Sedative-Hypnotic Drugs Institute of Pharmacology Lou haiyan Institute of Pharmacology School of Medicine Shandong University louhaiyan@sdu.edu.cn

Brain Waves: State of the Brain Normal brain function involves continuous electrical activity An electroencephalogram (EEG): used to diagnose and localize brain lesions, tumors, infarcts, infections, abscesses, and epileptic lesions A flat EEG (no electrical activity) is clinical evidence of death

Normal EEG and brain wave pattern

波形分类 频率 振幅 出现条件 皮层 意义 α波 20-100mV 清醒、安静、闭目；枕叶显著 安静 状态 β波 5-10 mV 8-13 Hz 20-100mV 清醒、安静、闭目；枕叶显著 安静 状态 β波 14-30 Hz 5-10 mV 睁眼或接受其它刺激 （或快波睡眠时相） 额叶和顶叶显著； 安静闭目时只在额叶出现 紧张 θ波 4-7 Hz 100-150 mV 困倦 抑制 δ波 0.5-3 Hz 20-200 mV 睡眠，极度疲劳或麻醉时

Wakefulness and Sleep

Sleep Sleep is a behavior and an altered state of consciousness Associated with an urge to lie down for several hours in a quiet environment Few movement occur during sleep (eye movements) We spend about a third of our lives in sleep A basic issue is to understand the function of sleep Dualism-mind is separate from the body Descartes believed that the pineal body directed fluid from the ventricles into the holow fibers we call nerves-this induced muscle action. The pineal gland is where the soul controls the physical body Monism: the belief that the mind is the working of the body (no need for a separate soul. Determinism-the notion that mental states are produced by physical mechanisms. Reductionists-we break complex phenomena into less complicated sytems.

Normal Sleep Patterns There are two major types of sleep: Non-rapid eye movement (NREM) sleep Rapid eye movement (REM) sleep

Normal sleep pattern dream 80-120min 20-30 min 4-5 REM and NREM 的交替循环 1 2 3 4 Sleep latency NREM REM 4 1 2 3 sws REM dream sws sws Night-walking and somnambulism

Phases of sleep 发生于REM之后，脑电波快而低，骨骼肌进一步松弛，有快动眼运动（50-60次/分），梦境多发生在此期。 1. REMS ( rapid eye movement sleep, 快动眼睡眠） FWS ( fast wave sleep，快波睡眠 ) 特点：眼球活动频繁，骨骼肌极度松弛，做梦，呼吸、心跳快，血压升高。 Play roles in brain and intellectual development long-term shorten will induce “rebound” after withdrawal, significantly increase the frequency and duration of REM, cause dreaminess, nightmare, anxiety and insomnia, finally leading to dependence. 脑电波慢而高（又称高幅慢波睡眠），肌肉仍保持一定紧张度，无快速眼球运动。 可分为4个阶段（steps）：1、2阶段睡眠较浅，3、4阶段睡眠深，称大脑睡眠,又称慢波睡眠(slow wave sleep,SWS) 。此时易出现惊梦、遗尿、夜间惊恐和夜游症。 发生于REM之后，脑电波快而低，骨骼肌进一步松弛，有快动眼运动（50-60次/分），梦境多发生在此期。

NREMS (non rapid eye movement sleep, 非快动眼睡眠) SWS ( slow wave sleep，慢波睡眠 ) 特点：由浅入深可分为SWS 1~4期（分别为入睡期、浅睡期占50%、中度睡眠期和深度睡眠期）, 夜惊和梦游多发生于3、4期。 Play roles in eliminating the fatigue and promote growth Shorten SWS 3、4 phase will clean up night-walking and somnambulism

Importance of Sleep Sleep is necessary for survival Sleep appears necessary for our nervous systems to work properly. During the SWS, growth hormone secretion increase and important for the infants growth and physical restorative process of adult During REM, brain blood flow and protein synthesis increase, and it is important for the mental development of infants and long-term memory and mental restoration in adults. Daily sleep requirements decline with age

What Happens if We are Deprived of Sleep? Lack of alertness Fatigue Memory problems Irritability Depression Lack of motivation Accidents

Tips for Getting a Good Night’s Sleep Avoid caffeine and alcohol after dinner Keep a routine Don’t nap during the day Don’t go to bed hungry or right after eating Exercise Stop smoking

Rules for Optimal Sleep Get an adequate amount of sleep every night Establish a regular sleep schedule Get continuous sleep Make up for lost sleep

Insomnia Symptoms of insomnia： 1. difficulty falling asleep 2. difficulty staying asleep 3. early morning waking 4. daytime drowsiness, fatigue or difficulty concentrating

Insomnia anxiety: the most common cause Causes of insomnia: 1. Psychological problems: anxiety 2. Medical problems 3. Medication 4. Sleep disorders anxiety: the most common cause

Epidemiology Studies throughout the world show that it occurs everywhere Depending on the area, study, etc., between 10-50% of the population are affected Increases with age Twice as common in females Up to the age of 30, there is little difference between sexes Beyond 30 years, it is more common in females Beyond 70 years, females are affected twice as much as males

Consequences of insomnia Decreases in mental performance and motor functioning Accidents Inability to accomplish daily tasks Mood disturbance More sadness, depression, and anxiety Interpersonal difficulties With families, friends, and at work

Definition of sedative-hypnotic drugs CNS depression (dose-dependent) Its major therapeutic use is to cause sedation (with concomitant relief of anxiety) — small dose encourage sleep — large dose

Classifications Benzodiazepines (BZ，苯二氮卓类) Barbiturates (巴比妥类) Others

Characteristics 1. Graded dose-dependent depression of CNS function Dose-response curves for two hypothetical sedative-hypnotics Drug A: barbiturates Drug B: benzodiazepines and certain newer hypnotics

*2. Different influences on sleep phases 3. Tolerance and dependence Physiologic dependence Psychologic dependence

Section 1 Benzodiazepines

Chemical Structure 1,4-benzodiazepines (1,4-苯并二氮卓）

Classifications Drugs T1/2(h) Long-acting 24~72 Diazepam (地西泮，安定） Flurazepam (氟西泮，氟安定） Chlordiazepoxide (氯氮卓，利眠宁) Intermediate-acting Alprazolam (阿普唑仑，佳乐定) 10~20 Estazolam (艾司唑仑，舒乐安定) Clonazepam(氯硝西泮，氯硝安定) Lorazepam(劳拉西泮，氯羟安定) Short-acting 3~8 Triazolam (三唑仑，海乐神) Oxazepam (奥沙西泮，去甲羟安定，舒宁)

【Pharmacological actions】 1. Antianxiety at the lowest effective doses relieve the anxiety state induced by various causes

焦虑反应、焦 虑 症 焦虑是一种N官能症，NS无明显形态改变;是一种心理现象。当预感到某种困难、危险将来临时所产生的紧张不安、担忧、害怕的情绪体验，亦有植物NS功能紊乱。 适度的焦虑属正常的反应（焦虑反应）。焦虑反应过度或没有明显原因经常出现的焦虑，认为是焦虑症。 女，因晋职称，提心吊胆、烦躁不安、胃部饱满、腹胀难受；心慌胸闷、呼吸急促、叹息、出汗、睡眠差、记忆减退 措施：自我调节、心态平衡、 心理免疫力、深呼吸、听音乐、欣赏大自然美景……； 镇静药物：地西泮…..

焦虑症病例 病例一：王**，女，30岁，一年前坐公交时因人多拥挤而出现心慌胸闷呼吸困难，以后每次上公交无论人多人少，都有这种感觉，以至不敢再乘车，发展到去商场广场，只要自己感觉人多就会发病。（广场恐怖症） 病例二：李**，男，22岁，因中学课堂发言时一个错误引起全班哄堂大笑，此后不敢再发言，常觉被人注视，做梦也梦见自己当众出丑。（社交恐怖症） 病例三：（疾病恐怖症）

心理治疗的疗效是肯定的 对焦虑症的心理治疗不可忽视

【Pharmacological actions】 2. Sedation and Hypnosis decrease sleep-induction time decrease the number of awakening increase the duration of sleep prolong stage 2 of NREMS shorten stage 3, 4 of NREMS (reduce night-waking and somnambulism) * seldom effect on REMS (little rebound)

【Pharmacological actions】 3. Anticonvulsant and antiepileptic effects 4. Central muscle relaxation 5. Others Anterograde amnesia (顺行性记忆缺失) Respiratory depression Cardiovascular depression larger dose→side effect

【Clinical uses】 1. For anxiety 2. For insomnia 3. For sedation and amnesia before medical and surgical procedures Premedication(麻醉前给药） Endoscopy (内窥镜检查) Electric defibrillation(电除颤)

【Clinical uses】 4. For treatment of convulsion and epilepsy convulsions due to various causes: tetanus (破伤风) eclampsia (子痫) febrile convulsion (高热惊厥) drug toxic convulsion (药物中毒性惊厥） status epilepticus (癫痫持续状态): Diazepam（iv.）is first choice

5. For muscle relaxation in specific neuromuscular disorder skeletal muscle spasticity in cerebral vascular accident and spinal cord injury

地西泮给药方案 焦虑：2.5mg/次，tid; 失眠：临睡前2.5-5mg; 惊厥、癫痫：iv,不超过5mg/min；

【 Mechanisms of action 】 1. Sites of action: Mainly acts on limbic system and midbrain reticular formation. 2. Interaction with GABAA receptor

GABAA receptor

Molecular Mechanism GABA GABA and GABA agonist Barbiturates BZs picrotoxin + + - - Cl-

【 Mechanisms of action 】

【 Mechanisms of action 】

【 Mechanisms of action 】 Benzodiazepine

Receptor binding GABA and benzodiazepine Receptor empty (no agonists) Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- GABA receptor Benzodiazepine receptor Empty receptor is inactive, and the coupled chloride channel is closed. Binding of GABA is enhanced by benzodiazepine, resulting in a greater entry of chloride ion. Binding of GABA causes the chloride ion channel to open Entry of Cl- hyperpolarizes cell making it more difficult to depolarize and therefore reduces neural excitability.

【 Mechanisms of action 】 1. Enhance the affinity of GABAA receptor for GABA ， promote GABA binding to GABAA receptor. 2. Increase the frequency of Cl- channel opening 3. Enhance hyperpolarization and further inhibit neural excitability 4. not substitute for GABA, but appear to enhance GABA’s effects

【 Pharmacokinetics 】 1. Absorption oral absorption is rapid and complete im: absorption is slow and irregular iv: acute 2. Distribution diazepam high plasma protein binding rate high lipid solubility→cross BBB and placental barrier

3. Metabolism: most of them metabolized by the liver to compounds that are also active. 4. Excretion excreted via kidney as inactive glucuronides detectable in breast milk

Biotransformation of benzodiazepines 氯氮卓 地西泮 普拉西泮 阿普唑仑 三唑仑 奥沙西泮 氟西泮 劳拉西泮 Boldface: drugs available for clinical use * :active metabolite

【 Adverse Reactions 】 1. CNS depression Most common: Hangover: drowsiness, exhaustion, dizziness, memory decay(记忆衰减） Diminished motor skills and impaired judgment → impact on driving ability Large dose →ataxia(共济失调) iv. too quick →inhibit respiratory and cadiovascular fuction 2. Tolerance and dependence withdrawal symptom

3. toxic reaction and detoxifcation Washing stomach Symptomatic treatment Benzodiazepine specific antagonist Flumazenil (氟马西尼，安易醒）: short t1/2, repeated administration GABA BZs Flumazenil -

氟马西尼 （ Flumazenil ，安易醒） DIAZEPAM FLUMAZENIL

【 Contraindications】 The elderly Heart/lung/liver/kidney dysfunction Pregnancy and lactation mothers Drivers, employees of aloft work and mechanized operation　 Myasthenia gravis (重症肌无力) Glaucoma (青光眼)

Alcohol and other CNS depressants Enzyme induction 【 Drug interactions 】 Alcohol and other CNS depressants Enzyme induction sodium phenobarbital or phenytoin, carbamazepine(卡马西平), rifampicin(利福平） shortern t1/2 Enzyme inhibition cimetidine prolong t1/2

Similar drugs Long acting—flurazepam（氟西泮） 特点：与地西泮相似，镇静催眠作用较强。代谢物(去烷基氟西泮）有活性，作用持久（t1/2 40-100h） Intermediate acting—nitrazepam（硝西泮）： 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 Short acting—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

Short acting —triazolam（三唑仑） BDZ类中代谢最快、作用最强的药物; 速效、强效（45-100倍）、极少蓄积为突出优点。 临床上曾广泛用于各种类型的失眠，现因依赖性少用。

Section 2 Barbiturates

Classifications Long-acting: phenobarbital (苯巴比妥, luminal, 鲁米那) Intermediate-acting: pentobarbital (戊巴比妥) Short-acting: secobarbital (司可巴比妥, seconal) Ultra-short-acting: thiopental sodium (硫喷妥钠)

【Pharmacological actions and clinical uses】 dose-dependent effects 1. Sedation and hypnosis shorten REMS→ “rebound” Easy to produce tolerance and dependence Hepatic enzyme inducer more adverse reactions , severe intoxication not sedative-hypnotics for routinely use

【Pharmacological actions and clinical uses】 2. Anticonvulsant and antiepileptic effects generalized tonic-clonic seizure (大发作) and status epilepticus 3. Anesthesia and premedication eg. thiopental sodium （硫喷妥钠） onset (30s), duration (15min) 4. Enhance the effects of other CNS depressants

【Mechanisms】 GABA mimetic (high dose activate GABA receptor) Extend opening time of Cl- channel inhibit excitatory neurotransmitter

Pharmacokinetics 1. Absorption: po,im 2. Hepatic enzyme inducer 3. Urine pH affects excretion

Detoxifcation Alkalization of the urine often aids in the elimination of phenobarbital—iv. NaHCO3

Adverse reactions Hangover Tolerance and dependence Respiratory depression： 深度的呼吸抑制死亡原因

Advantages of BZs 1. Higher therapeutic index, no anesthesia in large dose 2. Prolong stage 2 sleep, shorten stage 3, 4 sleep, little influences on REMS 3. Do not induce hepatic enzyme 4. Less rebound and dependence

Section 3 Other hypnotic agents

Other hypnotic agents Older sedative-hypnotics Chloral hydrate (水合氯醛) Meprobamate (甲丙氨酯，眠尔通) Newer drugs for anxiety and sleep disorders Buspirone (丁螺环酮) Non-GABAergic system Zolpidem (唑吡坦 , 思诺思) Zopiclone (佐匹克隆) more selective Zaloplone (扎来普隆) Melatonin (褪黑素)

Chloral hydrate（水合氯醛） 1. Hypnosis : strong, onset rapidly (15min), no effect on REM, no hangover, used for obstinate insomnia (顽固性失眠) 2. Anticonvulsant effects: febrile convulsion in children (小儿高热惊厥) 3. oral: need to dilute (10%), rectal administration (gastic mucosal irritation: not used for gastritis and ulcer patients) 4. Inhibit cardiac contractility (contraindicated to patients with severe heart, liver, kidney disease) 5. Tolerance and dependence 6. Low therapeutic index

Buspirone（丁螺环酮） 1. Used for anxiety 2. a partial agonist of 5-HT1A-R in brain ,inhibit the release of 5-HT, have no effect on GABAA-R 3. no sedative-hypnotic effects 4. no tolerance and dependence

Melatonin（褪黑素,MT） 作用：调节生物节律、神经内分泌、应激 反应，抑制肾上腺、性腺、甲状腺分泌， 抗炎、镇痛、镇静、催眠、抗氧化、清除 自由基。 机制：激活视交叉核上的MT－R增强GABA的 功能 用途：成年和老年人的睡眠障碍,不宜用于未成年人

催眠药应用原则： 1.消除诱因：环境、生活习惯、药物、疾病等 2.药物：健康人暂时性或老年人间断性失眠，用最低 有效量、短期应用、交替应用 3.长期失眠用非药物治疗（心理疗法），辅以药物

“理想的”安眠药 1. 迅速诱导睡眠，服后30min内即可入睡。 2. 不引起睡眠结构紊乱。 3. 没有宿醉作用，第二天无药物残留作用。 4. 无呼吸抑制 5. 长期使用不引起药物依赖性。 6. 与乙醇和其他药物无相互作用。

药物治疗失眠的基本原则 1. 应用最小有效剂量 2. 间断用药（每周2-4次） 3. 短期用药（不超过3-4周） 4. 逐渐停药

Summary 1. The pharmacological effect , mechanism of action, clinical use and adverse reactions of Benzodiazepines 2. Compare Benzodiazepines and Barbitals

Thank you!