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Intravenous Anesthetics and Sedatives

BabakSadighiJessicaBlack

Beforeexamininganyanestheticmedicationindetail,itisimportanttoconsiderwhatoccurswhenanintravenoussedativeisadministered.Unlikeinhaled
agents,themechanismsofactionforintravenoussedativesandanestheticsarewellcharacterized.
Initially,themedicationwillbetransportedanddilutedwithinthepatientscardiovascularsystem.Therewillbenochangeinthepatientslevelof
consciousness.Someofthemedicationwillbetransportedacrossthebloodbrainbarrierwhereitwillbecomeredistributedtoitseffectsiteandbindtothe
receptorsforwhichithasaffinity.
Asthemedicationbindstoitstargetreceptors,theonsetofsedationcanbeobserved.Therewillbeaprogressivediminutioninthepatientslevelof
consciousness,continuinguntilchemicalequilibriumisreachedattheeffectsite.Dependingonthemedicationandthequantityadministered,thisdecreased
levelofconsciousnessmayrangefromlightsedationwithpreservedspontaneousventilationtogeneralanesthesiawithapnea.
Themedicationthatiscirculatinginthecardiovascularsystemiseventuallyeliminatedfromthebody,metabolizedintoaninactiveordegradedform,or
redistributedandsequesteredintootherperipheraltissuesinwhichitproducesnoeffect.Theconcentrationofthemedicationwithinthecerebralcirculationwill
starttofall,andtheconcentrationgradientwilldrawthemedicationawayfromitseffectsite.Bindingatthetargetreceptorswithinthebrainthendecreases,
andrecoverytowardconsciousnessbegins.
Ifitisdesiredtoprolongthepatientssedation,additionalmedicationcanbeadministered.Inresponsetothesefurtherdoses,theconcentrationofmedication
willinsteadapproachanewequilibriumconcentrationwithacorrespondinglevelofclinicalsedation.Eventually,thepatientcanbeallowedtorecoverby
discontinuingtheinfusion.Theadditionalmedicationadministeredmustthenbeeliminated,metabolized,orredistributed.Themedicationwillreturninto
circulationfromtheperipheraltissuesintowhichithadbeensequestered.Thequantityofmedicationpresentmayalsotemporarilyexceedthemetabolic
capacityofthepathwaysbywhichitisdegraded.Consequently,theclinicalreturntoconsciousnesswillnowbeslowerthanbeforeandwilldependonthe
quantityanddurationofthemedicationsadministration.Finally,itmustbeconsideredthatanindividualmaynotrespondasexpectedormayhavean
unanticipatedadversereactiontothemedicationinstead.
Inthisvignette,therearefourpharmacologicthemes,illustratingtheclinicaluseofanintravenousanestheticorsedative:
1.Mechanismofaction:molecularinteractionofamedicationwithareceptor
2.Pharmacokineticprofile:thetrafficking,redistribution,andeliminationofthemedicationwithinthebody
3.Pharmacodynamicprofile:thebehaviorofaconcentrationofthismedicationatthepopulationofreceptorswithinthebrain
4.Adversereactions:theextenttowhichthemedicationmayproduceallergicorhypersensitivityreactions.

I. General Pharmacology of Intravenous Anesthetics

A. Mechanism of Action
Themostcommonlyusedintravenousanestheticagentsthebarbiturates,propofol,thebenzodiazepines,andetomidateallactatthesiteofthe
aminobutyricacidA(GABAA)receptor,asshownschematicallyinFigure91.GABAisthemaininhibitoryneurotransmitterwithinthecentralnervoussystem,
anditsactionattheGABAAreceptorcausesincreasedtransportofchloride(Cl)ionsacrossthemembraneandintothepostsynapticneuron.The
postsynapticneuronbecomeshyperpolarized,whichfunctionallyinhibitsfurtherpropagationofnervesignals.TheGABAAreceptoristhereforealigand
activatedionchannelcomposedoffivesubunits.IntravenousanestheticsthatbindtotheGABAAreceptordonotbindatthesamelocationasGABAitself
(theorthostericbindingsite),insteadtheybindatotherlocations(allostericsites)andchangetheeffectofGABAuponthereceptor.Theseintravenous
anestheticsarethereforepositiveallostericmodulatorsoftheGABAAreceptorandcausereceptorconformationalchangessuchthattheactionofGABAitself
ispotentiatedandsedationoccurs.ThesubunitcompositionofGABAAreceptorscanvary:thereare19differentpossiblesubunitsarisingfromeightdifferent
subunitclasses(16,13,13,,,,,and).Intravenousanestheticagentsmayonlybeactiveatreceptorsexpressingcertaincombinations:the
benzodiazepineallostericbindingsiteoccursonlyattheinterfaceofand2subunits,andetomidateisactiveprimarilyatGABAAreceptorsthatcontain2
or3subunits.

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GABAisthemaininhibitoryneurotransmitterwithinthecentralnervoussystem.ItsactionattheGABAAreceptorcausesincreasedtransportofchloride(Cl)
ionsacrossthemembrane,causingittobecomehyperpolarized.

Figure91SchematicmodeloftheaminobutyricacidA(GABAA)receptorcomplex,illustratingrecognitionsitesformanyofthesubstancesthatbindtothe
receptor.(FromWhitePF,EngMR.Intravenousanesthetics.In:BarashPG,CullenBF,StoeltingRK,etal.ClinicalAnesthesia.7thed.Philadelphia:Wolters
KluwerHealth/LWW,2013:480,withpermission.)

VIDEO91
GABAAReceptors

B. Pharmacokinetics and Metabolism

Theredistributionandeliminationofintravenousanestheticswithinthebodycanbeapproximatedwithasimplifiedthreecompartmentmodelofthebody.In
thismodel,medicationsareadministeredintoafirstwellmixedcentralcompartment.Diffusionoccursbackandforthbetweenthisfirstcompartmentandthe
additionalsecondandthirdperipheralcompartments.Thediffusionconstants(shownaskinFig.92)aresuchthatoneperipheralcompartmentequilibrates
quicklywiththecentralcompartmentandoneequilibratesmoreslowly.Thedrugisnotpharmacologicallyactiveintheseperipheralcompartments.Instead,
theyactasreservoirsintowhichmedicationsareredistributedandsequestered.Theseperipheralcompartmentsmodelhowtheactionofthemedicationmay
beterminatedbyredistribution.Theyalsomodelthewayinwhichaccumulationofmedicationwithintheseperipheralcompartmentscanleadtoprogressively
increasingcontextsensitivehalftimesasmedicationdiffusesbackintothecentralcompartment.Aneffectsitecompartmentmodelsthereceptorpopulation
atwhichthemedicationhasitsmechanismofaction.Diffusionalsooccursbetweenthecentralandtheeffectsitecompartments.Butbecausethequantityof
drugboundtothereceptorsatanygivenmomentisminorcomparedwiththetotalquantityofmedicationinthebody,theeffectsitecompartmentisassumed
tobesufficientlysmallthatitseffectonthemassofmedicationwithinthecentralcompartmentisnegligible.

Figure92Threecompartmentmodelforthepharmacokineticmodelingofintravenousmedicationadministration,redistribution,andelimination.Additionally,
aneffectsitecompartmentispresent.Thevolumeofthiscompartmentisassumedtobesufficientlysmallthattheeffectonthequantityofmedicationinthe
centralcompartmentisnegligible.
Thestructureofthesecompartments,withtheirassociatedvolumesanddiffusioncoefficients,allowsaseriesofdifferentialequationstobeproducedthat
modelthetraffickingofmedicationinresponsetochangesininfusionrates.Acomputercanbeusedtodetermineanidealsequenceofinfusionratechanges
sothattheconcentrationofdrugattheeffectsiteisbroughttothedesiredconcentrationwithintheoptimumtime(1).Thispracticeisknownastarget
controlledinfusion.

C. Pharmacodynamic Effects
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ManycombinationsofGABAAreceptorsubunitsarepossible.However,inpractice,thesevariationsarenotdirectlyaccountedforbetweenindividual
receptorswhenpredictingtheclinicaleffectofadosageofamedication.Instead,theeffectsiteinthepharmacokineticmodelrepresentsthecombined
populationofallthereceptors,andthelikelyclinicaleffectisdeterminedbyastatisticalmodelrelatingthisconcentrationtoaparticularclinicaloutcome.
Thesepharmacodynamicmodelsarecreatedfordifferentclinicaloutcomeswithdifferentmedications.Figure93showstwoseparatepharmacodynamic
models:theleftmostmodelrelatestheconcentrationofpropofolattheeffectsitetothelossoftheeyelashreflex,andtherightmostmodelrelatesthe
concentrationofpropofoltolossofconsciousness(2).Themostnotablecharacteristicisthestrongnonlinearityoftheserelationships.Itispossible,withonly
asmallincreaseinconcentrationofpropofol,totransitionrapidlyfromconsciousnesstounconsciousness.Thesenonlinearmodelshaveastandardform,
knownasthesigmoidEmaxmodelortheHillequation(3):

Figure93Pharmacodynamicmodelsfortheprobabilityoflossofeyelashreflexandfortheprobabilityoflossofconsciousnessbasedonpropofoleffectsite
concentration.

ThevariableEC50istheconcentrationattheeffectsiteatwhich50%ofthemaximaleffectisseen.Thisisameasureofthepotencyofthemedication.The
variableisthesigmoidcoefficient,andgreatervaluesofyieldmoreabrupttransitions.Asmallchangeinpropofoleffectsiteconcentrationcancausea
large,evenunexpected,clinicaleffect.

D. Hypersensitivity (Allergic) Reactions

Themostcommoncausesofhypotensionfollowinginductionwithintravenousanestheticagentsareunrecognizedhypovolemiaandunexpecteddrug
interactions.Truehypersensitivityreactionsarerare,althoughcasereportsofhistaminereleasewithallintravenousanestheticagents,withtheexceptionof
etomidate,havebeenalleged.Propofoldoesnotnormallycausehistaminereleasebutanaphylactoidreactionshavebeenreportedinpatientswithmultiple
drugallergies.Barbituratescanprecipitateacuteintermittentporphyriainsusceptiblepatients.

II. Comparative Physiochemical and Clinical Pharmacologic

Properties
A. Barbiturates
Themostcommonlyusedbarbituratesarethethiobarbiturates:thiopental(Pentothal,5ethyl5[1methylbutyl]2thiobarbituricacid),thiamylal(Surital,5allyl5
[1methylbutyl]2thiobarbituricacid),andtheoxybarbituratemethohexital(Brevital,1methyl5allyl5[1methyl2pentanyl]barbituricacid).
BarbituratesdepressthereticularactivatingsysteminthebrainstemandarebelievedtopotentiatetheactionofGABAAreceptors,increasingthedurationof
anassociatedchlorideionchannelopening.Barbituratesdecreasecerebralmetabolicrateofoxygen(CMRO2),cerebralbloodflow(CBF),andintracranial
pressure(ICP).Barbituratescaninduceanisoelectricelectroencephalogram(EEG),maximallydecreasingCMRO2.

Commonlyusedintravenousanestheticagentssuchasthebarbiturates,propofol,thebenzodiazepines,andetomidateactatthesiteoftheGABAAreceptor.
Barbituratesareformulatedassodiumsaltsandarereconstitutedinwaterorisotonicsodiumchloride(0.9%)toprepare2.5%thiopental,1%to2%
methohexital,and2%thiamylal.Thesepreparationsarehighlyalkaline(pH9to10).Whentheyareaddedtolactatedringersorotheracidicdrugpreparations,
crystallineprecipitationwilloccurandmayirreversiblyoccludeintravenoustubingandcatheters.Barbituratesrarelycausepainoninjectionbutwillcause
significanttissueirritationifextravasated.Inadvertentintraarterialinjectionofthiobarbituratescausesseriouscomplications,includingintense
vasoconstriction,thrombosis,andtissuenecrosis.Immediatetreatmentmayrequireintraarterialpapaverineandlidocaineorprocaine,regionalanesthesia
inducedsympathectomy(stellateganglionblock,brachialplexusblock),andheparinization.
Theanestheticactionofthebarbituratesisprimarilyterminatedbyredistributionfromthecentrallipophilictissuesofthebraintoperipheralleanmuscle
compartments.Barbituratesundergoslowterminaleliminationviahepaticmetabolism,biliaryconjugation,andrenalexcretion.Theterminaleliminationof
thiopentalisprolongedwithahalflifeof10to12hours.Methohexitalclearanceismoredependentonhepaticbloodflow,allowingforashortereliminationhalf
lifeof4hours.

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Careshouldbetakeninpatientswithporphyriasbecausebarbituratesstimulateporphyrinformationandcanprecipitateanacutecrisis.

B. Propofol
Propofol(Diprivan)isanalkylphenolcompoundpreparedinanegglecithinemulsionconsistingofsoybeanoil,glycerol,eggphosphatide,and
ethylenediaminetetraaceticacidormetabisulphiteasanantimicrobial.

VIDEO92
Propofol
PropofolincreasesthebindingaffinityofGABAwiththeGABAAreceptor.Coupledtoachloridechannel,theactivationleadstothehyperpolarization

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