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ClinicalPharmacologyof

InhaledAnestheticsDepartmentofAnesthesiologyUniversityofOttawaCoreProgramLectureSeriesSeptember2019ClinicalPharmacologyof

InhaAnoteforthoseatthelectureThoseIwasabletokeepawakemightnoticethatI’veadded/modifiedacoupleoftheslidestobetterreflecttheinformationinthelatestversionsofyourtextbooks.MuchthematerialonCVandRSeffectscanbeannoyinglyinconsistentbetweentextsandeditionsForthosewhoaskedabout“protection”andvolatileanesthesiaI’veappendedacoupleofrecentarticles“foryourinterest”“FYI”meansthatIwon’texamineyouonthisstuffbuttheRoyalCollegemight!Thisstuffisrelativelynewandpartofabroaderareaofresearchinischemicpreconditioning–youknow,ratstuffThanksforattending!AnoteforthoseatthelecturObjectivesIChemicalstructureStructure-functionrelationshipsPhysiochemicalpropertiesMechanismofactionPharmacokineticsofInhaledAgentsUptakeandDistributionFa/Ficurves,andfactorswhichaffectthemMetabolismofInhalationAnestheticsObjectivesIChemicalstructureObjectivesIIDefinitionofMACFactorswhichaffectMACCardiovasculareffectsPulmonaryeffectsCNSeffectsNeuromusculareffectsHepaticeffectsRenaleffectsUterineeffectsMarroweffectsObjectivesIIDefinitionofMACTherealityThere’sanawfullotofstuffhere-noneofitis“new”AllofitisinthetextbooksBarash4thEditionChapter15.InhalationAnesthesia.377-417.Miller5thEditionChapter3.MechanismsofAction.48-73Chapter4.UptakeandDistribution.74-95Chapter5a.CardiovascularPharmacology.96-124Chapter5b.PulmonaryPharmacology.125-146Chapter6.MetabolismandToxicity.147-173MuchofitrequiresrotememorizationSomeofituseful-allofit“test-able”Ican’tcoverallofitin3hoursTherealityThere’sanawfulloGreg’sgoalsforthislectureInflictmyviewofwhatyoushouldknowPutthisinaclinical(read:useful)contextExplainthatwhichneedsexplainingLeavethememoryworktoyouBebackonmyporch,beerinhand,by1730Greg’sgoalsforthislectureIChemicalstructureINitrousOxideDiethylEtherHalothaneChemicalstructureINitrousOxFunwithchemistryHalogenationreducesflammabilityFluorinationreducessolubilityTrifluorcarbongroupsaddstabilityAlkanesprecipitatearrythmiasFunwithchemistryHalogenationChemicalstructureIIIsofluraneSevofluraneDesfluraneChemicalstructureIIIsofluranPhysicalcharacteristicsPleasecramthecontentsoftheappropriatetable15.1fromBarash4thEdthenightbeforetheexam.Takehomepointsinclude:desfluraneboilsat24OChalothaneispreservedwiththymolvaporpressuresareneededforsomeexamquestionsknowledgeofblood:gaspartitioncoefficientsmayactuallybeusefulPhysicalcharacteristicsPleasePartitioncoefficientsRepresenttherelativeaffinityofagasfor2differentsubstances(solubility)Measuredatequilibriumsopartialpressuresareequal,but...Theamountsofgasdissolvedineachsubstance(concentration)aren’tequal.Wemostcommonlyrefertoblood:gaspcThelargerthenumber,themoresolubleinbloodPartitioncoefficientsRepresenBlood:gaspartitioncoefficientsTable15-1.Barash4thEdition.p378.Blood:gaspartitioncoefficienTheblood:gaspcisuseful,really.Anesthesiaisrelatedtothepartialpressureofthegasinthebrain.Ifadrugisdissolvedinblood,itisn’tavailableasagasMoremoleculesofasolublegasarerequiredtosaturateliquidphasebeforeincreasingpartialpressureSpeedofonset/offsetcloselyrelatedtosolubilityThelowertheblood:gaspc-thefastertheonsetTheblood:gaspcisuseful,reUptakeanddistributionAnesthesiadependsuponbrainpartialpressureAlveolarpartialpressure(PA)=PbrainThefasterPAapproachesthedesiredlevelthefasterthepatientisanesthetizedPAisabalancebetweendeliveryofdrugtothealveolusanduptakeofthatdrugintothebloodTimeforananalogyUptakeanddistributionAnestheToinduceanesthesiathebucket(PA)mustbefull.Unfortunatelythebuckethasaleak(uptake).Tofillthebucketyoumusteither(a)pouritinfaster(increasedelivery)or(b)slowdowntheleak(decreaseuptake).abToinduceanesthesiathebuckeFactorsinfluencingdeliveryAlveolarventilationBreathingsystemvolumefreshgasflowInspiredpartialpressure(PI)concentrationeffectsecondgaseffectFactorsinfluencingdeliveryAlConcentrationand2ndgaseffectsConcentrationand2ndgaseffeFactorsinfluencinguptakeSolubility(blood:gaspc)CardiacoutputAlveolar-venouspressuregradientForthoseofyouwholikeformulae:Uptake=?Q?(PA-Pv)/BPFactorsinfluencinguptakeSoluFA/FICurvesFA/FICurvesV/QdistributionanduptakeVentilation<perfusionbloodleavingshuntdilutesPAfromnormallunginductionwithlowsolubilityagentwillbedelayedlittledifferencewithsolubleagents(slowanyway)Ventilation>perfusionuptakeisdecreasedwhichenhancesriseinFAmayspeedinductionforsolubleagentslessdifferencewithlowsolubilityagents(fastanyway)V/QdistributionanduptakeVenNitrousOxideN20leavesblood34xmorethanN2absorbedSure,otheragentsaremoresolublebutwedon’tgivethemat70%end-tidalconcentrationdistensionofclosedairspaces70%N2Owilldoubleapneumoin10minutesNitrousOxideN20leavesbloodMechanismofActionMeyer-OvertonTheorylipidsolubleagentspreadsmembranesdistortingmembraneproteins(ieionchannels).ProteinReceptorHypothesisinhaledagentbindstomembraneproteinandchangesionconductanceNeurotransmitterAvailabilityinhaledagentpreventsbreakdownofGABAGreg’sPostulateifmorethanonetheory-thennoonereallyknowsMechanismofActionMeyer-OvertMetabolismofinhaledanestheticsFairlysmallcomponentofeliminationOccursatcytochromep450InducibleOxidativeo-dealkylationdehalogenationepoxidationReductiveoccursonlywithhalothaneinhypoxicconditionsMetabolismofinhaledanesthetThreedeterminantsofmetabolismChemicalstructureetherbondcarbon-halogenbondHepaticenzymeactivityBloodconcentrationThreedeterminantsofmetaboliMetabolismofinhaledanestheticsIITable15-1.Barash4thEdition.p378.MetabolismofinhaledanesthetBreakBreakMinimumalveolarconcentrationAlveolarconcentrationrequiredtopreventmovementin50%ofsubjectsstandardstimulusrepresentsbrainconcentrationconsistentwithinandbetweenspeciesadditiveMinimumalveolarconcentrationMACValuesTable15-1.Barash4thEdition.p378.MACValuesTable15-1.Barash4FactorsincreasingMACHyperthermiaChronicETOHabuseHypernatremiaIncreasedCNStransmittersMAOIAmphetamineCocaineEphedrineL-DOPATable15.4.Barash4thEdition.P389FactorsincreasingMACHypertheFactorsdecreasingMACIncreasingageHypothermiaHyponatremiaHypotension(MAP<50mmHg)PregnancyHypoxemia(<38mmHg)O2content(<4.3mlO2/dl)MetabolicacidosisNarcoticsKetamineBenzodiazepines2agonistsLiCO3LocalanestheticsETOH(acute)Andmanymore...Table15.5.Barash4thEdition.P390FactorsdecreasingMACIncreasiFactorswithnoinfluenceonMACDurationofanesthesiaSexAlkalosisPCO2HypertensionAnemiaPotassiumMagnseiumAndothersFactorswithnoinfluenceonMEffectsonorgansystemsCardiovascularPulmonaryCNSNeuromuscularHepaticRenalUterineMiscellaneousEffectsonorgansystemsCardioInhaledanestheticsandtheCVsystemEffectcanbehardtoquantifyInvitroandinvivoeffectscanbequitedifferentSympatheticstimulationBaroreceptorreflexesAnimalmodelvshumansubjectInformationprovidedinthislectureisabroadoverview.PleaserefertoMillerforadetaileddiscussionofthetopicInhaledanestheticsandtheCVBloodpressureAlldecreaseBP,exceptN2OEffectcausedbyacombinationofVasodilationMyocardialdepression’DecreasedCNStoneRelativecontributionofeachisdrugdependentBloodpressureAlldecreaseBP,HeartrateEffectsvariableandagent-specifichalothanedecreasesHRSevofluraneandenfluraneneutralDesfluraneassociatedwithtransienttachycardiaoccurswithrapidincreasesinMACassociatedwithincreasesinserumcatecholaminessimilareffectmaybeseenwithisofluraneHeartrateEffectsvariableandMyocardialcontractilityAllvolatileanestheticsaredirectmyocardialdepressantsinvitro,includingN2O.Effectoncirculationinvivomodifiedbyeffectsonpulmonarycirculationandsympatheticstimulation.Asbestaswecantell,at1MACanestheticsdepresscontractilityinthefollowingorderH=E>I=D=S.MyocardialcontractilityAllvoCardiacoutputDespitemyocardialdepressioncardiacoutputiswell-maintainedwithisofluraneanddesfluranepreservationofheartrategreaterreductioninSVRpreservationofbaroreceptorreflexesCardiacoutputDespitemyocardiSystemicvascularresistanceAllaredirectvasodilators,exceptN2OrelaxvascularsmoothmusclecAMP-Ca2+andornitricoxideinvolvedvariableeffectsonindividualvascularbedsSystemicvascularresistanceAlDysrhytmiasHalothanepotentiatescatecholamine-relateddysrhythmiasED50ofepinehrineproducingdysrhythmiasat1.25MAChalothane2.1g?kg-1isoflurane6.9g?kg-1enflurane10.9

g?kg-1

LidocainedoublesED50ofepinephrineChildrensomewhatmoreresistantDysrhytmiasHalothanepotentiatCoronarybloodflowIsofluraneisapotentcoronaryvasodilatorIntheory,dilationofnormalcoronaryvesselscandirectbloodflowawayfromstenoticcoronariesSteal-proneanatomytotalocclusionof1majorcoronaryvesselcollateralperfusionwith90%stenosisInpractice,doesn’tseemtobeaproblemCoronarybloodflowIsofluraneRespiratorypatternIncreasedfrequencyDecreasedtidalvolumeDecreasedminuteventilationAttributed(incats)tosensitizationofpulmonarystretchreceptors-notsupportedinhumansRespiratorypatternIncreasedfMechanoreceptorsSensetensioninmuscles/tendonsinintercostalmusclesIncreasedresistancedetectedandincreasedrespiratoryeffortrecruitedResponsestoinspiratoryandexpiratoryloadsdiminishedFurtherinhibitioninpatientswithCOPDMechanoreceptorsSensetensionChemoreceptorsApneicthresholdraisedResponsetoPCO2bluntedPCO2increasedwhilespontaneouslyventilatingE>D=I>S=Hhypoxicdriveabolishedby0.1MACChemoreceptorsApneicthresholdBronchialmusculatureReducevagaltoneDirectrelaxationincreasedcAMP(butnotviaadrenoreceptormediated)Whenbronchospastic,adosedependentreductioninRawoccurswithmostagentsBronchialmusculatureReducevaHypoxicpulmonaryvasoconstrictionInhaledanestheticsappeartobluntHPVandincreaseshuntShuntandPO2appearunchangedinstudiesofinhaledanestheticsduringonelungventilationIntrinsicchangesinHPVconfoundedbychangesincardiacoutputpulmonaryarterypressurepositionHypoxicpulmonaryvasoconstricCentralnervoussystemIncreasecerebralbloodflowIncreaseICPDecreasedCMRO2Decreasedfrequency-increasedvoltageonEEG2MACenfluraneincreasesseizureactivityDecreasedamplitude-increasedlatencyonSSEPCentralnervoussystemIncreaseNeuromuscularfunctionSkeletalmusclerelaxationPotentiateNDMRTriggerMHNeuromuscularfunctionSkeletalHepaticHepaticarterialbloodflowdecreasedbyhalothaneClearanceofdrugsdecreasedinkeepingwithreductionsinhepaticbloodflowHepatotoxicitymild,transient,postoperativeincreaseinLFTs?duetotransienthypoxia±reductivemetabolitesmassivehepaticnecrosisoxidativemetabolitebindstohepatocyterepeatexposureleadstoimmune-mediatednecrosisHepaticHepaticarterialbloodRenalDose-dependentdecreasesinrenalbloodflowglomerularfiltrationrateurineoutputRelatedtochangesinCOandBPnotADHFluoridenephrotoxicityatserumconc.50mol/lF-opposesADHleadingtopolyuriamethoxyflurane2.5MAC-hoursenflurane9.6MAC-hoursRenalDose-dependentdecreasesObstetricalN2OhasnoeffectHalogenatedvolatilesleadtodose-dependentuterinerelaxationreductionsinuterinebloodflowObstetricalN2OhasnoeffectMiscellaneousN2O-relatedmyelosupressionif>12hrexposureinhibitionofmethionine-synthetasemegaloblasticanemiaInhaledanesthetics,N2Oinparticular,decreaseleukocytefunctionTeratogenesiswithprolongedexposureinratsIncreasedrisk(RR=1.3)ofspontaneousabortionwithchronicexposuretoN20MiscellaneousN2O-relatedmyeloClinicalPharmacologyof

InhaledAnestheticsDepartmentofAnesthesiologyUniversityofOttawaCoreProgramLectureSeriesSeptember2019ClinicalPharmacologyof

InhaAnoteforthoseatthelectureThoseIwasabletokeepawakemightnoticethatI’veadded/modifiedacoupleoftheslidestobetterreflecttheinformationinthelatestversionsofyourtextbooks.MuchthematerialonCVandRSeffectscanbeannoyinglyinconsistentbetweentextsandeditionsForthosewhoaskedabout“protection”andvolatileanesthesiaI’veappendedacoupleofrecentarticles“foryourinterest”“FYI”meansthatIwon’texamineyouonthisstuffbuttheRoyalCollegemight!Thisstuffisrelativelynewandpartofabroaderareaofresearchinischemicpreconditioning–youknow,ratstuffThanksforattending!AnoteforthoseatthelecturObjectivesIChemicalstructureStructure-functionrelationshipsPhysiochemicalpropertiesMechanismofactionPharmacokineticsofInhaledAgentsUptakeandDistributionFa/Ficurves,andfactorswhichaffectthemMetabolismofInhalationAnestheticsObjectivesIChemicalstructureObjectivesIIDefinitionofMACFactorswhichaffectMACCardiovasculareffectsPulmonaryeffectsCNSeffectsNeuromusculareffectsHepaticeffectsRenaleffectsUterineeffectsMarroweffectsObjectivesIIDefinitionofMACTherealityThere’sanawfullotofstuffhere-noneofitis“new”AllofitisinthetextbooksBarash4thEditionChapter15.InhalationAnesthesia.377-417.Miller5thEditionChapter3.MechanismsofAction.48-73Chapter4.UptakeandDistribution.74-95Chapter5a.CardiovascularPharmacology.96-124Chapter5b.PulmonaryPharmacology.125-146Chapter6.MetabolismandToxicity.147-173MuchofitrequiresrotememorizationSomeofituseful-allofit“test-able”Ican’tcoverallofitin3hoursTherealityThere’sanawfulloGreg’sgoalsforthislectureInflictmyviewofwhatyoushouldknowPutthisinaclinical(read:useful)contextExplainthatwhichneedsexplainingLeavethememoryworktoyouBebackonmyporch,beerinhand,by1730Greg’sgoalsforthislectureIChemicalstructureINitrousOxideDiethylEtherHalothaneChemicalstructureINitrousOxFunwithchemistryHalogenationreducesflammabilityFluorinationreducessolubilityTrifluorcarbongroupsaddstabilityAlkanesprecipitatearrythmiasFunwithchemistryHalogenationChemicalstructureIIIsofluraneSevofluraneDesfluraneChemicalstructureIIIsofluranPhysicalcharacteristicsPleasecramthecontentsoftheappropriatetable15.1fromBarash4thEdthenightbeforetheexam.Takehomepointsinclude:desfluraneboilsat24OChalothaneispreservedwiththymolvaporpressuresareneededforsomeexamquestionsknowledgeofblood:gaspartitioncoefficientsmayactuallybeusefulPhysicalcharacteristicsPleasePartitioncoefficientsRepresenttherelativeaffinityofagasfor2differentsubstances(solubility)Measuredatequilibriumsopartialpressuresareequal,but...Theamountsofgasdissolvedineachsubstance(concentration)aren’tequal.Wemostcommonlyrefertoblood:gaspcThelargerthenumber,themoresolubleinbloodPartitioncoefficientsRepresenBlood:gaspartitioncoefficientsTable15-1.Barash4thEdition.p378.Blood:gaspartitioncoefficienTheblood:gaspcisuseful,really.Anesthesiaisrelatedtothepartialpressureofthegasinthebrain.Ifadrugisdissolvedinblood,itisn’tavailableasagasMoremoleculesofasolublegasarerequiredtosaturateliquidphasebeforeincreasingpartialpressureSpeedofonset/offsetcloselyrelatedtosolubilityThelowertheblood:gaspc-thefastertheonsetTheblood:gaspcisuseful,reUptakeanddistributionAnesthesiadependsuponbrainpartialpressureAlveolarpartialpressure(PA)=PbrainThefasterPAapproachesthedesiredlevelthefasterthepatientisanesthetizedPAisabalancebetweendeliveryofdrugtothealveolusanduptakeofthatdrugintothebloodTimeforananalogyUptakeanddistributionAnestheToinduceanesthesiathebucket(PA)mustbefull.Unfortunatelythebuckethasaleak(uptake).Tofillthebucketyoumusteither(a)pouritinfaster(increasedelivery)or(b)slowdowntheleak(decreaseuptake).abToinduceanesthesiathebuckeFactorsinfluencingdeliveryAlveolarventilationBreathingsystemvolumefreshgasflowInspiredpartialpressure(PI)concentrationeffectsecondgaseffectFactorsinfluencingdeliveryAlConcentrationand2ndgaseffectsConcentrationand2ndgaseffeFactorsinfluencinguptakeSolubility(blood:gaspc)CardiacoutputAlveolar-venouspressuregradientForthoseofyouwholikeformulae:Uptake=?Q?(PA-Pv)/BPFactorsinfluencinguptakeSoluFA/FICurvesFA/FICurvesV/QdistributionanduptakeVentilation<perfusionbloodleavingshuntdilutesPAfromnormallunginductionwithlowsolubilityagentwillbedelayedlittledifferencewithsolubleagents(slowanyway)Ventilation>perfusionuptakeisdecreasedwhichenhancesriseinFAmayspeedinductionforsolubleagentslessdifferencewithlowsolubilityagents(fastanyway)V/QdistributionanduptakeVenNitrousOxideN20leavesblood34xmorethanN2absorbedSure,otheragentsaremoresolublebutwedon’tgivethemat70%end-tidalconcentrationdistensionofclosedairspaces70%N2Owilldoubleapneumoin10minutesNitrousOxideN20leavesbloodMechanismofActionMeyer-OvertonTheorylipidsolubleagentspreadsmembranesdistortingmembraneproteins(ieionchannels).ProteinReceptorHypothesisinhaledagentbindstomembraneproteinandchangesionconductanceNeurotransmitterAvailabilityinhaledagentpreventsbreakdownofGABAGreg’sPostulateifmorethanonetheory-thennoonereallyknowsMechanismofActionMeyer-OvertMetabolismofinhaledanestheticsFairlysmallcomponentofeliminationOccursatcytochromep450InducibleOxidativeo-dealkylationdehalogenationepoxidationReductiveoccursonlywithhalothaneinhypoxicconditionsMetabolismofinhaledanesthetThreedeterminantsofmetabolismChemicalstructureetherbondcarbon-halogenbondHepaticenzymeactivityBloodconcentrationThreedeterminantsofmetaboliMetabolismofinhaledanestheticsIITable15-1.Barash4thEdition.p378.MetabolismofinhaledanesthetBreakBreakMinimumalveolarconcentrationAlveolarconcentrationrequiredtopreventmovementin50%ofsubjectsstandardstimulusrepresentsbrainconcentrationconsistentwithinandbetweenspeciesadditiveMinimumalveolarconcentrationMACValuesTable15-1.Barash4thEdition.p378.MACValuesTable15-1.Barash4FactorsincreasingMACHyperthermiaChronicETOHabuseHypernatremiaIncreasedCNStransmittersMAOIAmphetamineCocaineEphedrineL-DOPATable15.4.Barash4thEdition.P389FactorsincreasingMACHypertheFactorsdecreasingMACIncreasingageHypothermiaHyponatremiaHypotension(MAP<50mmHg)PregnancyHypoxemia(<38mmHg)O2content(<4.3mlO2/dl)MetabolicacidosisNarcoticsKetamineBenzodiazepines2agonistsLiCO3LocalanestheticsETOH(acute)Andmanymore...Table15.5.Barash4thEdition.P390FactorsdecreasingMACIncreasiFactorswithnoinfluenceonMACDurationofanesthesiaSexAlkalosisPCO2HypertensionAnemiaPotassiumMagnseiumAndothersFactorswithnoinfluenceonMEffectsonorgansystemsCardiovascularPulmonaryCNSNeuromuscularHepaticRenalUterineMiscellaneousEffectsonorgansystemsCardioInhaledanestheticsandtheCVsystemEffectcanbehardtoquantifyInvitroandinvivoeffectscanbequitedifferentSympatheticstimulationBaroreceptorreflexesAnimalmodelvshumansubjectInformationprovidedinthislectureisabroadoverview.PleaserefertoMillerforadetaileddiscussionofthetopicInhaledanestheticsandtheCVBloodpressureAlldecreaseBP,exceptN2OEffectcausedbyacombinationofVasodilationMyocardialdepression’DecreasedCNStoneRelativecontributionofeachisdrugdependentBloodpressureAlldecreaseBP,HeartrateEffectsvariableandagent-specifichalothanedecreasesHRSevofluraneandenfluraneneutralDesfluraneassociatedwithtransienttachycardiaoccurswithrapidincreasesinMACassociatedwithincreasesinserumcatecholaminessimilareffectmaybeseenwithisofluraneHeartrateEffectsvariableandMyocardialcontractilityAllvolatileanestheticsaredirectmyocardialdepressantsinvitro,includingN2O.Effectoncirculationinvivomodifiedbyeffectsonpulmonarycirculationandsympatheticstimulation.Asbestaswecantell,at1MACanestheticsdepresscontractilityinthefollowingorderH=E>I=D=S.MyocardialcontractilityAllvoCardiacoutputDespitemyocardialdepressioncardiacoutputiswell-maintainedwithisofluraneanddesfluranepreservationofheartrategreaterreductioninSVRpreservationofbaroreceptorreflexesCardiacoutputDespitemyocardiSystemicvascularresistanceAllaredirectvasodilators,exceptN2OrelaxvascularsmoothmusclecAMP-Ca2+andornitricoxideinvolvedvariableeffectsonindividualvascularbedsSystemicvascularresistanceAlDysrhytmiasHalothanepotentiatescatecholamine-relateddysrhythmiasED50ofepinehrineproducingdysrhythmiasat1.25MAChalothane2.1g?kg-1isoflurane6.9g?kg-1enflurane10.9

g?kg-1

LidocainedoublesED50ofepinephrineChildrensomewhatmoreresistantDysrhytmiasHalothanepotentiatCoronarybloodflowIsofluraneisapotentcoronaryvasodilatorIntheory,dilationofnormalcoronaryvesselscandirectbloodflowawayfromstenoticcoronariesSteal-proneanatomytotalocclusionof1majorcoronaryvesselcollateralperfusionwith90%stenosisInpractice,doesn’tseemtobeaproblemCoronarybloodflowIsofluraneRespiratorypatternIncreasedfrequencyDecreasedtidalvolumeDecreasedminuteventilationAttributed(incats)tosensitizationofpulmonarystretchreceptors-notsupportedinhumansRespiratorypatternIncreasedfMechanoreceptorsSensetensionin

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