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1、DRUGSUSEDFORANESTHESIA,MUSCLERELAXATIONA.LocalanesthesiaAsthenameimplies,localanestheticsareappliedlocallyandfunctiontoblocknerveconduction.1.GeneralinformationThemechanismbywhichlocalanestheticsworkiswellknownRecallthattheconcentrationofsodiumionsisnormallyhigherontheoutsideofneuronsthanontheinside
2、.Arapidfloodofsodiumionsintocellsisnecessaryforneuronstofireandconductanactionpotential.Localanestheticsactbyblockingsodiumchannels.Thisblockingisnonselective,whichmeansthatbothsensoryandmotorimpulsesareaffected.Thisblockingisbroughtaboutbytheanestheticreversiblybindingtoandinactivatingsodiumchannel
3、s.Sodiuminfluxthroughthesechannelsisnecessaryforthedepolarizationofnervecellmembranesandsubsequentpropagationofimpulsesalongthecourseofthenerve.Whenanervelosesdepolarizationandcapacitytopropagateanimpulse,theindividuallosessensationintheareasuppliedbythenerve.Example:Aninjectablelocalanestheticwhich
4、combinescapsaicinwithQX-314,avariationoflidocaineAlllocalanestheticshaveanaminefunctionalgroup,anaromaticring,andeitheranesteroramidegrouplinkingthem.aminearomaticringesteramideTherefore,alllocalanestheticsareclassifiedasestersoramides.Thisisimportantbecausetheamidesarechemicallystablein vivo,wherea
5、stheestersaresubjecttohydrolysis.Inaddition,thehydrolysisofanesterlocalanestheticleadstotheformationofPABA,whichcausesanallergicresponseinsomeindividuals.Localanestheticsmaybeadministeredtopically(i.e.nasalmucosa);throughinfiltration(injectionintothedermisandsofttissueslocatednearperipheralnerveendi
6、ngs);andin/nearthespinalcord(includescaudalblock,epiduralblock,andspinalnerveblock).Whichlocalanestheticshouldbeusedgenerallydependsonthedurationofactionoftheprocedure.Forshortprocedures,procainewouldberecommended.Anintermediatedurationofactionisfoundwithcocaine,lidocaine,andmepivacaine.Long-actingl
7、ocalanestheticsincludebupivacaine(andlevobupivacaine),ropivacaine,andtetracaine.2.EsterlocalanestheticsCommonlyusedlocalanestheticscontainingtheesterfunctionalgrouparebenzocaine,cocaine,procaine,andtetracaine.a.procaine(Novocain)Procaineistheprototypedrugofthelocalanesthetics.Ithasthelowestpotency(e
8、xceptforBenzocaine).Itisusedfornerveblock,epiduralandspinalanesthesia.Novocaineisgenerallynotusedindentistryanymore.b.benzocaineTopicaluseonlybenzocaine(Solarcaine,Orajel,Lanacaineetc)Itisusedforminormouthconditions(i.eteething,cankersores)sorethroat,sunburn,andotherminorskinconditionsc.cocaineCocai
9、neis2timesaspotentasprocaine.Itisusedforear,noseandthroatprocedures.d.tetracaine(Pontocaine)Usedfor:spinalanesthesiarequiring2to3hoursofanesthesiasurfaceanesthesiaoftheeye,noseandthroat.Itis16timesaspotentasprocaine.3.AmidelocalanestheticsCommonlyusedlocalanestheticscontainingtheamidefunctionalgroup
10、arebupivacaine,lidocaine,mepivacaine,andropivacaine.a.bupivacaine(Marcaine)andlevobupivacaine(Chirocaine)Theseareusedininfiltrationandepiduralanesthesia.Theyare16timesmorepotentthanprocaine.Generally,theyaremorecardiotoxicthantheotherlongactinglocalanesthetics.b.lidocaineUsedtopicallyforminordermato
11、logicalprocedures(i.eskintagremoval)Itis4timesmorepotentthanprocaineandhasreplacedprocaineintheareaofdentalanesthesia.c.mepivacaine(Carbocaine)Thislocalanestheticisusedfordentalprocedures,surgicalproceduresandduringlaboranddelivery.d.ropivacaine(Naropin)Thisisusedforsurgicalprocedures,includingcaesa
12、riansections.Althoughitissimilarpharmacologicallytobupivacaine,itislesscardiotoxic.4.Adverseeffectsa.Lowconcentrationdosages:dizzinesssleepinessrestlessnessb.Higherconcentrationdosages:musculartwitchingseizuresandhypotension(exceptforcocaine,whichcanresultinvasoconstrictionandhypertension,aswellasca
13、rdiacarrhythmias).B.Generalanesthesia1.generalinformationGeneralanesthesiaprovidesrapidandcompletelossofsensation.Itischaracterizedby:totalanalgesia(nopain)unconsciousnessdeeperthansleeplossofmemorycompletemusclerelaxation.Althoughsimilartosleepthereareprofounddifferences:Thereisthelossofthe“fightor
14、flightresponse,whichisnotlostduringsleep.Generalanestheticsstopmostnervousactivityinthebrain,sleeponlystopsactivityinveryspecificareas,andincreasesactivityinotherareas.Itistheultimate“alteredstate,likeflippingaswitchtotemporarilyturnoffthenervoussystem.InthepastdecadeithasbecomeapparentthattheGABAre
15、ceptor-chloridechannelisthetargetofmanygeneralanesthetics(inhaledanesthetics,BZs,barbiturates,propofol).TheGABAreceptorcomplexconsistsofalpha,beta,andgammasubunitssurroundingandcontrollingacentralchlorideionchannel.Allanestheticsbindatsitesintheandsubunits,whichareremovedfromtheGABAbindingsite.Thebi
16、ndingofGABA(gammaaminobutyricacid)toitsreceptorcausesanopeningofthechlorideionchannel.Theincreaseofchlorideionleadstoahyperpolarizationofthecell.ForIVbenzodiazepineanestheticsandtheinhalationanesthetics,bindingtotheGABAreceptorcomplex,concurrentwithGABAbinding,resultsinagreaterdurationofchloridechan
17、nelopening.Thisincreasestheentryofchlorideionintothecell.Theincreasedhyperpolarizationreducesneuralexcitabilitybymakingitmoredifficultforthecelltodepolarize.Thismeansthatamuchlargerthannormalstimulusisrequiredtoreachthethreshholdpotentialandgenerateanactionpotential.IVbarbituratebindingtotheGABArece
18、ptorcomplexalsoincreasesthedurationofGABA-activatedchloridechannelopening.Inaddition,higherconcentrationsofbarbituratesmaydirectlyactivatechloridechannelopeningevenintheabsenceofGABA,leadingtobarbiturateanesthesia.Inadditiontotheiractionsonthesechloridechannels,generalanestheticsalsodecreasethedurat
19、ionofopeningofvariouscationchannels(K1+,Ca2+).Thisenhancesthehyperpolarizationofthemembrane.Generalanesthesiausuallyrequiresmorethanonedrug.Multiplemedicationsareusedtorapidlycauseunconsciousnessandmusclerelaxationandtomaintaindeepanesthesia.IVagentsareusuallyadministeredfirstbecausetheyactwithinafe
20、wseconds.Afterthepatientlosesconsciousness,inhaledagentsareusedtomaintaintheanesthesia.ThisapproachallowsthedoseofinhalationanesthetictobelowersothattheprocedureissaferforthepatientGeneralanesthesiaoccursindistinctstepsorstages:Stage1Lossofpain,lossofgeneralsensation,butthepatientmaybeawakeStage2Exc
21、itementandhyperactivityThepatientmaytrytoresist,theirheartbeatandbreathingmaybecomeirregularandbloodpressurecanincrease.Theanesthesiologistwilltrytoquicklymovethroughstage2.OftenanIVagentwillbegiventocalmthepatientduringthisstage.Stage3CalledsurgicalanesthesiaSkeletalmusclesbecomerelaxed,cardiovascu
22、larandbreathingactivitiesstabilizeEyemovementsslowdownandthepatientbecomesverystill.Thisisthestagewhensurgerybeginsandremainsuntiltheprocedureends.Stage4,oroverdoseThisismarkedbyhypotensionorcirculatoryfailure.Deathmayresultifthepatientcannotberevivedquickly.2.InhaledgeneralanestheticsTheseagentsare
23、nonflammable,nonexplosivegasesorvolatileliquids.Oneoftheirmajoradvantagesisthatthedepthofanesthesiamaybeveryquicklychangedbyalteringtheconcentrationoftheagent.Themedianalveolarconcentration(MAC)isatermusedtodeterminethepotencyofvariousinhalationanesthetics.Itisthemedianeffectivedose(ED50)oftheanesth
24、etic,andisexpressedasthe%ofthegasinthemixturenecessarytoachieveananestheticeffect.ThesmallertheMAC,themorelipidsolubleistheanesthetic,andthelowertheconcentrationoftheanestheticneededtoproduceanesthesia.Therefore,themorepotentistheanesthetic.Anesthetic MAC value, in %Isoflurane1.2Sevoflurane2.0Desflu
25、rane6.0Nitrousoxide100Alloftheinhalationanesthetics(exceptnitrousoxide)arerespiratorydepressants.IsofluraneismoredepressantthandesfluraneandsevofluraneAll3increasetherestingpartialpressureofCO2inarterialblood(PaCO2),increasetheapneicthreshold,anddecreasetheventilatorresponsetohypoxia.Theseeffectscan
26、bemitigatedbymechanicallyassistingventilation.a.Nitrousoxide(laughinggas)Thisistheonlygasusedroutinelyforanesthesia.Itisnotverysolubleinbloodandtissues,whichenablesittomoveinandoutofthebodyveryrapidlyUsedfordentalproceduresandbriefobstetricalandsurgicalproceduresSeeYoutubevideofromthePinkPantherStri
27、kesagain(GooglevideoPeterSellers;Clouseau,Dentist)Itmayalsobeusedtogetherwithothergeneralanesthetics.Nitrousoxideinhigherdoseshasbeenfoundtodepresstheheart.3.VolatileanestheticsTheseareliquidatroomtemperature,convertedintoavaporandinhaledThemostcommonlyadministeredliquidvolatileagentsintheU.S.are:de
28、sflurane(Suprane)Sevoflurane(Ultane)Isoflurane(Forane)a.desfluraneAdvantages:rapidonsetandrecoveryofanesthesia(usefulforoutpatientprocedures)oneofleastmetabolizedtotoxicbyproductsDisadvantages:lowvolatility,sorequiresaspecialvaporizerpungentandirritatingtotheairway(leadingtomorecoughing,laryngospasm
29、,soitisnotasusefulforextendedsurgicalprocedures)Inaddition,whenhighinspiredgasconcentrationsareadministered,thereisasignificantincreaseinthepatientsbloodpressureandheartrate.sevoflurane:Advantages:rapidonsetandveryrapidrecoveryofanesthesia(usefulwithchildren)Notaspungentasdesflurane(alsousefulwithch
30、ildren)Hasgoodbronchodilatingpropertiesandistheagentofchoiceinpatientswithasthma,bronchitis,andCOPD.Ithaslittleeffectontheheartrate.Disadvantages:ItsmetabolismresultsinF1-whichmayreachtoxiclevelsinkidneysInaddition,carbondioxideabsorbentsinanesthesiamachinesdegradesevofluranetoafluorinatedhydrocarbo
31、n,whichisdegradedbyrenallyaseenzymestoathioacylhalide.Thiscompoundhasbeenobservedtocausenecrosisoftheproximaltubuleinrats.isoflurane:Advantages:Itcausesperipheralvasodilationandincreasedcoronarybloodflow(usefulinpatientswithischemicheartdisease)oneofleastmetabolizedtoF1-Disadvantages:moderatesolubil
32、ity,sorecoveryfromanesthesiamaybedelayedIsofluranecanmaketheheart“moresensitivetocirculatingcatecholamines(likeepinephrine).Thiscouldleadtoaventriculararrhythmiainpatientswithheartdiseasewhoaregivenepinephrineincombinationwithananesthetic,orinchronicallyanxious,“TypeApatients(theyhavehighercirculati
33、nglevelsofendogenousepinephrine).C.IntravenousanesthesiaIntravenousanesthesiaisusedfortherapidinductionof,butnotthemaintenanceofanesthesia.Themaintenanceofanesthesiaiswithaninhalationanesthetic.Thereare5categoriesofdrugsusedasintravenousanesthetics:1.Benzodiazepines(BZ)The3maindrugsusedinthiscategor
34、yarediazepam,lorazepamandmidazolam.Theysedate,relieveanxiety,andcontrolacuteagitation,thereforetheirprimaryindicationisforpremedication.Theyareinadequateforuseinsurgicalanesthesia“ontheirown,andmustthereforebeusedwithanotheranestheticagent(i.e.aninhalationanesthetic).a.diazepam(Valium)Thisistheproto
35、typedrugoftheBZsItiswater-insoluble,soIVuserequiresanonaqueousvehiclewhichcancauselocalirritation/painb.midazolam(Versed)Midazolamiswatersoluble,sodrugofchoiceforIVadministrationIthasamorerapidonsetandmorerapideliminationthantheotherBZs.Inaddition,midazolamisthemostpotentamnesticc.lorazepam(Ativan)I
36、tiswater-insoluble,soIVuserequiresanonaqueousvehiclewhichcancauselocalirritation/painItisalesspotentamnesticthanmidazolam,butamorepotentamnesticthandiazepam.2.BarbituratesThe3maindrugsusedinthiscategoryarethiopental,thiamylal,andmethohexital.Theirhypnoticactivityisduetosidechainsatposition5(especial
37、lyifoneofthemisbranched).Thereisamorerapidonsetandshorterdurationofactionifthereisasulfurinsteadofoxygenatomatposition2(so,thiamylalandthiopentalhavemorerapidonsetandshorterdurationofactionthanmethohexital).Noneofthesedrugsprovidesanalgesiaorsignificantmusclerelaxation.Likemostofthe“olderdrugs,barbi
38、turateshaveaworsetoxicologicalprofilethanthebenzodiazepinesTheyallmaycausecoughing,laryngospasm,bronchospasm,orapnea.a.ThiopentalThiopental,theflagshipofthebarbiturateanestheticgroup,hasbeenastandardanestheticinductionagentformorethan60yearsandisthedruginthiscategory,towhichallothersarecompared.b.Th
39、iamylalc.MethohexitolThiamylalisnotsignificantlydifferentfromthiopentalinpotency,incidenceoflaryngospasm,respiratorydepression,cardiotoxicityorrecoverytime.3.OpioidsThetermsopioidandopiateareoftenusedinterchangeably,buthavedifferentmeanings.Anopiateisderivedfromthejuiceoftheopiumpoppy,Papaver Somnif
40、erum,whichiscommonlycalledWhitePoppyandHerbofJoy.Anopioidisacompound,eithersynthetic,oranaturalproductwhichhasmorphine-likeeffects.Opioidsproducemoderatesedationandprofoundanalgesia.Theyexerttheireffectsbybindingwithopioidreceptorsinthecentralnervoussystem.Thereare3majoropioidreceptorsclassified,fun
41、ctionally,as(mu),(kappa),and(delta).Thereispharmacologicalevidenceforsubtypesofeachreceptorinadditiontoother,lesswell-knownopioidreceptors,epsilon(),zeta(),iota()andlambda().Thereisacommongeneralstructurefoundinallopioidreceptorsembeddedinplasmamembranes.Theyare,usually,linkedtoaGprotein.Oncetherece
42、ptorsarebound,aportionoftheGproteinisactivated,allowingittodiffusewithintheplasmamembrane.TheGproteinmoveslaterallywithinthemembraneuntilitreachesitstarget,anionchannel.TheionchannelsareinvolvedwitheitherareductionofCa2+influxoranincreaseinK1+efflux.Eitheroftheseresultsinhyperpolarization(becomingmo
43、renegative)whichimpairsthefiringofneuronsandneurotransmitterrelease.Opioidsmaybeusedtosupplementanesthesiawhenotheranestheticdrugsdontadequatelycontrolpainreactions.TheymaybeusedasinductionagentsorastheprimarydrugforthemaintenanceofanesthesiawhenhemodynamicstabilityisessentialThehighdosesrequiredtop
44、roduceunconsciousnessdonotdepressthemyocardium,nordotheycauseasignificantreductioninbloodpressure.Dosesmustbeatleast10timesthedoseusedforcontrolofpaininambulatorypatients,thusthisisreferredtoashighdoseopioid.OpioidsdepressrespirationbyinhibitingtheresponsivenessofthemedullaryrespiratorycentertoPCO2a
45、ndaltertherhythmofbreathing.Consequently,itisnecessarytoassistventilation.Sincerespiratorydepressionmayextendintothepost-operativeperiodasaresultofdrugaccumulationinthetissues,theuseofopioidswhoseclearancesareslowremainmostappropriateforpatientswhoareexpectedtorequirep.o.ventilatorycare.Theopioidsmo
46、stcommonlyusedarefentanyl(Sublimaze)sufentanilcitrate(Sufenta)alfentanil(Alfenta)remifentanil(Ultiva)a.fentanyl(Sublimaze)OneofthemostfrequentlyusedbecauseofhowquicklyitproducesanalgesiaFentanylisapotentsyntheticopioidagonistwithbetween50-100timestheanalgesicpotencyofmorphine.Fentanylisusedtoaidindu
47、ctionandmaintenanceofgeneralanesthesiaandtosupplementregionalandspinalanesthesia.Fentanylispreferredtomorphineinanesthesiaduetoitsabilitytomaintaincardiacstability.Fentanylmaybeadministeredaloneorincombinationwithinhalationanesthetics,localanesthetics,orbenzodiazepines.b.sufentanilcitrate(Sufenta)Ra
48、pidinductionofanalgesia(similartoFentanyl)c.alfentanil(Alfenta)Comparedtofentanylandsufentanil,alfentanilhasashorterdurationofactionbecauseitshighproteinbindingandrelativelylowlipidsolubilityfavoritssequestrationinplasmad.remifentanil(Ultiva)Remifentanilisultrashortactingandrapidlyclearedbecauseitse
49、sterlinkagesaresusceptibletohydrolysisbyesterasesintissuesandRBCs.Thisconvertstheesterfunctionalgroupintoaninactivecarboxylicacidmetabolite.Thisparticularopioidisusefulwhendealingwithpatientswithliverorkidneyfailure.Lesspotentopioidssuchasmorphineanddemerolhavefallenintodisfavorbecauseoftheiradverse
50、effectswhengiveninhighdoses.DemerolmaycauseV-tachMorphinemayproducehypotensionandbronchoconstrictionasaconsequenceofitshistamine-releasingaction.Oneofthemostseriousdrawbacksoftheopioidanestheticsoverall,isthepossibilityofinadequateanestheticdepth.Signsofthisincludesweating,wrinklingoftheforehead,and
51、openingoftheeyes.Topreventthis,thehighdoseopioidtechniquesmaybesupplementedwithinhalationanestheticsorhypnoticssuchasbenzodiazepines(midazolamforshortercases,lorazepamforcaseslongerthan4hours),ormorerecently,propofol.However,theuseofthesemayresultinsomelossofcardiovascularstability.4.Dissociativeane
52、stheticsThisrelatestoatypeofgeneralanesthesiathatischaracterizedbyamnesia,sedation,andanalgesia,althoughthepatientappearstobeawake.Oneofthedissociativeanestheticscommonlyusedisketamine(Vetalar,Ketaset).Ketamine,isanN-methyl-D-aspartate(NMDA)receptorantagonist.Ketamineblockstheionchannelinthefollowin
53、gdiagramItincreasesbloodpressureandincreasescardiacoutput(usefulinpatientsexperiencingshock)Ketaminehasbothverypoormusclerelaxationandanalgesicactivity.Ketaminemaybeused,alongwithdiazepamforcosmetic/reconstructivesurgeryanesthesia.Itisnotwidelyusedforanesthesiaasittendstoinducepostoperativehallucina
54、tions.Itissometimesusedasarecreationaldrug,butithasanumberofadverseeffects:lossofcoordinationexaggeratedsenseofstrengthblankstareslurredspeechABBCreportinMay2000claimedthatmedicalresearchhadshownthatcontrolledtestsonketamineusershadrevealedimpairedmemoryandmildschizophreniaseveraldaysaftertakingthed
55、rug.KetaminewasclassifiedasaClassCdrugin2005.OtherclassCdrugsincludecannabisandanabolicsteroids Ketamineplaysanextensiveroleintheseason2finaleofHouse,M.D,titled“Noreason5.Propofol(Diprivan)FromDI-isoPRopyl IV ANestheticchemicalname:2,6-diisopropylphenolPropofolisasedative/hypnoticthatcanbeusedforind
56、uctionormaintenanceofgeneralanesthesia.Itisalsousedforsedatingintubated,mechanicallyventilatedpatients.Analgesiceffectispoorandadditionofananalgesictotheanestheticregimenisnecessaryforsurgery.Advantages:RapidinductionandrecoverytimesItcanbegivenforprolongedperiodswithoutresultinginprolongedrecoveryD
57、isadvantages:apneabradycardiaandhypotension.Propofolsabuseasarecreationaldrug(itproduceseuphoria)hasbeenseen,insomeanesthesiologistswhohaveaccesstothedrug.Inaddition,MichaelJacksonsdeathinJune2021hasbeenattributedtoa“cocktailofpropofolandotherdrugsJacksonscardiologist,Dr.ConradMurrayhadbeenadministe
58、ringtoJackson50mgofpropofolIV,nightlyfor6weeksforhisinsomnia.FearingthatJacksonwasforminganaddictiontotheanesthetic,heattemptedtoweanhimbyloweringthedoseto25milligramsandaddingthesedativeslorazepamandmidazolam.AccordingtotheMSNBCnewsservice,thesequenceofdrugsgiven,onthedayofhisdeathwere:1:30 a.m. 10
59、 mg tablet of diazepam2 a.m. 2 mg, IV of lorazepam 3 a.m. 2 mg, IV of midazolam5 a.m. 2 mg, IV of lorazepam 7:30 a.m. 2 mg, IV of midazolam 10:40 a.m. 25 mg, IV of propofol diluted with lidocaine 10:50 a.m. Dr leaves Jacksons room; returns minutes later to him not breathing. Administers 0.2 mg of fl
60、umazenil (a BZ antagonist)D.NeuromuscularblockingdrugsThesedrugsareusedduringsurgery(especiallyintra-abdominalandintra-thoracic),andtoaidintubationforsurgicalanddiagnosticprocedures(endoscopy).Previously,adequatemusclerelaxationwasonlypossiblewithdeepanesthesia(whichleadstoCNSdepressanteffects).Cont
61、ractionofskeletalmusclesisvoluntarilycontrolledbyimpulsesthatoriginateintheCNS.Impulsesfromthebrainareconductedthroughthespinalcordtothesomaticmotorneutrons.Somaticmotorneuronseventuallyconnectwithskeletalmusclefibersforminganeuromuscularjunction(NMJ).Theneuronalendingsofthesomaticmotorfiberscontain
62、theneurotransmitteracetylcholine(ACH).WhenACHisreleasedintotheneuromuscularsynapses,itbindstoreceptorsknownasnicotinic-II(NII)receptors.NeuromuscularblockersinhibitskeletalmusclecontractionbyinterferingwiththeNIIreceptors.Thereare2typesofneuromuscularblockers:nondepolarizingdepolarizing1.Nondepolari
63、zingblockersThesebindtothereceptorsbutdonotstimulatethereceptors.TheyarestructurallysimilartoACHandfunctionasacompetitiveinhibitor.Bybindingtothenicotinicreceptor,theypreventACHfrombindingandinhibitmuscularcontraction.Theydonotcausethesodiumchannelsinthemembranetoopen,thereforenodepolarizationofther
64、eceptoroccurs.Remember,therestingmembranepotential(ontheinsideofthecellmembrane)istypically70mV,withclosedsodiumchannels.Anyshiftfromtherestingpotentialtoward0mViscalledadepolarization.AfterI.V.injection,thereisgenerally,arapidonsetofeffects:1st:Finemusclesaffected(thoseofeyes&fingers)2nd:limbs,neck
65、&trunk3rd:intercostalmuscles4th:diaphragmRecoveryisinthereverseordera.TubocurarineThisistheprototypeofthenon-depolarizingneuromuscularblockers.Itisfoundincurare,whichderivesfromtheSouthAmericanplantgenusStrychnos.Ithasaslowonset(5min)andalongdurationofaction(1-2hours),anditisnotcommonlyusedanymore.b
66、.Pancuroniumbromide(Pavulon)Fullmuscleparalysisformajorsurgeryisachievedinabout24minutes,recoveryisabout2-3hoursItisalsofoundasoneofthecomponentsinlethalinjections.AmnestyInternationalhasobjectedtothisusestatingthatitmaymaskthecondemnedprisonerssufferingduringtheexecution.Pancuroniumbromidewasoneoft
67、hecompoundsusedbyEfrenSaldivar,theAngelofDeath.Hewasaserialkillerwhomurderedpatientswhileworkingasarespiratorytherapist.HewasemployedbytheGlendaleAdventistMedicalCenter,workingthenightshift,whentherewerefewerstaffonduty.Thepolice,insearchingforevidencestrongenoughtoobtainacourtconviction,exhumedther
68、emainsof20patientswhohaddiedduringthetimeSaldivarwasonduty.TheywerespecificallylookingforunusuallyhighlevelsofPavuloninthecadaver,asthisdrugremainsidentifiableformanymonths.6ofthe20cadavershadevidenceofalethalconcentrationofPancuroniumbromide.In2002,Saldivarpleadedguiltytosixcountsofmurderandreceive
69、dsixconsecutivelifesentenceswithoutthepossibilityofparole.c.Atracuriumbesylate(Tracrium)anditsisomercisatricuriumbesylate(Nimbex)Theyarewidelyusedandhaveanintermediateduration(recoveryis95%completeonehourafterinjection).However,abreakdownproductofatracurium,laudanosinemayaccumulateduetoveryslowhepat
70、icmetabolismanduponcrossingintothebrainmaycauseseizuresCisatracuriumhaslesslaudanosineformedandlesshistaminereleasedthanatracurium.FederalregulatorshavecitedSt.MargaretMercyHealthcareCentersinIndianafordispensingTracriumtoHammondFireDepartmentCapt.MichaelMagdziarzinJanuary2002.Magdziarzhadunderwenta
71、successfulbypasssurgeryandwasrecovering.Hissurgeonhadorderedapenicillintofightinfection.Instead,thenurseadministeredTracrium.Hebecamerestless,complainedofshortnessofbreath,stoppedbreathingandsufferedcardiacarrest.d.Vecuroniumbromide(Norcuron)Thishasashorterdurationofactionthanpancuronium(recoveryis9
72、5%complete45minutestoonehourafterinjection).Itslackofsignificantcardiovasculareffectsandlackofdependenceongoodkidneyfunctionforeliminationprovideadvantagesoverotherneuromuscularblockingagents.Overall,theextentofadverseeffectsonthenondepolarizingneuromuscularblockersdependsonthespecificagent.Theolder
73、drugs(i.e.tubocurarine,pancuronium)tendtohavemorecardiovascularactions(bloodpressureandheartratechanges)aswellashistaminerelease,andmoredifficultywiththeircontrolledreversal.Thenewerdrugs(i.e.vercuronium)tendtohaveminimaltonocardiaceffects,slighttonohistaminerelease,andaneasierreversal.2.Depolarizin
74、gDepolarizingagentsarealsostructurallysimilartoacetylcholineandfunctionascompetitiveinhibitors.However,whentheybindtothenicotinicreceptor,theycausethesodiumchannelsinthemembranetoopen,leadingtodepolarizationofthereceptor.Thesesodiumchannelsonlyopenbrieflyandcannotbeopenedagainuntilthemembraneisrepol
75、arized.Depolarizingneuromuscularblockersactaspersistentagonistsatnicotinereceptors,butunlikeacetylcholine,theirrelativelyslowerdegradationrateresultsinparalysis.Generationofanactionpotentialrequiresarapidchange (increase)ofmembranepotentialfromanegativestate.Asthesedrugsareeventuallyclearedandrecept
76、orsbecomeunoccupied,theyreverttotheoriginalactivestate.Succinycholineistheonlydruginthisclassthatisusedbyanesthesiaproviderstoday.Thedurationofactionofsuccinylcholineisveryshort,becauseitismetabolizedinthebodyveryquicklybyanenzymecalledplasmacholinesterase.Thisshortdurationofactionmakessuccinylcholi
77、neausefuldruginsituationswheremusclerelaxationisneededforonlyashorttimesuchastofacilitateintubation.Sideeffectsofsuccinycholineinclude:fasciculations(smallmusclemovementscausedwhenthedrugbindstoreceptors)myalgias(musclesorenesswhichmaybetheresultofthefasciculations)cardiacrhythmdisturbancesincreases
78、inocularandgastricpressure,hyperkalemiainat-riskpatientsmalignanthyperthermia:adramaticincreaseinbodytemperature,acidosis,electrolyteimbalanceandshockThesyndromeisthoughtobeduetoareductioninthereuptakeofcalcium,whichisnecessaryforterminationofmusclecontraction.Consequently,musclecontractionissustained.
