DRUGSUSEDFORANESTHESIA,MUSCLERELAXATIONA.LocalanesthesiaAsthenameimplies,localanestheticsareappliedlocallyandfunctiontoblocknerveconduction.1.GeneralinformationThemechanismbywhichlocalanestheticsworkiswellknownRecallthattheconcentrationofsodiumionsisnormallyhigherontheoutsideofneuronsthanontheinside.Arapidfloodofsodiumionsintocellsisnecessaryforneuronstofireandconductanactionpotential.Localanestheticsactbyblockingsodiumchannels.Thisblockingisnonselective,whichmeansthatbothsensoryandmotorimpulsesareaffected.Thisblockingisbroughtaboutbytheanestheticreversiblybindingtoandinactivatingsodiumchannels.Sodiuminfluxthroughthesechannelsisnecessaryforthedepolarizationofnervecellmembranesandsubsequentpropagationofimpulsesalongthecourseofthenerve.Whenanervelosesdepolarizationandcapacitytopropagateanimpulse,theindividuallosessensationintheareasuppliedbythenerve.Example:AninjectablelocalanestheticwhichcombinescapsaicinwithQX-314,avariationoflidocaineAlllocalanestheticshaveanaminefunctionalgroup,anaromaticring,andeitheranesteroramidegrouplinkingthem.aminearomaticringesteramideTherefore,alllocalanestheticsareclassifiedasestersoramides.Thisisimportantbecausetheamidesarechemicallystablein vivo,whereastheestersaresubjecttohydrolysis.Inaddition,thehydrolysisofanesterlocalanestheticleadstotheformationofPABA,whichcausesanallergicresponseinsomeindividuals.Localanestheticsmaybeadministeredtopically(i.e.nasalmucosa);throughinfiltration(injectionintothedermisandsofttissueslocatednearperipheralnerveendings);andin/nearthespinalcord(includescaudalblock,epiduralblock,andspinalnerveblock).Whichlocalanestheticshouldbeusedgenerallydependsonthedurationofactionoftheprocedure.Forshortprocedures,procainewouldberecommended.Anintermediatedurationofactionisfoundwithcocaine,lidocaine,andmepivacaine.Long-actinglocalanestheticsincludebupivacaine(andlevobupivacaine),ropivacaine,andtetracaine.2.EsterlocalanestheticsCommonlyusedlocalanestheticscontainingtheesterfunctionalgrouparebenzocaine,cocaine,procaine,andtetracaine.a.procaine(Novocain)Procaineistheprototypedrugofthelocalanesthetics.Ithasthelowestpotency(exceptforBenzocaine).Itisusedfornerveblock,epiduralandspinalanesthesia.Novocaineisgenerallynotusedindentistryanymore.b.benzocaineTopicaluseonlybenzocaine(Solarcaine,Orajel,Lanacaineetc)Itisusedforminormouthconditions(i.eteething,cankersores)sorethroat,sunburn,andotherminorskinconditionsc.cocaineCocaineis2timesaspotentasprocaine.Itisusedforear,noseandthroatprocedures.d.tetracaine(Pontocaine)Usedfor:spinalanesthesiarequiring2to3hoursofanesthesiasurfaceanesthesiaoftheeye,noseandthroat.Itis16timesaspotentasprocaine.3.AmidelocalanestheticsCommonlyusedlocalanestheticscontainingtheamidefunctionalgrouparebupivacaine,lidocaine,mepivacaine,andropivacaine.a.bupivacaine(Marcaine)andlevobupivacaine(Chirocaine)Theseareusedininfiltrationandepiduralanesthesia.Theyare16timesmorepotentthanprocaine.Generally,theyaremorecardiotoxicthantheotherlongactinglocalanesthetics.b.lidocaineUsedtopicallyforminordermatologicalprocedures(i.eskintagremoval)Itis4timesmorepotentthanprocaineandhasreplacedprocaineintheareaofdentalanesthesia.c.mepivacaine(Carbocaine)Thislocalanestheticisusedfordentalprocedures,surgicalproceduresandduringlaboranddelivery.d.ropivacaine(Naropin)Thisisusedforsurgicalprocedures,includingcaesariansections.Althoughitissimilarpharmacologicallytobupivacaine,itislesscardiotoxic.4.Adverseeffectsa.Lowconcentrationdosages:dizzinesssleepinessrestlessnessb.Higherconcentrationdosages:musculartwitchingseizuresandhypotension(exceptforcocaine,whichcanresultinvasoconstrictionandhypertension,aswellascardiacarrhythmias).B.Generalanesthesia1.generalinformationGeneralanesthesiaprovidesrapidandcompletelossofsensation.Itischaracterizedby:totalanalgesia(nopain)unconsciousnessdeeperthansleeplossofmemorycompletemusclerelaxation.Althoughsimilartosleepthereareprofounddifferences:Thereisthelossofthe“fightorflightresponse,whichisnotlostduringsleep.Generalanestheticsstopmostnervousactivityinthebrain,sleeponlystopsactivityinveryspecificareas,andincreasesactivityinotherareas.Itistheultimate“alteredstate,likeflippingaswitchtotemporarilyturnoffthenervoussystem.InthepastdecadeithasbecomeapparentthattheGABAreceptor-chloridechannelisthetargetofmanygeneralanesthetics(inhaledanesthetics,BZs,barbiturates,propofol).TheGABAreceptorcomplexconsistsofalpha,beta,andgammasubunitssurroundingandcontrollingacentralchlorideionchannel.Allanestheticsbindatsitesintheandsubunits,whichareremovedfromtheGABAbindingsite.ThebindingofGABA(gammaaminobutyricacid)toitsreceptorcausesanopeningofthechlorideionchannel.Theincreaseofchlorideionleadstoahyperpolarizationofthecell.ForIVbenzodiazepineanestheticsandtheinhalationanesthetics,bindingtotheGABAreceptorcomplex,concurrentwithGABAbinding,resultsinagreaterdurationofchloridechannelopening.Thisincreasestheentryofchlorideionintothecell.Theincreasedhyperpolarizationreducesneuralexcitabilitybymakingitmoredifficultforthecelltodepolarize.Thismeansthatamuchlargerthannormalstimulusisrequiredtoreachthethreshholdpotentialandgenerateanactionpotential.IVbarbituratebindingtotheGABAreceptorcomplexalsoincreasesthedurationofGABA-activatedchloridechannelopening.Inaddition,higherconcentrationsofbarbituratesmaydirectlyactivatechloridechannelopeningevenintheabsenceofGABA,leadingtobarbiturateanesthesia.Inadditiontotheiractionsonthesechloridechannels,generalanestheticsalsodecreasethedurationofopeningofvariouscationchannels(K1+,Ca2+).Thisenhancesthehyperpolarizationofthemembrane.Generalanesthesiausuallyrequiresmorethanonedrug.Multiplemedicationsareusedtorapidlycauseunconsciousnessandmusclerelaxationandtomaintaindeepanesthesia.IVagentsareusuallyadministeredfirstbecausetheyactwithinafewseconds.Afterthepatientlosesconsciousness,inhaledagentsareusedtomaintaintheanesthesia.ThisapproachallowsthedoseofinhalationanesthetictobelowersothattheprocedureissaferforthepatientGeneralanesthesiaoccursindistinctstepsorstages:Stage1Lossofpain,lossofgeneralsensation,butthepatientmaybeawakeStage2ExcitementandhyperactivityThepatientmaytrytoresist,theirheartbeatandbreathingmaybecomeirregularandbloodpressurecanincrease.Theanesthesiologistwilltrytoquicklymovethroughstage2.OftenanIVagentwillbegiventocalmthepatientduringthisstage.Stage3CalledsurgicalanesthesiaSkeletalmusclesbecomerelaxed,cardiovascularandbreathingactivitiesstabilizeEyemovementsslowdownandthepatientbecomesverystill.Thisisthestagewhensurgerybeginsandremainsuntiltheprocedureends.Stage4,oroverdoseThisismarkedbyhypotensionorcirculatoryfailure.Deathmayresultifthepatientcannotberevivedquickly.2.InhaledgeneralanestheticsTheseagentsarenonflammable,nonexplosivegasesorvolatileliquids.Oneoftheirmajoradvantagesisthatthedepthofanesthesiamaybeveryquicklychangedbyalteringtheconcentrationoftheagent.Themedianalveolarconcentration(MAC)isatermusedtodeterminethepotencyofvariousinhalationanesthetics.Itisthemedianeffectivedose(ED50)oftheanesthetic,andisexpressedasthe%ofthegasinthemixturenecessarytoachieveananestheticeffect.ThesmallertheMAC,themorelipidsolubleistheanesthetic,andthelowertheconcentrationoftheanestheticneededtoproduceanesthesia.Therefore,themorepotentistheanesthetic.Anesthetic MAC value, in %Isoflurane1.2Sevoflurane2.0Desflurane6.0Nitrousoxide100Alloftheinhalationanesthetics(exceptnitrousoxide)arerespiratorydepressants.IsofluraneismoredepressantthandesfluraneandsevofluraneAll3increasetherestingpartialpressureofCO2inarterialblood(PaCO2),increasetheapneicthreshold,anddecreasetheventilatorresponsetohypoxia.Theseeffectscanbemitigatedbymechanicallyassistingventilation.a.Nitrousoxide(laughinggas)Thisistheonlygasusedroutinelyforanesthesia.Itisnotverysolubleinbloodandtissues,whichenablesittomoveinandoutofthebodyveryrapidlyUsedfordentalproceduresandbriefobstetricalandsurgicalproceduresSeeYoutubevideofromthePinkPantherStrikesagain(GooglevideoPeterSellers;Clouseau,Dentist)Itmayalsobeusedtogetherwithothergeneralanesthetics.Nitrousoxideinhigherdoseshasbeenfoundtodepresstheheart.3.VolatileanestheticsTheseareliquidatroomtemperature,convertedintoavaporandinhaledThemostcommonlyadministeredliquidvolatileagentsintheU.S.are:desflurane(Suprane)Sevoflurane(Ultane)Isoflurane(Forane)a.desfluraneAdvantages:rapidonsetandrecoveryofanesthesia(usefulforoutpatientprocedures)oneofleastmetabolizedtotoxicbyproductsDisadvantages:lowvolatility,sorequiresaspecialvaporizerpungentandirritatingtotheairway(leadingtomorecoughing,laryngospasm,soitisnotasusefulforextendedsurgicalprocedures)Inaddition,whenhighinspiredgasconcentrationsareadministered,thereisasignificantincreaseinthepatientsbloodpressureandheartrate.sevoflurane:Advantages:rapidonsetandveryrapidrecoveryofanesthesia(usefulwithchildren)Notaspungentasdesflurane(alsousefulwithchildren)Hasgoodbronchodilatingpropertiesandistheagentofchoiceinpatientswithasthma,bronchitis,andCOPD.Ithaslittleeffectontheheartrate.Disadvantages:ItsmetabolismresultsinF1-whichmayreachtoxiclevelsinkidneysInaddition,carbondioxideabsorbentsinanesthesiamachinesdegradesevofluranetoafluorinatedhydrocarbon,whichisdegradedbyrenallyaseenzymestoathioacylhalide.Thiscompoundhasbeenobservedtocausenecrosisoftheproximaltubuleinrats.isoflurane:Advantages:Itcausesperipheralvasodilationandincreasedcoronarybloodflow(usefulinpatientswithischemicheartdisease)oneofleastmetabolizedtoF1-Disadvantages:moderatesolubility,sorecoveryfromanesthesiamaybedelayedIsofluranecanmaketheheart“moresensitivetocirculatingcatecholamines(likeepinephrine).Thiscouldleadtoaventriculararrhythmiainpatientswithheartdiseasewhoaregivenepinephrineincombinationwithananesthetic,orinchronicallyanxious,“TypeApatients(theyhavehighercirculatinglevelsofendogenousepinephrine).C.IntravenousanesthesiaIntravenousanesthesiaisusedfortherapidinductionof,butnotthemaintenanceofanesthesia.Themaintenanceofanesthesiaiswithaninhalationanesthetic.Thereare5categoriesofdrugsusedasintravenousanesthetics:1.Benzodiazepines(BZ)The3maindrugsusedinthiscategoryarediazepam,lorazepamandmidazolam.Theysedate,relieveanxiety,andcontrolacuteagitation,thereforetheirprimaryindicationisforpremedication.Theyareinadequateforuseinsurgicalanesthesia“ontheirown,andmustthereforebeusedwithanotheranestheticagent(i.e.aninhalationanesthetic).a.diazepam(Valium)ThisistheprototypedrugoftheBZsItiswater-insoluble,soIVuserequiresanonaqueousvehiclewhichcancauselocalirritation/painb.midazolam(Versed)Midazolamiswatersoluble,sodrugofchoiceforIVadministrationIthasamorerapidonsetandmorerapideliminationthantheotherBZs.Inaddition,midazolamisthemostpotentamnesticc.lorazepam(Ativan)Itiswater-insoluble,soIVuserequiresanonaqueousvehiclewhichcancauselocalirritation/painItisalesspotentamnesticthanmidazolam,butamorepotentamnesticthandiazepam.2.BarbituratesThe3maindrugsusedinthiscategoryarethiopental,thiamylal,andmethohexital.Theirhypnoticactivityisduetosidechainsatposition5(especiallyifoneofthemisbranched).Thereisamorerapidonsetandshorterdurationofactionifthereisasulfurinsteadofoxygenatomatposition2(so,thiamylalandthiopentalhavemorerapidonsetandshorterdurationofactionthanmethohexital).Noneofthesedrugsprovidesanalgesiaorsignificantmusclerelaxation.Likemostofthe“olderdrugs,barbiturateshaveaworsetoxicologicalprofilethanthebenzodiazepinesTheyallmaycausecoughing,laryngospasm,bronchospasm,orapnea.a.ThiopentalThiopental,theflagshipofthebarbiturateanestheticgroup,hasbeenastandardanestheticinductionagentformorethan60yearsandisthedruginthiscategory,towhichallothersarecompared.b.Thiamylalc.MethohexitolThiamylalisnotsignificantlydifferentfromthiopentalinpotency,incidenceoflaryngospasm,respiratorydepression,cardiotoxicityorrecoverytime.3.OpioidsThetermsopioidandopiateareoftenusedinterchangeably,buthavedifferentmeanings.Anopiateisderivedfromthejuiceoftheopiumpoppy,Papaver Somniferum,whichiscommonlycalledWhitePoppyandHerbofJoy.Anopioidisacompound,eithersynthetic,oranaturalproductwhichhasmorphine-likeeffects.Opioidsproducemoderatesedationandprofoundanalgesia.Theyexerttheireffectsbybindingwithopioidreceptorsinthecentralnervoussystem.Thereare3majoropioidreceptorsclassified,functionally,as(mu),(kappa),and(delta).Thereispharmacologicalevidenceforsubtypesofeachreceptorinadditiontoother,lesswell-knownopioidreceptors,epsilon(),zeta(),iota()andlambda().Thereisacommongeneralstructurefoundinallopioidreceptorsembeddedinplasmamembranes.Theyare,usually,linkedtoaGprotein.Oncethereceptorsarebound,aportionoftheGproteinisactivated,allowingittodiffusewithintheplasmamembrane.TheGproteinmoveslaterallywithinthemembraneuntilitreachesitstarget,anionchannel.TheionchannelsareinvolvedwitheitherareductionofCa2+influxoranincreaseinK1+efflux.Eitheroftheseresultsinhyperpolarization(becomingmorenegative)whichimpairsthefiringofneuronsandneurotransmitterrelease.Opioidsmaybeusedtosupplementanesthesiawhenotheranestheticdrugsdontadequatelycontrolpainreactions.TheymaybeusedasinductionagentsorastheprimarydrugforthemaintenanceofanesthesiawhenhemodynamicstabilityisessentialThehighdosesrequiredtoproduceunconsciousnessdonotdepressthemyocardium,nordotheycauseasignificantreductioninbloodpressure.Dosesmustbeatleast10timesthedoseusedforcontrolofpaininambulatorypatients,thusthisisreferredtoashighdoseopioid.OpioidsdepressrespirationbyinhibitingtheresponsivenessofthemedullaryrespiratorycentertoPCO2andaltertherhythmofbreathing.Consequently,itisnecessarytoassistventilation.Sincerespiratorydepressionmayextendintothepost-operativeperiodasaresultofdrugaccumulationinthetissues,theuseofopioidswhoseclearancesareslowremainmostappropriateforpatientswhoareexpectedtorequirep.o.ventilatorycare.Theopioidsmostcommonlyusedarefentanyl(Sublimaze)sufentanilcitrate(Sufenta)alfentanil(Alfenta)remifentanil(Ultiva)a.fentanyl(Sublimaze)OneofthemostfrequentlyusedbecauseofhowquicklyitproducesanalgesiaFentanylisapotentsyntheticopioidagonistwithbetween50-100timestheanalgesicpotencyofmorphine.Fentanylisusedtoaidinductionandmaintenanceofgeneralanesthesiaandtosupplementregionalandspinalanesthesia.Fentanylispreferredtomorphineinanesthesiaduetoitsabilitytomaintaincardiacstability.Fentanylmaybeadministeredaloneorincombinationwithinhalationanesthetics,localanesthetics,orbenzodiazepines.b.sufentanilcitrate(Sufenta)Rapidinductionofanalgesia(similartoFentanyl)c.alfentanil(Alfenta)Comparedtofentanylandsufentanil,alfentanilhasashorterdurationofactionbecauseitshighproteinbindingandrelativelylowlipidsolubilityfavoritssequestrationinplasmad.remifentanil(Ultiva)RemifentanilisultrashortactingandrapidlyclearedbecauseitsesterlinkagesaresusceptibletohydrolysisbyesterasesintissuesandRBCs.Thisconvertstheesterfunctionalgroupintoaninactivecarboxylicacidmetabolite.Thisparticularopioidisusefulwhendealingwithpatientswithliverorkidneyfailure.Lesspotentopioidssuchasmorphineanddemerolhavefallenintodisfavorbecauseoftheiradverseeffectswhengiveninhighdoses.DemerolmaycauseV-tachMorphinemayproducehypotensionandbronchoconstrictionasaconsequenceofitshistamine-releasingaction.Oneofthemostseriousdrawbacksoftheopioidanestheticsoverall,isthepossibilityofinadequateanestheticdepth.Signsofthisincludesweating,wrinklingoftheforehead,andopeningoftheeyes.Topreventthis,thehighdoseopioidtechniquesmaybesupplementedwithinhalationanestheticsorhypnoticssuchasbenzodiazepines(midazolamforshortercases,lorazepamforcaseslongerthan4hours),ormorerecently,propofol.However,theuseofthesemayresultinsomelossofcardiovascularstability.4.DissociativeanestheticsThisrelatestoatypeofgeneralanesthesiathatischaracterizedbyamnesia,sedation,andanalgesia,althoughthepatientappearstobeawake.Oneofthedissociativeanestheticscommonlyusedisketamine(Vetalar,Ketaset).Ketamine,isanN-methyl-D-aspartate(NMDA)receptorantagonist.KetamineblockstheionchannelinthefollowingdiagramItincreasesbloodpressureandincreasescardiacoutput(usefulinpatientsexperiencingshock)Ketaminehasbothverypoormusclerelaxationandanalgesicactivity.Ketaminemaybeused,alongwithdiazepamforcosmetic/reconstructivesurgeryanesthesia.Itisnotwidelyusedforanesthesiaasittendstoinducepostoperativehallucinations.Itissometimesusedasarecreationaldrug,butithasanumberofadverseeffects:lossofcoordinationexaggeratedsenseofstrengthblankstareslurredspeechABBCreportinMay2000claimedthatmedicalresearchhadshownthatcontrolledtestsonketamineusershadrevealedimpairedmemoryandmildschizophreniaseveraldaysaftertakingthedrug.KetaminewasclassifiedasaClassCdrugin2005.OtherclassCdrugsincludecannabisandanabolicsteroids Ketamineplaysanextensiveroleintheseason2finaleofHouse,M.D,titled“Noreason5.Propofol(Diprivan)FromDI-isoPRopyl IV ANestheticchemicalname:2,6-diisopropylphenolPropofolisasedative/hypnoticthatcanbeusedforinductionormaintenanceofgeneralanesthesia.Itisalsousedforsedatingintubated,mechanicallyventilatedpatients.Analgesiceffectispoorandadditionofananalgesictotheanestheticregimenisnecessaryforsurgery.Advantages:RapidinductionandrecoverytimesItcanbegivenforprolongedperiodswithoutresultinginprolongedrecoveryDisadvantages:apneabradycardiaandhypotension.Propofolsabuseasarecreationaldrug(itproduceseuphoria)hasbeenseen,insomeanesthesiologistswhohaveaccesstothedrug.Inaddition,MichaelJacksonsdeathinJune2021hasbeenattributedtoa“cocktailofpropofolandotherdrugsJacksonscardiologist,Dr.ConradMurrayhadbeenadministeringtoJackson50mgofpropofolIV,nightlyfor6weeksforhisinsomnia.FearingthatJacksonwasforminganaddictiontotheanesthetic,heattemptedtoweanhimbyloweringthedoseto25milligramsandaddingthesedativeslorazepamandmidazolam.AccordingtotheMSNBCnewsservice,thesequenceofdrugsgiven,onthedayofhisdeathwere:1:30 a.m. 10 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 flumazenil (a BZ antagonist)D.NeuromuscularblockingdrugsThesedrugsareusedduringsurgery(especiallyintra-abdominalandintra-thoracic),andtoaidintubationforsurgicalanddiagnosticprocedures(endoscopy).Previously,adequatemusclerelaxationwasonlypossiblewithdeepanesthesia(whichleadstoCNSdepressanteffects).ContractionofskeletalmusclesisvoluntarilycontrolledbyimpulsesthatoriginateintheCNS.Impulsesfromthebrainareconductedthroughthespinalcordtothesomaticmotorneutrons.Somaticmotorneuronseventuallyconnectwithskeletalmusclefibersforminganeuromuscularjunction(NMJ).Theneuronalendingsofthesomaticmotorfiberscontaintheneurotransmitteracetylcholine(ACH).WhenACHisreleasedintotheneuromuscularsynapses,itbindstoreceptorsknownasnicotinic-II(NII)receptors.NeuromuscularblockersinhibitskeletalmusclecontractionbyinterferingwiththeNIIreceptors.Thereare2typesofneuromuscularblockers:nondepolarizingdepolarizing1.NondepolarizingblockersThesebindtothereceptorsbutdonotstimulatethereceptors.TheyarestructurallysimilartoACHandfunctionasacompetitiveinhibitor.Bybindingtothenicotinicreceptor,theypreventACHfrombindingandinhibitmuscularcontraction.Theydonotcausethesodiumchannelsinthemembranetoopen,thereforenodepolarizationofthereceptoroccurs.Remember,therestingmembranepotential(ontheinsideofthecellmembrane)istypically70mV,withclosedsodiumchannels.Anyshiftfromtherestingpotentialtoward0mViscalledadepolarization.AfterI.V.injection,thereisgenerally,arapidonsetofeffects:1st:Finemusclesaffected(thoseofeyes&fingers)2nd:limbs,neck&trunk3rd:intercostalmuscles4th:diaphragmRecoveryisinthereverseordera.TubocurarineThisistheprototypeofthenon-depolarizingneuromuscularblockers.Itisfoundincurare,whichderivesfromtheSouthAmericanplantgenusStrychnos.Ithasaslowonset(5min)andalongdurationofaction(1-2hours),anditisnotcommonlyusedanymore.b.Pancuroniumbromide(Pavulon)Fullmuscleparalysisformajorsurgeryisachievedinabout24minutes,recoveryisabout2-3hoursItisalsofoundasoneofthecomponentsinlethalinjections.AmnestyInternationalhasobjectedtothisusestatingthatitmaymaskthecondemnedprisonerssufferingduringtheexecution.PancuroniumbromidewasoneofthecompoundsusedbyEfrenSaldivar,theAngelofDeath.Hewasaserialkillerwhomurderedpatientswhileworkingasarespiratorytherapist.HewasemployedbytheGlendaleAdventistMedicalCenter,workingthenightshift,whentherewerefewerstaffonduty.Thepolice,insearchingforevidencestrongenoughtoobtainacourtconviction,exhumedtheremainsof20patientswhohaddiedduringthetimeSaldivarwasonduty.TheywerespecificallylookingforunusuallyhighlevelsofPavuloninthecadaver,asthisdrugremainsidentifiableformanymonths.6ofthe20cadavershadevidenceofalethalconcentrationofPancuroniumbromide.In2002,Saldivarpleadedguiltytosixcountsofmurderandreceivedsixconsecutivelifesentenceswithoutthepossibilityofparole.c.Atracuriumbesylate(Tracrium)anditsisomercisatricuriumbesylate(Nimbex)Theyarewidelyusedandhaveanintermediateduration(recoveryis95%completeonehourafterinjection).However,abreakdownproductofatracurium,laudanosinemayaccumulateduetoveryslowhepaticmetabolismanduponcrossingintothebrainmaycauseseizuresCisatracuriumhaslesslaudanosineformedandlesshistaminereleasedthanatracurium.FederalregulatorshavecitedSt.MargaretMercyHealthcareCentersinIndianafordispensingTracriumtoHammondFireDepartmentCapt.MichaelMagdziarzinJanuary2002.Magdziarzhadunderwentasuccessfulbypasssurgeryandwasrecovering.Hissurgeonhadorderedapenicillintofightinfection.Instead,thenurseadministeredTracrium.Hebecamerestless,complainedofshortnessofbreath,stoppedbreathingandsufferedcardiacarrest.d.Vecuroniumbromide(Norcuron)Thishasashorterdurationofactionthanpancuronium(recoveryis95%complete45minutestoonehourafterinjection).Itslackofsignificantcardiovasculareffectsandlackofdependenceongoodkidneyfunctionforeliminationprovideadvantagesoverotherneuromuscularblockingagents.Overall,theextentofadverseeffectsonthenondepolarizingneuromuscularblockersdependsonthespecificagent.Theolderdrugs(i.e.tubocurarine,pancuronium)tendtohavemorecardiovascularactions(bloodpressureandheartratechanges)aswellashistaminerelease,andmoredifficultywiththeircontrolledreversal.Thenewerdrugs(i.e.vercuronium)tendtohaveminimaltonocardiaceffects,slighttonohistaminerelease,andaneasierreversal.2.DepolarizingDepolarizingagentsarealsostructurallysimilartoacetylcholineandfunctionascompetitiveinhibitors.However,whentheybindtothenicotinicreceptor,theycausethesodiumchannelsinthemembranetoopen,leadingtodepolarizationofthereceptor.Thesesodiumchannelsonlyopenbrieflyandcannotbeopenedagainuntilthemembraneisrepolarized.Depolarizingneuromuscularblockersactaspersistentagonistsatnicotinereceptors,butunlikeacetylcholine,theirrelativelyslowerdegradationrateresultsinparalysis.Generationofanactionpotentialrequiresarapidchange (increase)ofmembranepotentialfromanegativestate.Asthesedrugsareeventuallyclearedandreceptorsbecomeunoccupied,theyreverttotheoriginalactivestate.Succinycholineistheonlydruginthisclassthatisusedbyanesthesiaproviderstoday.Thedurationofactionofsuccinylcholineisveryshort,becauseitismetabolizedinthebodyveryquicklybyanenzymecalledplasmacholinesterase.Thisshortdurationofactionmakessuccinylcholineausefuldruginsituationswheremusclerelaxationisneededforonlyashorttimesuchastofacilitateintubation.Sideeffectsofsuccinycholineinclude:fasciculations(smallmusclemovementscausedwhenthedrugbindstoreceptors)myalgias(musclesorenesswhichmaybetheresultofthefasciculations)cardiacrhythmdisturbancesincreasesinocularandgastricpressure,hyperkalemiainat-riskpatientsmalignanthyperthermia:adramaticincreaseinbodytemperature,acidosis,electrolyteimbalanceandshockThesyndromeisthoughtobeduetoareductioninthereuptakeofcalcium,whichisnecessaryforterminationofmusclecontraction.Consequently,musclecontractionissustained.