Sedative-HypnoticDrugsLouhaiyanInstituteofPharmacologySchoolofMedicineShandongUniversitylouhaiyan@1BrainWaves:StateoftheBrainNormalbrainfunctioninvolvescontinuouselectricalactivityAnelectroencephalogram(EEG):

usedtodiagnoseandlocalizebrainlesions,tumors,infarcts,infections,abscesses,andepilepticlesionsAflatEEG(noelectricalactivity)isclinicalevidenceofdeath2NormalEEGandbrainwavepattern3波形分類頻率振幅出現(xiàn)條件皮層意義α波8-13Hz20-100mV清醒、安靜、閉目；枕葉顯著安靜狀態(tài)β波14-30Hz5-10mV睜眼或接受其它刺激（或快波睡眠時相）額葉和頂葉顯著；安靜閉目時只在額葉出現(xiàn)緊張狀態(tài)θ波4-7Hz100-150mV困倦抑制δ波0.5-3Hz20-200mV睡眠，極度疲勞或麻醉時抑制4WakefulnessandSleep5SleepSleepisabehaviorandanalteredstateofconsciousnessAssociatedwithanurgetoliedownforseveralhoursinaquietenvironmentFewmovementoccurduringsleep(eyemovements)WespendaboutathirdofourlivesinsleepAbasicissueistounderstandthefunctionofsleep6NormalSleepPatternsTherearetwomajortypesofsleep:Non-rapideyemovement(NREM)sleepRapideyemovement(REM)sleep7NormalsleeppatternNREMREM4-5REMandNREM的交替循環(huán)80-120min20-30minNREMNREMNREMREMREMREMNREMSleeplatency

01234sws123sws4swsNight-walkingandsomnambulismdreamREM81.REMS(rapideyemovementsleep,快動眼睡眠）

FWS(fastwavesleep，快波睡眠)

特點：眼球活動頻繁，骨骼肌極度松弛，做夢，呼吸、心跳快，血壓升高。PhasesofsleepPlayrolesinbrainandintellectualdevelopment

long-term

shortenwillinduce“rebound”afterwithdrawal,

significantlyincreasethefrequencyanddurationofREM,cause

dreaminess,nightmare,

anxietyandinsomnia,finallyleadingtodependence.

9特點：由淺入深可分為SWS1~4期（分別為入睡期、淺睡期占50%、中度睡眠期和深度睡眠期）,夜驚和夢游多發(fā)生于3、4期。NREMS(nonrapideyemovementsleep,非快動眼睡眠)SWS(slowwavesleep，慢波睡眠)Playrolesineliminatingthe

fatigueandpromotegrowthShortenSWS3、4phasewillcleanupnight-walkingand

somnambulism10ImportanceofSleepSleepisnecessaryforsurvivalSleepappearsnecessaryforournervoussystemstoworkproperly.DuringtheSWS,growthhormonesecretionincreaseandimportantfortheinfantsgrowthandphysicalrestorativeprocessofadultDuringREM,brainbloodflowandproteinsynthesisincrease,anditisimportantforthementaldevelopmentofinfantsandlong-termmemoryandmentalrestorationinadults.Dailysleeprequirementsdeclinewithage11WhatHappensifWeare

DeprivedofSleep?LackofalertnessFatigueMemoryproblemsIrritabilityDepressionLackofmotivationAccidents12TipsforGettingaGoodNight’sSleepAvoidcaffeineandalcoholafterdinnerKeeparoutineDon’tnapduringthedayDon’tgotobedhungryorrightaftereatingExerciseStopsmoking13RulesforOptimalSleepGetanadequateamountofsleepeverynightEstablisharegularsleepscheduleGetcontinuoussleepMakeupforlostsleep14InsomniaSymptomsofinsomnia：1.difficultyfallingasleep2.difficultystayingasleep3.earlymorningwaking4.daytimedrowsiness,fatigueordifficultyconcentrating15Insomnia

Causesofinsomnia:1.Psychologicalproblems:anxiety2.Medicalproblems3.Medication4.Sleepdisordersanxiety:

themostcommoncause16EpidemiologyStudiesthroughouttheworldshowthatitoccurseverywhereDependingonthearea,study,etc.,between10-50%ofthepopulationareaffectedIncreaseswithageTwiceascommoninfemalesUptotheageof30,thereislittledifferencebetweensexesBeyond30years,itismorecommoninfemalesBeyond70years,femalesareaffectedtwiceasmuchasmales17ConsequencesofinsomniaDecreasesinmentalperformanceandmotorfunctioningAccidentsInabilitytoaccomplishdailytasksMooddisturbanceMoresadness,depression,andanxietyInterpersonaldifficulties Withfamilies,friends,andatwork18CNSdepression(dose-dependent)Itsmajortherapeuticuseistocausesedation

(withconcomitantreliefofanxiety)—smalldoseencouragesleep

—largedose

Definitionofsedative-hypnoticdrugs19Benzodiazepines(BZ，苯二氮卓類)

Barbiturates(巴比妥類)Others

Classifications201.Gradeddose-dependentdepressionofCNSfunctionCharacteristics

Dose-responsecurvesfortwohypotheticalsedative-hypnoticsDrugA:barbituratesDrugB:benzodiazepinesandcertainnewerhypnotics21*2.Differentinfluencesonsleepphases3.Toleranceanddependence

Physiologicdependence

Psychologicdependence22

Section1Benzodiazepines23ChemicalStructure1,4-benzodiazepines(1,4-苯并二氮卓）24DrugsT1/2(h)Long-acting24~72

Diazepam(地西泮，安定）

Flurazepam(氟西泮，氟安定）

Chlordiazepoxide

(氯氮卓，利眠寧)Intermediate-acting

Alprazolam(阿普唑侖，佳樂定)10~20

Estazolam(艾司唑侖，舒樂安定)

Clonazepam(氯硝西泮，氯硝安定)

Lorazepam(勞拉西泮，氯羥安定)

Short-acting3~8

Triazolam(三唑侖，海樂神)

Oxazepam(奧沙西泮，去甲羥安定，舒寧)Classifications25

1.Antianxiety

【Pharmacologicalactions】

atthelowesteffectivedosesrelievetheanxietystateinducedbyvariouscauses26

焦慮是一種N官能癥，NS無明顯形態(tài)改變;是一種心理現(xiàn)象。當預感到某種困難、危險將來臨時所產(chǎn)生的緊張不安、擔憂、害怕的情緒體驗，亦有植物NS功能紊亂。適度的焦慮屬正常的反應（焦慮反應）。焦慮反應過度或沒有明顯原因經(jīng)常出現(xiàn)的焦慮，認為是焦慮癥。

女，因晉職稱，提心吊膽、煩躁不安、胃部飽滿、腹脹難受；心慌胸悶、呼吸急促、嘆息、出汗、睡眠差、記憶減退

措施：自我調(diào)節(jié)、心態(tài)平衡、

心理免疫力、深呼吸、聽音樂、欣賞大自然美景……；

鎮(zhèn)靜藥物：地西泮…..焦慮反應、焦慮癥27焦慮癥病例病例一：王**，女，30歲，一年前坐公交時因人多擁擠而出現(xiàn)心慌胸悶呼吸困難，以后每次上公交無論人多人少，都有這種感覺，以至不敢再乘車，發(fā)展到去商場廣場，只要自己感覺人多就會發(fā)病。（廣場恐怖癥）病例二：李**，男，22歲，因中學課堂發(fā)言時一個錯誤引起全班哄堂大笑，此后不敢再發(fā)言，常覺被人注視，做夢也夢見自己當眾出丑。（社交恐怖癥）病例三：（疾病恐怖癥）28心理治療的療效是肯定的

對焦慮癥的心理治療不可忽視292.Sedation

andHypnosisdecreasesleep-inductiontimedecreasethenumberofawakeningincreasethedurationofsleepprolongstage2ofNREMSshortenstage3,4ofNREMS(reducenight-wakingandsomnambulism)

*

seldomeffectonREMS(littlerebound)

【Pharmacologicalactions】303.Anticonvulsantandantiepilepticeffects

【Pharmacologicalactions】4.Centralmusclerelaxation5.Others

Anterogradeamnesia

(順行性記憶缺失)RespiratorydepressionCardiovasculardepressionlargerdose→sideeffect31【Clinicaluses】1.Foranxiety2.Forinsomnia3.ForsedationandamnesiabeforemedicalandsurgicalproceduresPremedication(麻醉前給藥）Endoscopy(內(nèi)窺鏡檢查)Electricdefibrillation(電除顫)32【Clinicaluses】4.Fortreatmentofconvulsionandepilepsyconvulsionsduetovariouscauses:

tetanus(破傷風)

eclampsia(子癇)febrileconvulsion(高熱驚厥)drugtoxicconvulsion(藥物中毒性驚厥）

statusepilepticus(癲癇持續(xù)狀態(tài)):

Diazepam（iv.）isfirstchoice

335.Formusclerelaxationinspecificneuromusculardisorder

skeletalmusclespasticity

incerebralvascularaccident

andspinalcordinjury34地西泮給藥方案焦慮：2.5mg/次，tid;失眠：臨睡前2.5-5mg;驚厥、癲癇：iv,不超過5mg/min；癲癇持續(xù)狀態(tài)：5-10mg/次，再發(fā)作時可反復應用35【Mechanismsofaction】1.Sitesofaction:2.InteractionwithGABAAreceptorMainlyactsonlimbicsystemandmidbrainreticularformation.36GABAAreceptor37MolecularMechanismGABA+-+-GABAandGABAagonistBZsBarbituratespicrotoxinCl-38【Mechanismsofaction】39【Mechanismsofaction】40【Mechanismsofaction】Benzodiazepine41BindingofGABAisenhancedbybenzodiazepine,resultinginagreaterentryofchlorideion.BindingofGABAcausesthechlorideionchanneltoopenEmptyreceptorisinactive,andthecoupledchloridechannelisclosed.Receptorempty(noagonists)Cl-Cl-Cl-ReceptorbindingGABAReceptorbindingGABAandbenzodiazepineCl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-Cl-EntryofCl-hyperpolarizescellmakingitmoredifficulttodepolarizeandthereforereducesneuralexcitability.GABAreceptorBenzodiazepinereceptorBenzodiazepineGABA42

1.EnhancetheaffinityofGABAAreceptorforGABA，promoteGABAbindingtoGABAAreceptor.2.IncreasethefrequencyofCl-channelopening3.Enhancehyperpolarizationandfurtherinhibitneuralexcitability4.notsubstituteforGABA,butappeartoenhance

GABA’seffects【Mechanismsofaction】43

oralabsorptionisrapidandcomplete

im:absorptionisslowandirregular

iv:acute【Pharmacokinetics】1.Absorptionhigh

plasmaproteinbindingratehighlipidsolubility→crossBBBandplacentalbarrier2.Distribution

diazepam443.Metabolism:mostofthemmetabolizedbythelivertocompoundsthatarealsoactive.4.Excretion

excretedviakidneyasinactiveglucuronides

detectableinbreastmilk45Biotransformationofbenzodiazepines地西泮*:activemetaboliteBoldface:

drugsavailableforclinicaluse奧沙西泮氯氮卓普拉西泮三唑侖勞拉西泮氟西泮阿普唑侖461.CNSdepression

Mostcommon:Hangover:drowsiness,exhaustion,dizziness,memorydecay(記憶衰減）Diminishedmotorskillsandimpairedjudgment

→impactondrivingabilityLargedose→ataxia(共濟失調(diào))iv.tooquick→inhibitrespiratoryandcadiovascular

fuction

【AdverseReactions】2.Toleranceanddependence

withdrawalsymptom47WashingstomachSymptomatictreatmentBenzodiazepinespecificantagonist

Flumazenil(氟馬西尼，安易醒）:shortt1/2,repeatedadministration3.toxicreactionanddetoxifcation

GABABZsFlumazenil-48氟馬西尼

（Flumazenil

，安易醒）DIAZEPAMFLUMAZENIL

49【Contraindications】TheelderlyHeart/lung/liver/kidneydysfunctionPregnancyandlactationmothersDrivers,employeesofaloftworkandmechanizedoperation

Myastheniagravis(重癥肌無力)Glaucoma

(青光眼)50

AlcoholandotherCNSdepressantsEnzymeinduction

sodiumphenobarbitalorphenytoin,

carbamazepine(卡馬西平),

rifampicin(利福平）

shorternt1/2

Enzymeinhibition

cimetidine

prolongt1/2【Druginteractions】51Intermediateacting—nitrazepam（硝西泮）：特點：口服吸收好，30分起效，維持睡眠6～8小時;醒后無明顯后遺效應;兼抗癲癇作用Shortacting—艾司唑侖（estazolam，舒樂安定)特點：吸收快，口服后20～60分鐘入睡，維持5～8小時;副作用?。患婵拱d癇、抗驚厥作用Longacting—flurazepam（氟西泮）特點：與地西泮相似，鎮(zhèn)靜催眠作用較強。代謝物(去烷基氟西泮）有活性，作用持久（t1/240-100h）

Similardrugs52Shortacting—triazolam（三唑侖）BDZ類中代謝最快、作用最強的藥物;速效、強效（45-100倍）、極少蓄積為突出優(yōu)點。臨床上曾廣泛用于各種類型的失眠，現(xiàn)因依賴性少用。53Section2Barbiturates54Classificationsthiopentalsodium(硫噴妥鈉)Long-acting:

phenobarbital(苯巴比妥,luminal,魯米那)Intermediate-acting:pentobarbital(戊巴比妥)Short-acting:secobarbital(司可巴比妥,seconal)

Ultra-short-acting:551.Sedationandhypnosis

shortenREMS→“rebound”EasytoproducetoleranceanddependenceHepaticenzymeinducer

moreadversereactions,severe

intoxication

notsedative-hypnoticsforroutinelyuse

【Pharmacologicalactionsandclinicaluses】dose-dependenteffects563.Anesthesiaandpremedication

eg.thiopentalsodium（硫噴妥鈉）onset(30s),duration(15min)4.EnhancetheeffectsofotherCNSdepressants

【Pharmacologicalactionsandclinicaluses】2.Anticonvulsantandantiepilepticeffectsgeneralizedtonic-clonicseizure(大發(fā)作)andstatusepilepticus

57【Mechanisms】GABAmimetic(highdoseactivateGABAreceptor)

ExtendopeningtimeofCl-channelinhibitexcitatoryneurotransmitter58

Pharmacokinetics1.Absorption:po,im2.Hepaticenzymeinducer3.UrinepHaffectsexcretion59Alkalizationoftheurineoftenaidsintheeliminationofphenobarbital—iv.NaHCO3

Detoxifcation60

AdversereactionsHangoverToleranceanddependenceRespiratorydepression：

深度的呼吸抑制

死亡原因

61

AdvantagesofBZs1.Highertherapeuticindex,no

anesthesiainlargedose2.Prolongstage2sleep,shortenstage3,4sleep,littleinfluencesonREMS3.Donotinducehepaticenzyme4.Lessreboundanddependence62Section3Otherhypnoticagents63NewerdrugsforanxietyandsleepdisordersBuspirone(丁螺環(huán)酮)Zolpidem(唑吡坦,思諾思)Zopiclone(佐匹克隆)Oldersedative-hypnoticsChloralhydrate(水合氯醛)Meprobamate(甲丙氨酯，眠爾通)OtherhypnoticagentsmoreselectiveNon-GABAergicsystemZaloplone(扎來普隆)Melatonin(褪黑素)64Chloralhydrate（水合氯醛）1.Hypnosis:s