutput•Despitemyocardialdepressioncardiacoutputiswell-ma

intainedwithisofluraneanddesflurane•preservationofheartrate•greaterreductioninSVR•preservationofbaroreceptorreflexesDepartmentofAnesthesiologyCiv

icCampusSystemicvascularresistance•Allaredirectvasodilators,exceptN2O•relaxvascularsmoothmuscle•cAMP-Ca2+andornitricoxideinvolved•variabl

eeffectsonindividualvascularbedsDepartmentofAnesthesiologyCivicCampusDysrhytmias•Halothanepotentiatescatecholamine-relat

eddysrhythmias•ED50ofepinehrineproducingdysrhythmiasat1.25MAC•halothane2.1g•kg-1•isoflurane6.9g•kg-1•enflurane10.9g•kg-1•Lidocainedoubl

esED50ofepinephrine•ChildrensomewhatmoreresistantDepartmentofAnesthesiologyCivicCampusCoronarybloodflow•Isofluraneisapotentco

ronaryvasodilator•Intheory,dilationofnormalcoronaryvesselscandirectbloodflowawayfromstenoticcoronaries•Steal-pronean

atomy•totalocclusionof1majorcoronaryvessel•collateralperfusionwith90%stenosis•Inpractice,doesn’tseemtobeaproblemDepartmentofAnesthesiolo

gyCivicCampusRespiratorypattern•Increasedfrequency•Decreasedtidalvolume•Decreasedminuteventilation•Attribute

d(incats)tosensitizationofpulmonarystretchreceptors-notsupportedinhumansDepartmentofAnesthesiologyCivic

CampusMechanoreceptors•Sensetensioninmuscles/tendonsinintercostalmuscles•Increasedresistancedetectedandin

creasedrespiratoryeffortrecruited•Responsestoinspiratoryandexpiratoryloadsdiminished•FurtherinhibitioninpatientswithCOPDDepartmentofAnest

hesiologyCivicCampusChemoreceptors•Apneicthresholdraised•ResponsetoPCO2blunted•PCO2increasedwhilespontaneouslyventilating•E>D=I>S=H•hypoxi

cdriveabolishedby0.1MACDepartmentofAnesthesiologyCivicCampusBronchialmusculature•Reducevagaltone•Direct

relaxation•increasedcAMP(butnotviaadrenoreceptormediated)•Whenbronchospastic,adosedependentreductioninRawoc

curswithmostagentsDepartmentofAnesthesiologyCivicCampusHypoxicpulmonaryvasoconstriction•InhaledanestheticsappeartobluntHPVandincreaseshun

t•ShuntandPO2appearunchangedinstudiesofinhaledanestheticsduringonelungventilation•IntrinsicchangesinHPVconfoundedby•changesincardiacoutput•

pulmonaryarterypressure•positionDepartmentofAnesthesiologyCivicCampusCentralnervoussystem•Increasecerebralbloodflow•IncreaseICP•DecreasedCMRO2•Decr

easedfrequency-increasedvoltageonEEG•2MACenfluraneincreasesseizureactivity•Decreasedamplitude-increas

edlatencyonSSEPDepartmentofAnesthesiologyCivicCampusNeuromuscularfunction•Skeletalmusclerelaxation•Potenti

ateNDMR•TriggerMHDepartmentofAnesthesiologyCivicCampusHepatic•Hepaticarterialbloodflowdecreasedbyhalothane•Clearanceofd

rugsdecreasedinkeepingwithreductionsinhepaticbloodflow•Hepatotoxicity•mild,transient,postoperativeincreaseinLFTs•?duetotransienthypoxia±re

ductivemetabolites•massivehepaticnecrosis•oxidativemetabolitebindstohepatocyte•repeatexposureleadstoimmune-media

tednecrosisDepartmentofAnesthesiologyCivicCampusRenal•Dose-dependentdecreasesin•renalbloodflow•glomerularfiltrationrate•urineoutput•Rel

atedtochangesinCOandBPnotADH•Fluoridenephrotoxicityatserumconc.50mol/l•F-opposesADHleadingtopolyuria•methoxyflurane2.5MAC-hours•enflurane9.

6MAC-hoursDepartmentofAnesthesiologyCivicCampusObstetrical•N2Ohasnoeffect•Halogenatedvolatilesleadtodose-dependent•uterinerel

axation•reductionsinuterinebloodflowDepartmentofAnesthesiologyCivicCampusMiscellaneous•N2O-relatedmyelosupressionif>12hrexposure•inhibitiono

fmethionine-synthetase•megaloblasticanemia•Inhaledanesthetics,N2Oinparticular,decreaseleukocytefunct

ion•Teratogenesiswithprolongedexposureinrats•Increasedrisk(RR=1.3)ofspontaneousabortionwithchronicexposuretoN20更多精品资请访问更多品资源请访问