seizuresuch toxicology program 2005药物诱导的癫痫发作这样的毒理学计划课件

Drug InducedSeizures DrIanTFCheungAEDPrinceofWalesHospital 9thMarch2005 Definitions SeizureAbnormalelectricalactivityofthebrainLeadstolossofneurologicfunctionAbnormalmotor sensory cognitive oremotionalactivityLeadstoabnormalbehaviorsThetermconvulsionisusedtodescribeaseizurethatresultsinmotoractivity Focalvsgeneralized DifferentialDiagnosis IdiopathicepilepsyIdiopathicepilepsywithsub therapeuticdruglevelsTraumaElectrolyteandmetabolicabnormalitiesGlucose sodium oxygenDruginduced PrimaryeventdirectreductionofseizurethresholdSecondaryevent cellularhypoxiacausedbye g CO Virtuallyanydrugcancauseseizureasaterminalevent Small moleculesNeurotransmittersandNeuropeptides Mechanisms ImpairedinhibitionEnhancedexcitationDisorderedconductionMetabolicfailure MortalityandStatusEpilepticus TowneAR etal Epilepsia1994 35 27 34 GABAAAntagonism GABAAAntagonism Synergy BDZ Barb GABAAntagonism PreventsGABAbindingPicrotoxin TCA PenicillinReducesGABAIsoniazidMonomethylhydrazine GABAAgonism GABAAntagonism Pyridoxine B6 andGABA GlutamineGlutamicAcid brain GABA NH2 COOH GAD PyridoxalPyridoxine5 Phosphate PLP Pyridoxinekinase Isoniazid MechanismofactionEnhancespyridoxineeliminationPreventsactivationofpyridoxineBlocksactivatedpyridoxine Isoniazid ToxidromeNauseaandvomitingUsuallywithin30minutesto2hoursSeizuresRapidonset nearthetimeofvomiting ProgressiontostatusepilepticusDelayedhepatotoxicity Isoniazid MostGABAagonistsrequireGABATryabenzodiazepineNoroleforphenytoin doesn twork Saad Noroleforphenobarbital takestoolong Givepyridoxine PyridoxineDosing Empiric70mg kgupto5gramsKnowningestionGramforgramFirstdosenottoexceed70mg kgIVpreferred oralacceptableFollowwithbenzodiazepines INHInducedStatusEpilepticus UseintubatingbarbituratesOpenCl channelwithoutGABAConsiderNMBstopreventhyperthermiaandmetaboliccomplicationsEEGmonitoringConsiderhemodialysisGivepyridoxineforprolongedcoma Brent Adenosine atleastfoursubtypesoftheadenosinereceptor A1 A2A A2BandA3receptors A1receptorsarehighlyexpressedinthebrain especiallyinthehippocampus thalamus cerebellumandcortex A3receptorsaremoderatelyexpressedinthebrainA2receptorslimiteddistributioninCNS mostlyconcentratedoncerebralvasculature Adenosine Excitation Seizures Celldeath A G GTATP Glut ATP ADP AMP ATP ADP AMP Adenosine Inosine AK ADA catabolism Na Adenosine Netresult Preventspre synapticexcitatoryneurotransmitterreleaseReducespost synapticeffectsofexcitatoryneurotransmitterSuppliescriticalcellswithglucose oxygenVasodilatesRemovestoxicmetabolicbyproducts Theophylline ComplexmechanismsofactionIncreaseincatecholaminesAdenosineantagonismPhosphodiesteraseinhibitionFluidandelectrolyteabnormalities Theophylline ToxidromeNauseaVomitingTachycardiaHypotensionCardiacdysrhythmiasSeizures TheophyllineInducedSeizures ImplicationsPoorassociatedprognosisAdenosineantagonismallowsfor ProgressiontostatusepilepticusRapidmetabolicfailureNeurologicalinjury TheophyllineInducedSeizures TreatmentA B CandD checkglucose AggressiveseizurecontrolDiazepamorlorazepamBarbiturateMosteffectiveinpreventandeliminatemethylxanthine inducedseizureEtomidate Propofol Avoidphenytoin notonlyineffectivebutactuallyincreaseslikelihoodofseizureandmortality Strategy OneortwodosesofbenzodiazepinesSecureairwayandterminateseizuresIntubatingbarbiturate propofol etomidateTrytogetEEGmonitoringCorrecthemodynamicsandelectrolytesMultipledoseactivatedcharcoal WBIHemodialysis Hemoperfusion IndicationforcharcoalHemoperfusion Hemodialysis AllPatientsLevel 40ug mlandanyofthefollowing SeizureHypotensionunresponsivetofluidsVentriculardysrhythmiasProtractedvomitingdespiteantiemetic cannotreceiveactivatedcharcoal IndicationforcharcoalHemoperfusion Hemodialysis AcuteLevel 90ug mlAcuteonChronicLevel 70ug ml 4hoursafteringestionofSRChronicControversial Considerwhenlevel 60ug mlorlevel40 60ug mlifage 60 Tricyclics ComplexdrugsBlockthere uptakeofbiogenicaminesBlockalphaadrenergicreceptorsBlockmuscarinicreceptorsBlockfastsodiumchannelsBindtothepicrotoxinreceptor Tricyclics ToxidromeRapidonsetofsedationAnticholinergiceffectsSeizuresHypotensionWidenedQRScomplexonECG PhenytoinandTCAs OncethoughttobethedrugofchoiceIntheoryNarrowsQRSNarrowsQTcTerminatesseizuresInrealityExacerbatesV tach Callaham Doesn ttreatseizures GABAA DecreasingAlcoholLevelAlcoholicTremulousnessHypertensionTachycardiaHyperthermiaTremorDiaphoresisDeliriumTremens AlcoholWithdrawalAlcoholicHallucinosisSeizure OnsetofSeizures Hoursfromlastdrink Number NumberofSeizures ofpatients ofseizures TimeFromFirsttoLastSeizure ofpatients Timeinhours n 77 Chlordiazepoxide Blum JToxicol1976 3 427 BenzodiazepineDosing ChoiceofbenzodiazepinesIntravenousvsoralActivemetabolitesvs inactivemetabolitesRapidityofonsetPRNvs standingordersAlldecisionsfavorintravenousdiazepam RoleofMagnesiuminWithdrawal Randomizeddouble blindstudyin100alcoholics4IMinjectionsof2gofMgSO4q6horNSAllgotbenzodiazepinesasneeded3observersratedwithdrawalscoresNodifferencebetweengroupswithregardtowithdrawalscoretotalbenzodiazepinedose Wilson Alcoholism1984 8 542 Haloperidol Blum JToxicol1976 3 427 BenzodiazepineFailures FailureduetocrosstoleranceLargedosesinshortperiodsoftimeLargedoseswithnoclinicaleffect 200mgofdiazepam BenzodiazepineFailures Midazolam rapidonsetivLorazepam noactivemetabolites maybeusedinsevereliverdxpatient Phenobarbital slowonsetiv narrowtherapeuticindex Propofol rapidonsetiv easytotitrate rapidoffset Propofol GABAagonistNMDAantagonistRapidlyactingHighlylipophilic largeVd 600 800L EasetotitrateSupportedbycasereportsMcCowan CritCareMed2000 28 1781 1784Coomes AnnEmergMed1997 30 825 828Olmedo JToxicolClinToxicol2000 38 537 PhenytoinforWithdrawalSeizures 90patientswithalcoholrelatedseizuresRandomassignmenttophenytoin 1gm orplaceboEndpointsSeizurerecurrence12hourseizurefreeperiodNobenefitdemonstratedwithstrongpoweranalysis 14 Alldredge AmJMed1989 87 645 ProblemSeizures Definition Seizu