药理2.docx
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药理2.docx
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药理2
Centralnervoussystemdrugs
1.Sedative-Hypnotics
☆Benzodiazepines(BDZ)(苯二氮卓类)(全面)
(一)Classification:
1.Short-actingBDZs(t1/2<6h):
triazolam(三唑仑),midazolam(咪达唑仑),andoxazepam(奥沙西泮).
2.Intermediate-actingBDZs(t1/2=6-20h):
lorazepam(劳拉西泮),estazolam(艾司唑仑)andnitrazepam(硝西泮).
3.Long-actingBDZs(t1/2>20h):
diazepam(地西泮),chlordiazepoxide(氯氮卓),andflurazepam(氟西泮).
(二)Pharmacokinetics:
1.AbsorptionandDistribution
——Wellabsorbedorally.TheratesoforalabsorptionofBDZdifferdependingonanumberoffactorsincludinglipidsolubility.
——ThebioavailabilityofseveralBDZs(diazepam,chlordiazepoxide)maybeunreliableafterintramuscularinjection.
——Whenusedtotreatanxietyorsleepdisorders,BDZsareusuallygivenorally.
——Whenusedtotreatepilepticstate,givenintravenously.
——LipidsolubilityplaysamajorroleindeterminingtherateatwhichBDZsenterstheCNS.(triazolam>chlordiazepoxide,lorazepam)
——Crosstheplacentalbarrierduringpregnancy.IfBDZsaregiveninthepredeliveryperiod,theymaycontributetothedepressionofneonatalvitalfunctions(respiration).
——Detectableinbreastmilk:
depressanteffectsonCNSfunctioninthenurslinginfant.
——Highproteinbindingrate(95%)
2.MetabolismandExcretion
——MostBDZundergomicrosomaloxidation(phaseIreactions)
——Themetabolitesaresubsequentlyconjugated(phaseIIreactions)toformglucuronides.
——ManymetabolitesofBDZsareactive,withhalf-livesgreaterthantheparentdrugs.
——ThemetaboliteofBDZsareexecretedmainlyviakidney.
——Diazepamhashepatoenteralcirculation,theeliminationofdiazepamisslowanditseffectpersistsforalongertime.
3.Diazepam:
Pharmacologicaleffects:
(1)Antianxiety:
highselectivity
——Withsmallerdosethansedativedose,Diazepamshowsanxiolyticeffectsandalsoexerts"taming"effect,allowinganimalstobehandledmuchmoreeasily
——Diazepammayrelievethepatientfromtension,agitation,fear,anxiety,restlessnessandgastrointestinaltractdisturbancesorinsomniainducedbyanxiety.
——inhibitingneuronalcircuitsinthelimbicsystemofthebrain.
(2)Sedationhypnosis:
①Ifhighenoughdosesaregiven,alltheBDZswillinducesleep,decreasethelatencyofsleeponset.
②ThecharacteristicsofsedationhypnosisofBDZs:
——Increasethedurationofstage2NREM.
——DecreasethedurationofSWS(decreasetheprobabilityofsomnambulismandnightterrors).
——NomarkedeffectonREM.
Advantagesofdiazepam:
①Therapeuticindexishigh,largedosagedoesnotinduceanesthesia.
②nohepaticenzymeinductioneffect
③mildsideeffects,lessdangerofoverdosagetoxicity.
④afterwithdrawalofthedrug,thereboundissmall.
⑤Tolerance,psychologicandphysiologicdependenceissmall.
(3)Anticonvulsanteffects,antiepilepticeffects:
——Cannotinhibittheonsetofabnormaldischarge.
——ButcaninhibitthespreadofepileptiformactivityinCNS.
——Itcanexertanticonvulsanteffectswithoutmarkedcentralnervoussystemdepression,sothatmentalactivityandphysiologicactivityarerelativelyunaffected.
(4)Central/peripheralmusclerelaxation
①Relievemusclespasmduetobrain/spinalcordinjury,relieveacutelocalmusclespasm
②Especiallywhenthedrugisgivenintravenously.
③Noeffectonnormalactivity.
——Atsmallerdose,itinhibitsfacilitationofreticularformationdescendingsystemonspinalgneuron;
——Atlargerdose,itpotentiatespresynapticinhibitionofspinalneuronsandinhibitspolysynapticreflexes,
——Athighdosesmaydepresstransmissionattheskeletalmyoneuraljunction.
(5)Inhibitionrespiration
①Hypnoticdoses:
noeffectonrespirationinnormalsubjects,exceptchildrenandindividualswithimpairedhepaticfunction,suchasalcoholics
②Higherdoses:
slightlydepressalveolarventilationandcauserespiratoryacidosis;especiallyinpatientswithchronicobstructivepulmonarydisease(COPD)
(6)CardiovascularSystem
——Minorinnormalsubjects
——Preanestheticdoses:
decreaseBPandincreaseHR.
4.Mechanismofaction
①BDZsactbybindingtoaspecificregulatorysiteontheGABAA-receptorinneuronalmembranesinthecentralnervoussystem,thusenhancingtheinhibitoryeffectofGamma-aminobutyricacid(GABA,γ-氨基丁酸)
②GABA:
majorinhibitoryneurotransmitterintheCNS.
③GABAreceptors:
GABAA&GABABreceptors.
④GABAA:
mainGABAreceptorinthebrain,composedof5subunits.GatingreceptorofCl-channel.
⑤GABAcaninteractwithαandβsubunitsofGABAAreceptortriggeringCl-channelopeningwithresultantmembranehyperpolarization,andinducepost-synapticinhibitoryeffect.
⑥BDZsdonotactivateGABAAreceptorsdirectly;rather,actallostericallybymodulatingtheeffectsofGABA.
⑦BDZscombinewithGABA-receptor-chlorideionchannelcomplex.ItcanpromotethebindingofGABAandGABAAreceptor.Then,increasetheopeningfrequencyofCl-channel.butdoesnotdirectlyinitiateCl-current.
5.Clinicaluses
(1)Sedativeandantianxiety:
①relievetheanxietyofgeneralizedanxietydisorderandinsomepatientspanicattacksyndrome.
②BDZisoftenusedasapre-anestheticmedication
——Reduceanxiety
——Decreasethedoseofanesthetics
——Decreasethedangerofaccidentaloroverdosage.
(2)Hypnotic:
——Usedtotreatinsomnia.
——Accordingtothedifferenceofsleepproblems,selectdifferenttreatment
——abruptdiscontinuanceofmanysedative-hypnoticscanleadtoreboundinsomnia.
——Usedonlyforshortperiods(<4weeks)andforsevereinsomnia.
(3)Anticonvulsant,antiepileptic:
——Convulsion:
Usedtotreattetanus(lockjaw),eclampsia(hypertensivedisorderofpreganncy),convulsioninducedbydrugintoxicationandfever(children).
——Epilepsy:
Diazepamgivenintravenouslyorrectallyishighlyeffectiveforstoppingcontinuousseizureactivity,especiallygeneralizedtonic-clonicstatusepilepticus.Itisthefirstchoiceofdrugtotreatstatusepilepticus
(4)Skeletalmusclerelaxant:
——Diazepamreducesmuscletone.
——Itisusedtoreducemusclerigidityinducedbycerebralpalsy,cerebralvascularaccidentorspinalcorddamage.
——Relievemusclespasminducedbyjointpathologicalchanges.
(5)Anterogradeamnesiceffects:
——Beforeusingendoscope(bronchoscopy,rectoscopy,colonoscopy)andcardioversion,intravenousinjectionofdiazepammayinducetemporaryamnesia,withoutleavingunpleasantmemories.
——Thiseffectisutilizetoadvantageinuncomfortableprocedure(minorsurgicalprocedures).
——Anterogradeamnesia:
inabilitytoremembereventsoccuringduringthedrug’saction
——Retrogradeamnesia:
unabletorecalleventsthatoccurredbeforethedevelopmentoftheamnesia
6.AdverseEffects
(1)ResultfromdepressionofCNSfunction
——drowsiness,fatigue,dizziness
——impairmentondrivingability,mentalandmotorfunction,ataxia
——anterogradeamnesia:
impairabilitytolearnnewinformation
——Rapidintravenousinjectionofthedrugmaycauserespiratoryandcirculatorydepression
——CautionshouldbeexercisedinusingthemwithotherCNSdepressants.
——Glaucoma
(2)AdverseEffectsoflongtermuse
——Tolerance:
Decreasedresponsivenesstoadrugfollowingrepeatedexposure.Associatedwithdown-regulationofbrainBDZsreceptors.
——Psychologicdependenceismanifestedbycompulsivedrugseekingbehaviorinwhichtheindividualusesthedrugrepetitivelyforpersonalsatisfaction.
——Physiologicdependencecanbedescribedasanalteredphysiologicstatethatrequirescontinuousdrugadministrationtopreventtheappearanceofanabstinenceorwithdrawlsyndrome.
——Withdrawalsyndromeischaracterizedbystatesofincreaseanxiety,insomnia,andCNSexcitabilitythatmayprogresstoconvulsion.
——Theperceiveddesirablepropertiesofreliefanxiety,andpromotionofsleephaveledtocompulsivemisuseofsedative-hypnotics.
7.BenzodiazepineReceptorAntagonist:
Flumazenil(氟马西尼)
(1)Clinicaluse:
——BDZintoxication:
rapidonset,shorthalf-life.IVwithin5-15min,itmayawakethepatient.
——Hepatogenicencephalopathy:
Transientimprovementinmentalstatus
(2)Sideeffects:
Causeasevereabstinencesyndromeinpatientswhohavedevelopedphysiologicbenzodiazepinedependence.
8.CharacteristicsofDifferentDrugs
(1)Chlordiazepoxide(氯氮卓,利眠宁)
——Long-actinganxiolytic
——Wellabsorbedorally
——Activemetabolites,biotransformedmoreslowly.
——Usedtotreatanxiety,insomniaaccompanyingwithanxietyandalcoholwithdrawalsymptoms.
(2)Oxazepam(奥沙西泮)
——short-actinganxiolytic,activemetaboliteofdiazepam
——t1/2:
5-10h.
——Weakhypnoticandmusclerelaxant,buthasstrongantianxietyeffect.
——Clinicaluses:
anxiety,insomniaandepilepsy
(3)Nitrazepam(硝西泮)
——Intermediate-actinganxiolytics
——Nitrazepamhashypnotic,anticonvulsant,antianxiety.
——Usedforinsomnia,epilepsy(epilepticstate、infantilespasm、paroxysmalmyospasm),pre-anestheticmedication.
(4)Estazolam(艾司唑仑,舒乐安定)
——Intermediate-actinganxiolytics
——Strongsedativeandhypnoticeffects.Afteroraladministration,40minuteswillinducesleepandsleepkeepsfor5-8hrs.
——Widelyusedfortreatmentofanxiety,insomnia,epilepsyandpre-anesthesiamedication.
(5)Flurazepam(氟西泮)
——Long-actingsedative-hypnotics.
——Itiswellabsorbedbyoraladministration,buthasafirst-passeffect,Thehalf-lifeofitsactivemetabolitedemethyl-flurazepamis40-100hrs→aftereffect
——similartothatofdiazepam,butithasrelativelystrongsedativeandhypnoticeffects
——Ithassmalltolerance.
——Usedtotreatdifferenttypesofinsomnia,especiallytreatthepatientscannottolerateotherhypnoticsforashortterm.
(6)Triazolam(三唑仑)
——Short-actinganxiolytics。
——Ithasprominentsedative-hypnoticeffectwithrapidonset(15-30min)andshortdurationofaction.Itst1/2is2-3hours.
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