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Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,*,*,单击此处编辑母版标题样式,*,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,第1,3,章 镇静催眠药,SEDATIVE- HYPNOTICS DRUGS,1,失眠,(insomnia),失眠分类,(1),按病程的长短分,:,暂时性失眠,短期失眠,慢性失眠,(2),按病因分,:,原发性失眠症,继发性失眠症,1,Introduction,2,What is insomnia?,Insomnia,inability to fall or remain asleep,Struggle to fall asleep at night,(initial insomnia),Wake in the middle of the night and struggle to fall asleep again,(middle insomnia).,Wake in the early hours of the morning, long before they need to get up,(terminal insomnia).,3,失眠的病因,1,环境因素,2,生活习惯因素,3,躯体因素,4,精神心理因素,5,精神疾病,6,药物原因,7,年龄因素,8,与睡眠相关疾病,4,Anxiety is the sense of threat that danger and bad events is coming.,Anxiety can be thought of as consisting of anxious thinking plus nervous tension.,Mr.,Anxiety,5,Causes of Anxiety,1),Medical,:,Respiratory,Endocrine,Cardiovascular,Metabolic,Neurologic,6,Causes of Anxiety,2).,Drug-Induced,:,Stimulants,Amphetamines, cocaine, caffeine.,Sympathomimetics,Ephedrine, epinephrine,AnticholinergicsAntihistaminergics,benztropine, meperidine,Dopaminergics,Amantadine, L-Dopa,7,焦虑症状，除烦躁不安、紧张焦虑、恐惧失眠等精神异常外，还出现植物神经功能紊乱，心悸、多汗，呼吸急促、尿频尿急等,焦虑障碍,广泛性焦虑障碍（,GAD,）,社交焦虑障碍（,SP,）,惊恐障碍（,PD,）,强迫障碍（,OCD,）,创伤应激障碍（,PTSD,）,8,Sedative :,缓解烦躁不安,安静,剂量,入睡困难/,容易,觉醒次数/,减少,睡眠时间短/,延长,Hypnotics :,改善睡眠障碍,促进与维持近似生理睡眠,小剂量,剂量,9,Normal,Relief from Anxiety,_,_,SEDATION,(Drowsiness/decrease reaction time),HYPNOSIS,Confusion, Delirium, Ataxia,Surgical Anesthesia,Depression of respiratory and vasomotor center in the brainstem,COMA,DEATH,10,Respiratory,Depression,Coma/,Anesthesia,Ataxia,Sedation,Anxiolytic,Anticonvulsant,DOSE,RESPONSE,BARBS,BDZs,ETOH,11,快动眼时相,(rapid eye movement sleep, REM),特点,：,眼球活动频繁，骨骼肌极度松弛，多梦，呼吸、心跳快，血压升高,Physiological sleep & pharmacological sleep,特点,：,在后期阶段为深睡眠（慢波睡眠,slow wave sleep,），大脑皮层高度抑制，,易出现惊梦、遗尿、夜间惊恐和夜游症,非快动眼时相,(non rapid eye movement sleep, NREM,),12,There are four recognized stages of sleep, from the first and lightest stage to the deepest fourth stage. The EEG gets progressively more synchronous with each deeper stage. Every time you return to stage 1, you enter REM sleep - a period of sleep characterized by,r,apid,e,ye,m,ovements. REM sleep is also called paradoxical sleep, because the body appears to be more deeply asleep than in any other stage, but the EEG looks very much like the waking brain. The desynchronous activity of the brain may be due to dreaming, which also occurs during REM sleep.,13,14,15,Pharmacological sleep,REM,缩短,/SWS,缩短,*,NREM/REM,交替数增多，总睡眠时延长,*,长期用药停药后出现,“反跳”,现象，,REM,频率增加，时间延长，患者主诉多梦、恶梦，病人不愿停药，出现滥用,(abuse),，产生依赖和成瘾,Physiological sleep,NREM：,夜惊、夜游症在,SWS,REM：,梦境,多梦、恶梦,.,与反跳现象有关,16,2,苯并二氮 类,Benzodiazepines,BZs,17,苯二氮 类,常用药物,长效类,：地西泮（,Diazepam，,安定,Valium）t1/2：3060h,中效类,：氯氮 （,t1/2：515h）,短效类,：三唑仑（,t1/2：24h）,18,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,-,羟代谢物,结合物,肾排泄,BZs,生物转化过程,* 为活性代谢物,19,PHARMACOLOGY EFFECTS AND CLINICAL USE,1.,抗焦虑、镇静、暂时记忆缺失：,焦虑模型,对边缘系统选择性高,焦虑状态、焦虑症、麻醉前给药,心脏电击复律和内窥镜检查前给药,2.,催眠:,失眠症、小儿夜惊、夜游症,入睡潜伏期,夜间觉醒次数， 睡眠时间, 醒后自觉恢复精力;延长,NREM,的2期、或缩短,NREM,4相,地西泮,20,大鼠奖惩冲突实验（焦虑模型）,大白鼠、灯光、竹杆、食物、电栅板,条件反射：,闪光 踩杆 食物,（奖赏）, 破坏条件反射：,闪光 踩杆 电击足部,（惩罚）,闪光 ,（焦虑）,小剂量地西泮,：闪光 踩杆,电击,仍吃食,抗焦虑,21,CHARACTERS COMPARED WITH,BARBITURATES,治疗指数高, 增加剂量亦不易引起麻醉作用, 反跳现象轻;夜惊、夜游症少, 无肝药酶诱导作用, 依赖性轻,是常用的镇静催眠药,22,3. 抗惊厥,：各种惊厥，破伤风、子痫、小儿高热惊厥、药物中毒惊厥等。,地西泮、三唑仑,最强,4. 抗癫痫,：,iv,治疗,癫痫持续状态,，首选！ 因再分布，维持时间短（,30-40,分钟），提倡,iv,后立即口服,地西泮、硝西泮、氯硝西泮,等,PHARMACOLOGY EFFECTS AND CLINICAL USE,23,5. 肌肉松弛,：中枢性。脑血管意外、脊髓损伤等中枢性肌强直以及腰肌劳损所致肌肉痉挛,小手术、胃镜、膀胱镜和麻醉前肌松,地西泮,6.,其他作用,1,）与其他中枢抑制药有协同作用；有麻醉增强作用。用于麻醉前给药,2,）抑制夜间胃酸分泌（可降低,50%),24,Sites of action,大脑边缘系，抑制边缘系统反复激活网状结构，对网状结构上行激活系统影响小，对由于焦虑引起失眠效好,25,Mechanisms of effects,BDZ,与,BDZ-R,结合后，易化,GABA,与,GABA-R,的结合，,Cl,-,离子通道开放，,Cl,-,内流，突触后膜超极化，增加,GABA,突触后抑制效应。,BDZ,增加,Cl,-,通道开放频度但不影响平均开放时间,BDZ-R,，,GABA,A,-R,和,Cl,-,通道相结合，在神经细胞膜上形成,GABA,A,R-Cl,-,通道复合物 （ 又称超分子,Supermolecular,功能单位）,BDZ,的作用是通过超分子功能单位发出的,26,GABAergic SYNAPSE,GABA,glutamate,glucose,Cl,-,GAD,27,GABA-A Receptor,Oligomeric (,abdgepr),glycoprotein.,Major player in Inhibitory Synapses.,It is a Cl,-,Channel.,Binding of GABA causes the channel to open and Cl,-,to flow into the cell with the resultant membrane hyperpolarization.,GABA AGONISTS,BDZs,d,BARBs,e,28,UNWANTED EFFECTS,1.,副反应：头昏、嗜睡、乏力,.,偶有核黄疸，粒细胞降低，唾液、气管分泌增加,2.长期大剂量：耐受性、依赖性,3.,有致畸（兔唇）报道,.,孕妇、哺乳妇忌用,4.,急性中毒：昏迷、呼吸抑制,解毒药：,氟马西尼,29,中效,硝西泮（,nitrazepam,）：,特点：,口服吸收好，,30,分起效，维持睡眠,6,8,小时；醒后无明显后遗效应,;,兼抗癫痫作用,短效,艾司唑仑（,estazolam,，,舒乐安定,),特点：,吸收快，口服后,20,60,分钟入睡，维持,5,8,小时,;,副作用小；兼抗癫痫、抗惊厥作用,长效,氟西泮（,flurazepam,）,特点：,与地西泮相似，镇静催眠作用较强。代谢物有活性，作用持久,同类药物,30,3,巴 比 妥 类,BARBITURATES,苯巴比妥,异戊巴比妥,司可巴比妥,硫喷妥,31,巴比妥类药物的构效关系图,32,表15-2,33,中枢抑制作用；选择性低,镇静催眠、抗惊厥、抗癫痫、麻醉、抑制呼吸和循环、昏迷、死亡, ,GABA,能,N,功能，延长,Cl,-,通道开放时间；拟,GABA,作用,PHARMACOLOGY EFFECTS AND CLINICAL USE,34,UNWANTED EFFECTS,1. 后遗效应,2. 过敏反应,3. 反跳现象,4. 耐受性、依赖性,5. 急性中毒,35,其他镇静催眠药,水合氯醛,（,Chloral hydrate）,催眠：顽固性失眠,抗惊厥：子痫、破伤风,甲丙氨酯,（,meprobamate,眠尔通）,格鲁米特,（,glutethimide）,甲喹酮,（,methaqualone）,36,丁螺环酮（,buspirone,）,4,新型抗焦虑药和催眠药,特点：,小剂量即缓解焦虑。不同于,BDZ,类,无抗惊厥、催眠和中枢性肌松作用,作用于海马,5-HT,1A,受体，为受体部分激动剂，产生抗焦虑作用；降低体内,5-HT,2,受体敏感性，有抗抑郁作用,37,谢谢观看,/,欢迎下载,BY FAITH I MEAN A VISION OF GOOD ONE CHERISHES AND THE ENTHUSIASM THAT PUSHES ONE TO SEEK ITS FULFILLMENT REGARDLESS OF OBSTACLES. BY FAITH I BY FAITH,内容总结,第13章 镇静催眠药 SEDATIVE- HYPNOTICS DRUGS。REM缩短/SWS缩短 *。长效类：地西泮（Diazepam，安定Valium）t1/2：3060h。入睡潜伏期,夜间觉醒次数， 睡眠时间, 醒后自觉恢复精力。延长NREM的2期、或缩短NREM 4相。小剂量地西泮：闪光 踩杆电击仍吃食抗焦虑。 增加剂量亦不易引起麻醉作用。因再分布，维持时间短（30-40分钟），提倡iv后立即口服。BDZ增加Cl-通道开放频度但不影响平均开放时间。BDZ的作用是通过超分子功能单位发出的。3.有致畸（兔唇）报道.孕妇、哺乳妇忌用。中效硝西泮（nitrazepam）：。特点：口服吸收好，30分起效，维持睡眠68小时。短效艾司唑仑（estazolam，舒乐安定)。特点：吸收快，口服后2060分钟入睡，维持58小时。谢谢观看/欢迎下载,
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