Sedative-Hypnotic Drugs CHEN Zhong 陈 忠 Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang University chenzhong@zju.edu.cn 医学院科研楼B402-420，88208228 2014.6

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）： Hypnotics （催眠药）： 能缓和激动，消除躁动，恢复安静情绪的药物 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）

Insomnia: Anxiety 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 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

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 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

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

A. Benzodiazepines Diazepam 地西泮（安定） R1 R2 R3 R7 R4 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。

A. Benzodiazepines 2. Mechanisms of actions (1) Sites of action: mainly acts on limbic system and midbrain reticular formation. (2) Interaction with GABAA 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 1. Pharmacological effects and clinical uses (1) Antianxiety at small doses 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; not remarkably affect on REM used for insomnia（失眠） and preanesthetic medication

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

A. Benzodiazepines (3) Antiepileptic and anticonvulsant effects 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. Used for the treatment of skeletal muscle spasms caused by central or peripheral diseases(Brain injury). (5) Others Amnesia (短暂性记忆缺失, i.v.斯诺斯） Respiratory and CVS effects

3. Adverse effects (1) Central depression (2) Tolerance and dependence Most common: drowsiness (potentiated by ethanol or other central depressants). Ataxia (共济失调); cognitive impairment Complex sleep-related behaviors:eating, driving, sex Anxiety, hallucinations and confusion Antagonized by BZ receptor antagonist flumazenil（氟马西尼） (2) Tolerance and dependence 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.

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

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

B. Barbiturates Phenobarbital 苯巴比妥 如果羰基被巯基取代，脂溶性增强，作用迅速，但维持时间缩短 The first barbiturate drug, barbital, was synthesized in 1902 by German chemists Emil Fischer and Joseph von Mering at Bayer. By 1904 several related drugs, including phenobarbital, had been synthesized by Fischer. Phenobarbital was brought to market in 1912 by the drug company Bayer using the brand Luminal. It remained a commonly prescribed sedative and hypnotic until the introduction of benzodiazepines in the 1960s.[6] 如果羰基被巯基取代，脂溶性增强，作用迅速，但维持时间缩短

B. Barbiturates 2. Pharmacological effects and clinical uses Sedative-hypnotic effects 可缩短REM，反跳明显； (2) Preanesthetic medication (3) Antiepileptic and anticonvulsant effects 引起非生理性睡眠，反跳明显，有强的肝药酶诱导作用，易产生依赖和耐受；

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 alkalizing urine hemodialysis（血液透析）

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! http://southernwingsaircraft.com/howmarilyndied.html During the autopsy the toxicologist Raymond Abernathy found her blood concentration of pentobarbital {Nembutal} to be 4.5 mg percent. This converts to 45 ppm {parts per million}. According to the PDR {Physicians Desk Reference} the toxic amount of Nembutal in the blood starts at 12 ppm and increases to the "Usual Death Level" of between 15 to 40 ppm. The autopsy shows 13.0 mg percent of pentobarbital in the liver. This converts to 130 ppm or over 10 times the amount that the blood can handle. Death usually occurs at 15 ppm, Marilyn was 45 ppm. A lethal dose of Nembutal is between 2 grams and 10 grams in the average person. Marilyn was taking 100 mg capsules so 2 grams would be 20 capsules {or the minimum lethal dose}. So if Marilyn's blood shows to be 3 times the lethal amount then that would be 60 capsules. Now add in the amount that was found in her liver to this amount. The autopsy shows 8.0 mg percent of Chloral Hydrate in the blood. This converts to 80 mcg/ml. According to Micromedix the toxic level of CH starts at 30 mcg/mL and goes to the lethal level of 100 mcg/ml. This means that she had almost 3 times the toxic amount of CH and just under the lethal dose. So she just almost had enough Chloral Hydrate in her blood to kill her. As far as amount of pills consumed. Marilyn was taking 500 mg capsules of CH. A normal dose of CH is between 500-1000 mg. The lethal does is considered to be 10 grams which is 20 capsules. Marilyn had roughly 80% of the lethal dose of 20 capsule amount in her blood so she would have had to take 17 capsules. 急性巴比妥中毒！ 自杀可能！ 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

C. Others Chloral hydrate 水合氯醛 Hydroxyzine 羟嗪（安泰乐） Sedative-hypnotic effects Anticonvulsant effect: usually used in children （久用易产生耐受和成瘾，戒断症状严重） Hydroxyzine 羟嗪（安泰乐） 唑吡坦（Zolpidem，斯诺斯） 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

Summary of clinical uses of sedative-hypnotics

Central stimulants Psychomotor stimulants Respiratory center stimulants

A Psychomotor 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) antipyretic-analgesic drugs： 解热镇痛药

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.

B Respiratory center 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

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

Schutte-Rodin S, et al. J Clin Sleep Med. 2008;4:487-504.[17]