镇静催眠药和抗焦虑药

Dr.Ji-qunCaiDepartmentofPharmacologySection3DrugsAffectingtheCenterNervousSystem(1)Chapter14Sedatives，hypnoticsandAnxiolytics镇静催眠药和抗焦虑药定义（Definitions）镇静药：降低人体的活动(度)，抑制激动和兴奋，使人趋向于平静。催眠药：产生困倦感,加速进入睡眠，并能保持近似生理的睡眠状态。抗焦虑药:解除患者焦虑、不安、兴奋和紧张。睡眠的各个阶段StagesofSleepBeforesubjectfallsasleep,EEGmarkedbyburstsofwaves(largeamplitude)—indicatewakefulstate.Whensubjectfallsasleep,EEGprogressesthroughstages:StagesofSleepInitialstage1–EEGlow-voltage,fastactivitysimilarto,(slightlyslower)thanwakefulness.Stage2–EEGhighervoltage&slowerthanstage1–Kcomplexes(singlelargenegativewavefollowedbysinglelargepositivewave)–sleepspindles睡眠梭(1-to-2-secwaxing-and-waningburstsof12-to-15-Hzwaves).FourStagesofSleepStage3–EEGdefinedbypresenceofdeltawaves,thelargest&slowestEEGwavesStage4–EEGdefinedbypredominanceofdeltawavesOncestages1-4,goesbackthroughstagestostageIEEGwhenbacktostageIEEG,referredasemergentstage1–emergesfromotherstates生物节律CircadianRhythms以24小时为周期（人和其它生物）伴随有温度、激素、血压的波动WhatisthedifferencebetweenStage1&EmergentStage1?–Onlyemergentstage1isthereREMREMsleepalsocalledparadoxical非常规sleep(paradoxthatsubjectssleptwhileEEGssuggestedwakefulness)Stages2,3,&4together(slow-wavesleep)Stages3&4(deltasleep)ProgressionofEEGstageschangesduringtypicalnight'ssleep–Eachcycleapproximately90minuteslong–Asnightprogresseslesstimespentinstages3&4(moreinREMsleep)–Briefperiodsofwakefulness--normallyforgotteninthemorningREMSleepandDreamingKleitman(1953)DreamingoccursduringREMsleepWokesubjectsupduringvariousstages&askediftheyhadweredreaming–80%inREMsleepreporteddreaming–only7%ofinnonREM-sleepreporteddreamingWhyDoWeSleep?RecuperationTheory(恢复理论)beingawakedisrupts分离homeostasis体内环境恒定&sleepisrequiredtorestoreitthisiswaythatmostpeoplethinkaboutsleepWhyDoWeSleep?CircadianTheory(昼夜节律)REMSleepandDreamingAresomnambulism(梦游)&sleeptalkingtheactingoutofdreams?–no,usuallyoccurduringstage4睡眠紊乱SleepDisordersInsomnia(失眠症)–complaintsoftoolittlesleep–Ofteniatrogenic医源性(physicianinduced)personwithminorsleepingdifficultiesgivenpills(benzodiazepinesValiumorLibrium)Viciouscircle-tolerancedevelops=severeinsomniaaswithdrawalsymptom=increasedrugusedrugtakingSleepDisordersSleepapnea(睡眠呼吸暂停)–spasmsofthroatmusclesblockairintakeseveraltimesnight–ifmanyawakeningsarenotrecalledexcessivesleepinessnextdayleadtodiagnosisofhypersomniaNocturnalmyoclonus(夜间肌痉挛)–Subjectsbrieflyawakenedatnightbysuddenlegtwitches–Canleadtodiagnosisofhypersomnia睡眠过度forsamereasonSleepDisordersRestlesslegs(多动腿)–Hard-to-describetensioninlegs,keepspeoplefromfailingasleep;leadstodiagnosisofinsomniaBDZsalsohavemusclerelaxant,anxiolytic,andanticonvulsiveeffectsPseudoinsomniacs(假性失眠症)–Usedtobepracticetoassumepeoplewhocomplainedofinsomniabutsleptmorethan6.5hourswereneurotic–Manypeoplediagnosedasneuroticsufferedfromsleep-disturbingproblemsNightterrors–mostlyoccurinchildren,tendtogoawaywithage.Childsitsupinbed,screaming,unresponsivetostimuli.UsuallyoccurinNREMsleep,unlikenightmares,whichoccurduringREM.Sleepwalking–persongetsupandwandersabout.Mostlyseeninchildrenanddeclineswithage.AlsooccursduringNREMsleep.镇静催眠药的历史酒精阿片酊草药溴化物巴比妥类苯二氮卓类（Librium利眠宁，1965）共合成了3000多种苯二氮卓类化合物，目前有35种在全世界应用吸收完全、不良反应少、不易成瘾19世纪19-20世纪镇静催眠药的分类苯二氮卓类巴比妥类其它类14.1苯二氮卓类地西泮（Diazepam,安定Valium）药理作用与应用：1，抗焦虑：小于镇静量，消除不安、紧张和激动2，镇静催眠：缩短入睡潜伏期，减少觉醒次数。对REM睡眠有轻度影响，优于巴比妥类。取代巴比妥类的原因：1，安全2，耐受性轻3，不良反应少4，反跳现象轻3，抗惊厥抗癫痫：可有效拮抗印防已毒素、荷包牡丹碱等的致惊厥作用。临床可用于治疗破伤风等疾病引起的惊厥，癫痫大发作的首选药物。4，中枢性肌肉松弛作用小剂量：抑制网状结构下行易化系统大剂量：增强突触前抑制作用机理BDZ与受体结合后可以增强与促进脑内A型γ-氨基丁酸（GABA）神经的功能。GABAA受体与离子通道偶联，激活受体后，增进Cl-通道的开放频率，使Cl-跨膜流动增加，使膜超极化，降低神经元的兴奋性。药名商品名血浆t1/2（小时）催眠剂量（成人口服）地西泮（diazepam）安定（Valium）20~402.5~5mg氯氮卓（chlordiazepoxide）利眠宁（Librium）6~3010~20mg硝西泮（nitrazepam）硝基安定（Mogadon）21~255~10mg氟西泮（flurazepam）氟安定（Dalmane）50~10015~30mg苏拉西泮（lorazepam）氯羟去甲安定（Ativan）10~181~2mg奥沙西泮（oxazepam）舒宁（Serax）3~2115~30mg常见的苯二氮卓类衍生物的药动学参数苯二氮卓类衍生物的药动学Pharmacokinetics1口服吸收良好F=55---1002与血浆蛋白结合率为77-99%3在体内部分药物可以产生活性代谢产物:Flurezepamdesalkylflurazepam脱烷基西泮(alongactingactivemetabolite)不良反应Sideeffects:1一般来说安全usuallysafeexcessivehypersomniasataxia(嗜睡)共济失调2ivtoofastcauseCNSdepression3addiction成瘾BDZReceptorAntagonist苯二氮卓受体结抗剂Flumazenil氟马西尼主要用于苯二氮卓类过量中毒易引起惊厥巴比妥类Barbituratesweakacid分类Classification:Drugt½(h)onsetduration(h)Phenobarbital80-120+6-8(luminal)Amobarbital10-40++3-6(amytal)Secobarbital15-40+++2-3Thiopental8-10++++0.25药理作用和应用Actionanduse:1镇静催眠sedativeandhypnosis2抗惊厥anticonvulsiveaction(phenobarbital)3抗癫痫antiepilepticaction(phenobarbital)4麻醉和麻醉前给药anesthesiaandpreanestheticmedication(thiopental)不良反应Adverseeffect:1CNS:drowsiness,impairedconcentrationtirednessafterawakes2inducetheP-450systemandthereforemaydecreasetheeffectofotherdrug3addiction,abruptwithdrawalmaycausetremor,anxiety,weakness,restlessness,nauseaandvomiting.4poisoning:overdosescancausedeath,depressionofrespirationandcentralcardiovasculardepression.Alkalinizationofbloodandurine其它类Othersedatives:Chloralhydrate（水合氯醛）多用于儿科Buspirone(布斯哌隆，丁螺环酮)5-HT1A受体的部分激动剂，只用于抗焦虑。Ethanol（乙醇）AntianxietysedativeeffectsToxicpotentialbenefitsChapter15抗癫痫和抗惊厥药Antiepilepticandanticon