药理学英文版教学课件：Chapter 14 sedative-hyponotics

Sedative-Hypnotics(p90)Case12.5yearsoldboySwallowed2coins3hoursago,checkedbyX-rayexamination.Preparingfortakingoutthecoinsthroughgastroscope(胃镜).Slowlyi.v.diazepam0.3~0.5mg/kg10minbeforeoperation.Case2CharlieChaplin(卓别林)Chaplindiedduringsleepintheearlymorningof25December1977athishomeinSwitzerland.AfterahappyfamilypartyatChristmasEvewithalotofwine,hecouldnotfillintosleep,thentakesomesedative-hypnotic.Physiologicalsleeprapideyemovementsleep,REM--dream,nightmarenonrapideyemovementsleep,NREM(slowwavesleep慢波睡眠)--Therearefourrecognizedstagesofsleep,fromthefirstand“lightest”stagetothedeepestfourthstage.TheEEGgetsprogressivelymoresynchronouswitheachdeeperstage.Everytimeyoureturntostage1,youenterREMsleep-aperiodofsleepcharacterizedbyrapideyemovements.REMsleepisalsocalledparadoxical(异相)sleep,becausethebodyappearstobemoredeeplyasleepthaninanyotherstage,buttheEEGlooksverymuchlikethewakingbrain.Thedesynchronousactivityofthebrainmaybeduetodreaming,whichalsooccursduringREMsleep.Insomnia(失眠)inabilitytofallorremainasleep:1.Struggletofallasleepatnight(initialinsomnia),

2.Wakeinthemiddleofthenightandstruggletofallasleepagain(middleinsomnia).

3.Wakeintheearlyhoursofthemorning,longbeforetheyneedtogetup(terminalinsomnia).Anxiety(焦虑)isthesenseofthreatthatdangerandbadeventsiscoming.Anxietycanbethoughtofasconsistingofanxiousthinkingplusnervoustension.Mr.Anxiety

pharmacologicalsleepShorterREM/longerSWS:reboundNREM/REMinterchangeClassification1stgeneration:barbiturates,19032ndgeneration:benzodiazepines,1960s3rdgeneration:zolpidem(唑吡坦，思诺思)§1Benzodiazepines,BZs(苯二氮类)Diazepam(地西泮,安定Valium)PrototypebenzodiazepineFirstchoiceforemergencycontrolofstatusepilepticus（癫痫持续状态）andacuteseizures;Pharmacodynemics&Uses1.anxiolyticeffect:reductionofanxiety2.Sedation&Hypnosis:calmingeffectsinducesleepLatencyofsleeponsetisdecreasedDurationofNREMincreasedandREMdecreased3.Anticonvulsant&antiepilepticeffects:1stchoice4.musclerelaxation5.temporarymemorylose,Mechanismofaction:GABAergicSYNAPSEGABAglutamateglucoseCl-GADGABA-AReceptorOligomeric(abdgepr)glycoprotein（糖蛋白）.MajorplayerinInhibitorySynapses.ItisaCl-Channel.BindingofGABAAcausesthechanneltoopenmorefrequently(频率增加)andmoreCl-toflowintothecellmembranehyperpolarization(超极化).GABAagonistBDZs

d

BARBs

ePharmacokineticsAbsorption:p.oquicklyandreadilythani.mDistribution:proteinbinding95%,easilypassBBB.Livermetabolism:Activemetabolites.Urineexcretion地西泮奥沙西泮*氟西泮三唑仑氯氮唑去甲地西泮*地莫西泮*去甲氯氮唑*羟乙基地西泮去烷基氟西泮α-羟代谢物结合物肾排泄

BZs生物转化过程

*为活性代谢物表14常用苯二氮类药物作用时间及分类作用时间药物达峰浓度时间（h）t1/2（h）代谢物t1/2（h）短效类(3~8h)三唑仑（triazolam）奥沙西泮（oxazepam）12~42~310~20有活性（7）无活性中效类（10~20h）阿普唑仑（alprazolam）艾司唑仑（estazolam）劳拉西泮（lorazepam）替马西泮（temazepam）氯硝西泮（clonazepam）1~2222~3112~1510~2410~2010~4024~48无活性无活性无活性无活性弱活性长效类（24~72h）地西泮（diazepam）氟西泮（flurazepam）氯氮（chlordiazepoxide）夸西泮（quazepam）1~21~22~4220~8040~10015~4030~100有活性（80）有活性（80）有活性（80）有活性（73）Adverseeffectsdrowsiness,dizzy,decreasedmotorskillsEnhanceddepressionofCNSifusedwithotherCNSinhibitorydrugs:opioids,anticonvulsants,alcoholTolerance,drugdependence—withdrawalsyndromeFlumazenil(氟马西尼)foroverdosetoxication§2BarbituratesCommonlyuseddrugsPhenobarbitol(苯巴比妥，luminal，鲁米那)pentobarbitalsodium（戊巴比妥钠）thiopentalsodium（硫喷妥钠）MechanismInhibitmulti-synapticresponsesbyactivatingGABAAreceptorsMimictheeffectsofGABA,increasetheopeningtime(延时)ofCl-channel,membranehyperpolarizationInhibittheexcitiveresponseofglutamicacidonitsreceptorsOthermechanismsClinicalusesSedationHypnosisAnticonvulsantAnaesthesia:thiopental(硫喷妥钠)JaundiceofNewborn(新生儿黄疸)AdverseeffectsDrowsiness（困倦）,dizzy（眩晕）,damagedmotorskillsInhibitoryeffectsonrespiratorycenterinCNS,coma,