CHEN Zhong 陈 忠 Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University CHEN Zhong 陈 忠 Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University 医学院科研楼 B ， Sedative-Hypnotic Drugs

1. 掌握：以地西泮为代表，苯二氮卓类的药理作用、 临床应用和不良反应特点；以苯巴比妥为代表，巴 比妥类的药理作用、作用机制和临床应用。 2. 了解：中枢兴奋药及其他主要镇静催眠药的特点。

Sedatives （镇静药）： 能缓和激动，消除躁动，恢复安静情绪的药物 Hypnotics （催眠药）： 能促进和维持近似生理睡眠的药物 中枢抑制药多数随剂量增加而出现镇静、催眠 等中枢抑制作用，故合称为镇静催眠药 （ sedative-hypnotics ）

- is characterized by excessive, exaggerated anxiety and worry about everyday life events with no obvious reasons for worry; - can be extremely debilitating, having a serious impact on daily life. Anxiety Insomnia: -1-5%, more in old women; - trouble in falling asleep or too easily to be waken up; - can be primary or secondary; - harmful to daily life: excessive daytime sleepiness and a lack of energy, feel anxious, depressed, or irritable. -50% of patients under clinical care report symptoms of insomnia

Several kinds of sleep deficits § 无法入睡 § 浅睡、易醒 § 早醒 § 睡后焦虑、烦躁 § 梦游 § 嗜睡 § 发作性睡眠障碍 What’s the mechanism? Receptor? Neurotransmitter? Neuropeptide? stimulator pathway? When should start drug treatment?

Molecular Neuropharmacology

A schematic drawing showing key components of the ascending reticular activating system (ARAS)

Chemical classification aztr a §Benzodiazepines: diazepam, nitrazepam, oxazepam, estazolam, triazolam, etc (with same nucleus and different substituents) §Barbiturates: pentobarbital, secobarbital, etc

Modulation mode of the central inhibitory transmitter GABA and the action sites of drugs Not direct GABA agonist Enhance GABA binding Sleep onset, sleep continuity,clinical insomnia symptoms

(5) Classification according to action duration Short-acting: triazolam, laorazepam, oxazepam, etc Medium and long-acting: nitrazepam, chlordiazepoxide, flurazepam etc 1. ADME (1)Oral absorption c b (2)Lipid solubility-dependent distribution, placental penetrability (3)Hepatic metabolism ---active metabolites (4)Urinary excretion A. Benzodiazepines

Diazepam 地西泮（安定） R1 R2 R3 R4 R7 1950s 开始使用，由于其安 全性，对肝药酶无诱导性， 低成瘾性，逐渐代替了巴比 妥类。 不同的基团，导致作用强度 的变化，代谢时间及产物发 生变化，作用时间随之改变。

2. Mechanisms of actions (1) Sites of action: mainly acts on limbic system and midbrain reticular formation. (2) Interaction with GABA A receptor Benzodiazepines bind to specific, high affinity sites on the cell membrane, which are separate from but adjacent to the receptor for  -aminobutyric acid (GABA). The binding of benzodiazepines enhances the affinity of GABA receptor for this neurotransmitter, resulting in a more frequent opening of adjacent chloride channels. - coagonist This in turn results in enhanced hyperpolarization （超极化） and further inhibition of neuronal firing. A. Benzodiazepines

Modulation mode of the central inhibitory transmitter GABA and the action sites of drugs

1. Pharmacological effects and clinical uses (1) Antianxiety at small doses at small doses acting on limbic system （边缘系统， 杏仁核、海马 ） acting on limbic system （边缘系统， 杏仁核、海马 ） (2) Sedative-hypnotic effects （ inhibits arousal system ） at relatively larger doses, no anesthetic effect; at relatively larger doses, no anesthetic effect; not remarkably affect on REM not remarkably affect on REM used for insomnia （失眠） and preanesthetic medication used for insomnia （失眠） and preanesthetic medication A. Benzodiazepines

NREM Stages 3 Stages 3 and 4 are deep sleep. Growth hormone is released during these stages. Slow wave sleep BZs

(3) Antiepileptic and anticonvulsant effects Convulsion due various causes; status epilepticus (i.v.) （ clinical window—drug resistent ） Convulsion due various causes; status epilepticus (i.v.) （ clinical window—drug resistent ） (4) Centrally acting muscle relaxant effect Relaxing the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord. Relaxing the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord. Used for the treatment of skeletal muscle spasms caused by central or peripheral diseases. Used for the treatment of skeletal muscle spasms caused by central or peripheral diseases. (5) Others Amnesia ( 短暂性记忆缺失, i.v. ） Amnesia ( 短暂性记忆缺失, i.v. ） Respiratory and CVS effects Respiratory and CVS effects A. Benzodiazepines

3. Adverse effects (1) Central depression Most common: drowsiness and confusion (potentiated by ethanol or other central depressants). Most common: drowsiness and confusion (potentiated by ethanol or other central depressants). Ataxia ( 共济失调 ); cognitive impairment Ataxia ( 共济失调 ); cognitive impairment Complex sleep-related behaviors:eating, driving, sex Complex sleep-related behaviors:eating, driving, sex Anxiety, hallucinations Anxiety, hallucinations Antagonized by BZ receptor antagonist flumazenil （氟马西尼） Antagonized by BZ receptor antagonist flumazenil （氟马西尼） (2) Tolerance and dependence Withdrawal syndrome: central excitation Withdrawal syndrome: central excitation Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. The use of sedative-hypnotics for more than 1–2 weeks leads to some tolerance to their effects on sleep patterns.

(3) Others local pain, respiratory and CVS reactions (i.v.) local pain, respiratory and CVS reactions (i.v.) teratogenic effects （致畸效应） teratogenic effects （致畸效应） (4) Contraindications Myasthenia gravis 肌无力 Myasthenia gravis 肌无力 Infants < 6 months Infants < 6 months Pregnancy and lactation mothers Pregnancy and lactation mothers Elderly, heart/lung/liver/kidney dysfunction Elderly, heart/lung/liver/kidney dysfunction Fine motor coordination Fine motor coordination A. Benzodiazepines

Other benzodiazepines According to the metabolisms §Long-acting ： diazepam, chlordiazepoxide ( 氯氮卓 ), flurazepam ( 氟西泮 ) diazepam, chlordiazepoxide ( 氯氮卓 ), flurazepam ( 氟西泮 ) §Intermediate-acting ： Nitrozepam ( 硝西泮 ), flunitrozepam ( 氯硝西泮 ), Nitrozepam ( 硝西泮 ), flunitrozepam ( 氯硝西泮 ), oxazepam ( 奥沙西泮 ), estazolam ( 艾司唑仑） oxazepam ( 奥沙西泮 ), estazolam ( 艾司唑仑） §Short-acting ： triazolam ( 三唑仑 ) A. Benzodiazepines 艹

Phenobarbital 苯巴比妥 B. Barbiturates

1. ADME §Inducing hepatic enzymes §Alkalining urine: excretion  § 硫喷妥钠脂溶性极高，故易通过 BBB ，易发生再 分布； § 苯巴比妥脂溶性低，不易在肝脏代谢； § 脂溶性高，血浆蛋白结合率高。 B. Barbiturates

2. Pharmacological effects and clinical uses (1)Sedative-hypnotic effects 可缩短 REM ，反跳明显； 可缩短 REM ，反跳明显； (2) Preanesthetic medication (3) Antiepileptic and anticonvulsant effects B. Barbiturates

3. Adverse effects (1) Central depression: including after effect (hangover “ 宿醉 ”) (2) Tolerance and dependence: long-term uses (3) Acute poisoning supporting therapies supporting therapies alkalizing urine alkalizing urine hemodialysis （血液透析） hemodialysis （血液透析） B. Barbiturates

1962 年 8 月 5 日梦露在洛杉矶布莱登木寓所的卧室内被发现已 经去世，终年 36 岁 In her circulation system: 8 % chloral hydrate (3% toxic level and 10% lethal level) 4.5 % Nembutal (pentobarbital ) (death level 1.5-4%) In her stomach and duodenum: No drug crystal found! 急性巴比妥中毒！ 自杀可能！

§Chloral hydrate 水合氯醛 Sedative-hypnotic effects Sedative-hypnotic effects Anticonvulsant effect: usually used in children Anticonvulsant effect: usually used in children §Hydroxyzine 羟嗪（安泰乐） §Meprobamate 甲丙氨酯（眠尔通） §Buspirone 丁螺环酮 §Methaqualone 安眠酮 C. Others

§Antihistamines 抗组胺药 §Ethanol 乙醇 §Melatonin 褪黑素 C. Others

Summary of clinical uses of sedative- hypnotics

Central stimulants §Psychomotor stimulants §Respiratory center stimulants

Cortex stimulants (mainly acting on cerebral cortex) Xanthines: caffeine 咖啡因 Related drugs Respiratory center stimulants Direct stimulation: 尼可刹米 Indirect stimulation (reflex) Spinal cord stimulants ：士的宁 A Psychomotor stimulants

Caffeine 咖啡因 A Psychomotor stimulants

1. Pharmacological effects (1) Central stimulation (2) CVS effects: cardiac stimulation, dilatation of vessels (3) Relaxing smooth muscles: airways, GI (4) Other effects: Gastric acid secretion, diuretic effect (5) Mechanisms of action ： inhibiting PDE- cAMP  ； antagonizing A1 adenosine receptor & GABA receptor A Psychomotor stimulants

2. Clinical uses §Central depression §Adjuvant of migraine ( 偏头痛 ) and antipyretic- analgesic drugs 3. Adverse effects §Central excitation §Convulsion (overdose) A Psychomotor stimulants

Methylphenidate 哌甲酯（利他灵） §used for central depression caused by drugs or diseases; mild depression; child hyperactivity; enuresis; etc. Meclofenoxate 甲氯芬酯（氯酯醒） §Adjuvant of central depressive diseases; enuresis; etc. A Psychomotor stimulants

Nikethamide 尼可刹米 B Respiratory center stimulants

1. Pharmacological effects §Direct (respiratory centre) and indirect (reflex via chemoreceptor) stimulation 2. Clinical uses §Respiratory failure 3. Adverse effects §Elevation of BP, tachycardia, tremor, convulsion

Dimefline 二甲弗林 （回苏灵） §Direct stimulation Lobeline 洛贝林（山梗菜碱） §Indirect stimulation B Respiratory center stimulants