藥理學教學課件：1 sedative and hypnosis

DrugsAffectingtheCentralNervousSystemRenjieNeuronsynapseDrugsAffectingtheCentralNervousSystemSedativeAndHypnosisAntiepilepticAndAnticonvulsiveDrugsParkinson'sDiseaseAntipsychoticDrugsAnalgesicsAntipyretic-analgesicAgents

sedative-hypnoticdrugsWhatisinsomnia?Insomnia,inabilitytofallorremainasleepStruggletofallasleepatnight(initialinsomnia),

Wakeinthemiddleofthenightandstruggletofallasleepagain(middleinsomnia).

Wakeintheearlyhoursofthemorning,longbeforetheyneedtogetup(terminalinsomnia).TreatmentforinsomniaRemoveoriginaldiseasesDrugtherapyisonlyadjunctivemethodfornon-drugtreatmentTheleastdosageandshortestperiodDisadvantages:Tolerance(enzymeinduction,de-sensitivity)Physical/psychicdependence

History

In1960,thefirstreceptor-specificdrugs,thebenzodiazepineswasdiscovered.Bythemid1990’s,non-benzodiazepines,withhopefullyfewersideeffectsandalowerriskfordependence,suchasbuspirone(丁螺環(huán)酮,Buspar),ananxiolyticandzolpidem(唑吡坦,Ambien)ahypnoticweredeveloped.Presently,thesearchcontinuesformoreeffectiveandsaferagents.DefinitionsAsedativedrugdecreasesactivity,moderatesexcitement,andcalmstherecipient.Ahypnoticdrugproducesdrowsinessandfacilitatestheonsetandmaintenanceofastateofsleepthatresemblesnaturalsleep,andfromwhichthepatientcanbeeasilyaroused.Drugs:

Benzodiazepines(BDZs)BarbituratesOthers:chloralhydrateBenzodiazepines

BDZs地西泮（安定）Diazepam奧沙西泮Oxazepam三唑侖TriazolamDrugsEliminationhalflife(hours)Dosage（mg）sedativehypnoticDiazepam30~60

2.5~5

tid5~10Oxazepam5~1015~30,qd,tid15~30Triazolam1.5~3-0.25~0.5（15~30min)BenzodiazepinesBDZsActionsanduses:

antianxiety

-

Theanxiolyticactionscanbeoccurredatlowerdosage.

-

Inhibitingneuronalcircuitsinthelimbicsystemofthebrainselectively

Sedativeandhypnosis

-

Decreasedanxietyleadstocalmingeffect,Noeffectsonmotorormentalfunctions

-

mainlyprolongstage2ofNREMS,shortenSWSandREMSandlatencyofsleeponsetDiazepam地西泮(valium,安定)rapideyemovementsleep,REM

dreamingnonrapideyemovementsleep,NREMSomnambulism&sleeptalking1,2stages3,4stages

Anticonvulsantandantiepilepticaction

ivdiazepamisthebestchoiceforstatusepilepticus(癲癇持續(xù)狀態(tài))

Centralmusclerelaxingtreatmentforcentralmyotonia(肌強直)causedbycerebralaccident(腦血管意外)orspinalcord

injury(脊髓損傷)

Premedicationforoperations,sedationfor

minorsurgicalproceduresantianxiety2.5mgsedative-hypnotic5.0mganti-epileptic7.5mgmusclerelaxation10.0mgCharacteristicsAdvantagesHigherTherapeuticindex,safeLesseffectonREM,solessreboundthanbarbiturate;shortenorcancelphase4ofNREM,decreaseoccurrenceofnightterrorsornightwalkingAdvantagesNoeffectonliverdrugenzymeandmetabolismsofotherdrugsLessdependenceandabstinencesyndromeLess

sideeffects:drowsiness,ataxia(incoordination)BDZsimproveGABAbindingtoGABAAreceptor.increasefrequencyofchannel-openingeventsofchlorideionchannel.BDZsMechanism:ligand-gatedchloridechannelγ-butylaminoacid,GABA(inhibitoryneurotransmitter)Common:hypersomnia,drowsiness,ataxia,impairedjudgment,diminishedmotorskills.i.v.toofast-respiratoryandcardivascularinhibitionandCNSdepression,evenheartarrestrarelyfatalevenfollowingveryhighdosesContraindications:thepresenceofothercentralnervoussystemdepressants;child,elderpatients；patientswithsevereliverdiseaseSideeffects:

ToleranceDecreaseinresponsetothemedicationeffects

DependencePhysicalDependence:whenmedicationisstopped,withdrawalordiscontinuationsymptomsoccurAddiction:complexbehavioralsyndromethatincludesanobsessionwithobtainingandusingthedrug,excessive,prolongedandharmfulusedespiteadverseconsequences,denial,rationalization,minimizationandjustification

AbuseTakingprescribedmedicationinappropriatelyUsuallymultiplesubstancesinvolvedMultipleusesforpolysubstanceabuseEnhanceeuphorianteffectsofopioids(boostmethadonedoses)Alleviatewithdrawal(betweenheroinfixes)TempercocainehighsAugmentalcoholeffectsandmodulatewithdrawalstateIntoxicationandrescueintoxication:overdosescancausedeath,depressionofrespirationandcentralcardiovasculardepression.Treatment:artificialrespiration;purgingthestomachofitscontents;;HemodialysisflumazenilBarbituratesDrugt?(h)Onset(h)duration(h)LongactionPhenobarbital(luminal)苯巴比妥24-1400.5-16-8MiddleactionAmobarbital(amytal)異戊巴比妥8-420.25-0.53-6ShortactionSecobarbital司可巴比妥19-340.252-3SupershortactionThiopental硫噴妥3-830si.v.1-4ClassificationRespiratoryDepressionComa/AnesthesiaSedationAnxiolyticAnticonvulsantDOSERESPONSEBARBSBDZsETOHhypnosis

Normal

RelieffromAnxiety_________

_________________

SEDATION(Drowsiness/decreasereactiontime)

HYPNOSIS

anticonvulsant

Anesthesia

Depressionofrespiratoryandvasomotorcenter inthebrainstem COMA

DEATH

doseActions:

sedative,hypnotic,antiepilepsy,anticonvulsion,anesthesia

DepressionofCNSLowdoses-sedationHighdoses–Hypnosis…→Anesthesia→Coma→DeathnoanalgesicpropertyEnzymeinductioninduceP-450microsomalenzymeintheliverUse:sedativeandhypnosisrarelybeused

LargelyreplacedbybenzodiazepinesbecauseoftheirabilitytocausecomaintoxicdosesLowsafetymargin(differsfrombenzodiazepines)shortenREMS,rebounddosedependenceUse:anticonvulsant:(phenobarbital)Long-TermManagementoftonic-clonicseizures,statusepilepticus,andgrandmal.drugofchoicefortreatmentofyoungchildrenwithrecurrentfebrileseizuresandpregnantwomen(eclampsia),tetanus.anesthesiaandpre-anestheticmedication(thiopental)super-short-actingbarbiturates,i.v.toinduceanesthesiatocalm,removetensionMechanismBarbiturates:prolongopeningdurationofCl-

channel

BDZ:increasetheopeningfrequencyofCl-channelItimitatesGABAandactivatesGABAAreceptor,potentiatesGABAactionandchlorideentryintotheneuron.Adverseeffect

CNS(Drowsiness),drughangover宿醉:tirednessafterawakes,drowsiness,ataxia,difficulttoconcentrate,andmentalandphysicalsluggishness.Potentialforaddiction

(Dependencemayoccur),withdrawalsyndromemaycausetremor,anxiety,weakness,restlessness,nauseaandvomiting,seizure,delirium,cardiacarrest,VertigoTolerance:induceP-450systemrespiratorydepressionPassplacentabarrierandsecretintomilkallergy:urticarial蕁麻疹Intoxicationandrescueintoxication:overdosescancausedeath,depressionofrespirationandcentralcardiovasculardepression.Treatment:artificialrespiration;purgingthestomachofitscontents;alkalinizationofbloodandurine(sodiumbicarbonate);hemodialysisInducessleepinabout15minutesandlast