药理学教学课件：Chapter 16 Sedative-Hypnotics

Chapter16Sedative-Hypnotics

Thesedative-hypnoticdrugindicatesthatitsmajortherapeuticuseistocausesedationortoencouragesleep.Anxietystatesandsleepdisordersarecommonproblems,andsedative-hypnoticsarethemostwidelyprescribeddrugsworldwide.conceptPhasesofSleeprapideyemovementsleep：REM25%ofthetotalsleep,aboutlasts30mindreamnon-rapideyemovementsleep：NREM75%oftotalsleep,aboutlasts90minInman,thephysiologicalsleepconsistsof4-5cyclesofalternativeREMandNREMsleepAneffectivesedative(anxiolytic)agentreducesanxietyandexertacalmingeffectwithlittleeffectonmotorormentalfunctions.Ahypnoticsproducesdrowsinessandencouragetheonsetandmaintenanceofastateofsleepthatasfaraspossibleresemblesthenaturalsleepstate.Idealsedative-hypnoticsLowerdose,sedativeeffectsHigherdose,hypnoticeffectsAtstillhigherdoses,sedative-hypnoticsmaydepressrespiratoryandvasomotorcentersinthemedulla,leadingtocomaanddeath.DoseandEffectSpecificity1.Dose-dependentdepressionofCNSfunction

TypeAsedation

hypnosisanesthesiacomaparalysis

failureTypeBsedation

hypnosisanesthesia?

Specificity2.Tolerance

metabolictolerance(enzymeinducer)pharmacodynamictolerance(down-regulation)

3.DependencePsychologicaldependencePhysiologicaldependenceCHEMICALCLASSIFICATION

Benzodiazepines(BZs)：

themostimportantsedative-hypnotics.Barbiturates：someolderandlesscommonlyusedsedative-hypnotics.Others:

chloralhydrate(水合氯醛)

zopiclone(佐匹克隆)

zolpidem（唑吡坦）

Section1BENZODIAZEPINES

1,4-benzodiazepines(BZs)

ClassificationsofBZsDrugT1/2(h)

Short-acting<6hTriazolam三唑仑2~4Oxazepam奥沙西泮5~10

Intermediate6~24h

Lorazepam

劳拉西泮9~20

Clonazepam氯硝西泮18~28

Long>24h

Diazepam地西泮30~60Flurazepam氟西泮50~100Chlordiazepoxide氯氮卓20-24II.

BENZODIAZEPINES

A.Pharmacokinetics1.Absorption:

theoralabsorptionwell,Cmaxabout1hour:themostrapidistriazolam.

TheratesoforalabsorptionofBZsdifferdependingonanumberoffactors,includinglipophilicity.2.Distribution:

lipidsolubilityplaysamajorrolehighlipidsolubility,enterstheCNSquickly,thendistributestoothertissues---rapidonset,shortdurationplacentalbarrier/breastmilkAllsedative-hypnoticscrosstheplacentalbarrierduringpregnancy.highplasmaproteinbindingBenzodiazepinesbindextensivelytoplasmaproteins,rangesfrom60%toover95%.

Diazepam:99%3.Biotransformation:

MostBZsundergomicrosomaloxidation(phaseIreactions).Themetabolitesaresubsequentlyconjugated(phaseIIreactions)toformglucuronidesthatareexcretedintheurine.However,manyphaseImetabolitesareactive,withhalf-livesgreaterthantheparentdrugs.4.Excretion:

Thewater-solublemetabolitesofBZsareexcretedmainlyviathekidney.Inmostcases,changesinrenalfunctiondonothaveamarkedeffectontheeliminationofparentdrugs.5.FactorsAffectingBiotransformation

particularlyalterationsinhepaticfunctionresultingfromdisease,oldage,ordrug-inducedincreasesordecreasesinmicrosomalenzymeactivities.B.PharmacodynamicsThe

BZs,thebarbiturates,andtheimidazopyridines(咪唑并吡啶)suchaszolpidem（唑吡坦）bindtomolecularcomponentsoftheGABAAreceptorpresentinneuronalmembranesintheCNS.GABA：Gamma-aminobutyricacid1.MolecularMechanismsAtransmembraneheteroligomeric异质二聚体的proteinthatfunctionsasachlorideionchannel,isactivatedbytheinhibitoryneurotransmitterGABA.GABAAreceptorchlorideionchannelmacromolecularcomplextohaveapentamericstructureassembledfromfivesubunits.GABAAreceptorGABAAreceptorchlorideionchannelcomplex:

--hasrevealedthatcombinationsofthethreemajorsubunits--α,β,γ

--areessentialfornormalphysiologicandpharmacologicfunctions.AmodelofthehypotheticalGABA-BZreceptor-chlorideionchannelmacromolecularcomplex,Fig11-5.SubunitsofGABAAreceptorGABAisthemajorinhibitoryneurotransmitterintheCNS.BZpotentiateGABAergicinhibitionatalllevelsoftheneuraxis(脑脊髓).BZbindstoBZbindingsiteonGABArecetor.ActionofBZBZappearstoincreasetheaffinityofGABAbindstoGABAreceptor(facilitatedGABAreceptor),increasedtheinfluxofCl-.Highdose,BZincreasesthefrequency

ofCl-channel-openingevents.ActionofBZ2.PharmacologicalEffectsand

Applications(1)Antianxiety

---occursinlowesteffectivedosesofthecommonlyusedsedative-hypnotics

---inhibitedlimbicsystemselectively---usedforanxietydisordersSuchas：diazepam,alprazolam阿普唑仑,triazolam

(2)SedationandHypnosis

Lowdose,sedationhighdose,hypnosisSedative-hypnoticswillinducesleepifhighenoughdosesaregiven.usage：

--insomnia--preanestheticmedication

--usedbeforeendoscopyWeakeffectsonFWS,“REMrebound”occursgently;Highertherapeuticindex,noeffectonrespiration,noanesthesiainlargedose;Donotinducehepaticenzyme（CYP450）;WeakdependenceandwithdrawalsyndromeLowaftereffectMeritsofBZcomparedtoBarbiturates(3)AnticonvulsantandantiepilepsyeffectsMostoftheBZarecapableofinhibitingthedevelopmentofepileptiformactivity.Diazepamandtriazolamhaveselectiveactionsinthemanagementofseizurestates.RelatedtofacilitatedGABAfunction.Usage:

convulsions;Statusepilepticus癫痫持续状态(4)Musclerelaxation

SomeBZexertinhibitoryeffectsonpolysynapticreflexesandinternuncial(联络的)transmission.Athighdoses,BZmayalsodepresstransmissionattheskeletalneuro-muscularjunction.Usefulnessforrelaxingcontractedvoluntarymuscle

随意肌injointdiseaseormusclespasm.(5)Hysteria癔症：diazepam，imC.AdverseReactionCNSdepression:1.drowsiness,fatigue,dizziness;2.ataxia共济失调;3.coma;inhibitionofrespirationInhibitionofcardiovascularfunctionToleranceandDependenceC.AdverseReactionTolerance

--isacommonfeatureofsedative-hypnoticuse.Itmayresultinanincreaseinthedoseneededtomaintainsymptomaticimprovementortopromotesleep.Dependencesandaddiction

Thedesirablepropertiesofreliefofanxiety,euphoria,disinhibition,andpromotionofsleephaveledtothecompulsivemisuseofallsedative-hypnotics.DirectToxicActions:

CNSdepressantadverse:drowsiness,impairedjudgment,anddiminishedmotorskills,asignificantimpactondrivingability,jobperformance.Itcanexacerbatebreathingproblemsinpatientswithchronicpulmonarydisease.InteractionswithotherCNSdepressantdrugs,leadingtoadditiveeffects.

Usage:aspreanestheticmedication.However,ifnotanticipated,theycanleadtoseriousconsequences.DrugInteractions:

D.BenzodiazepineAntagonists

Flumazenil（氟马西尼）TheonlyantagonistavailableUsefordiagnosisandtherapyinreversingtheCNSdepressanteffectsofBZoverdoseandtohastenrecovery.Ashorthalflife,sorequiringrepeatedadministrationSection2Barbiturates【Structure】derivative

ofbarbituricacidhasnoeffectsofparentnucleus;OorSinC2，onlytwohydrogenarereplacedbydifferentradicalgroupinC5BarbituratesBARBITURATESA.

Pharmacokinetics1.Absorption:

Thebarbituratesareusuallyabsorbedveryrapidlyintothebloodfollowingoraladministration.2.Distribution:

Thethiobarbiturates硫巴比妥酸盐(eg,thiopental),inwhichtheoxygenonC2isreplacedbysulfur,areverylipid-soluble,andahighrateofentryintotheCNScontributestotherapidonset(severalseconds)oftheircentraleffects.Durationofactionofbabituratesdependsondegreeoflipidsolubility.Thiopental:redistributionThethiobarbiturateshaveshownthattheyarerapidlyredistributedfromthebrain,firsttohighlyperfusedtissuessuchasskeletalmuscleandsubsequentlytopoorlyperfusedadiposetissue.Shortmaintenance,10~15min.Distributionofthiobarbiturates3.Biotransformationandexcretion:

metabolizedbyhepaticenzymesexcretedbyurine,MetaboliteslackactivityPhenobarbitalisexcretedunchangedintheurine(20-30%inhumans),anditseliminationratecanbeincreasedsignificantlybyalkalinizationoftheurine.weakacid,

usedforPhenobarbitalintoxication

5.Druginteractions

phenobarbitalhasenzymeinduction,resultinanincreaseintheirownmetabolismaswellasthatofcertainotherdrugs.Self-inductionofmetabolismcontributestothedevelopmentoftolerancetosedative-hypnotics.B.PharmacodynamicsofBarbiturates

1.MechanismofactionBarbituratesalsofacilitatetheactionsofGABAatmultiplesitesintheCNS,butincontrasttoBZ：--theyappeartoincreasethedurationoftheGABA-gatedchlorideionchannelopenings.Athighconcentrations,thebarbituratesmayalsobeGABA-mimetic,directlyactivatingchlorideionchannels.Barbituratesarelessselective

intheiractionsthanbenzodiazepines,sincetheyalsodepresstheactionsofexcitatoryneurotransmitters.Barbituratescaninhibitvoltage-dependentNa+andK+channel.2.PharmacologicalEffectsandClinicalApplicationsdose-dependentrelationship.(1)SedationandHypnosis:

--thedurationofREMsleepisobviouslydecreased.--"REMrebound"canbedetectedfollowingcessationofdrug.(2)AnticonvulsantandAntiepilepticeffects

Phenobarbitaliseffectiveinthetreatmentofgeneralizedtonic-clonicseizures全身性强直-阵挛发作.(3)Intravenousanesthesiaandadministrationpreanesthesia

Thiopentalareverylipid-soluble,penetratingbraintissuerapidlyfollowingintravenousadministration.

Rapidtissueredistributionaccountsfortheshortdurationofaction,whicharethereforeusefulininductionofanesthesia.(4)Potentiatetheeffectsofothercentralnervousdepressants:

Alcohol,Anesthetics,AntipsychoticAgents,Analgesics,

Anti-histaminedrugs,Antipyretic-AnalgesicandAnti-inflammatoryDrugs,etc.（5）Highbloodbilirubin高胆红素血症andIntrahepaticcholestasisjaundice胆汁淤积性黄疸3.AdverseReaction(1)aftereffect(residualeffect):(2)T