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Sedative-Hypnotic Drugs

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. 2013.6. 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.

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Sedative-Hypnotic Drugs

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  1. Sedative-Hypnotic Drugs CHEN Zhong 陈 忠Department of Pharmacology, College of Pharmaceutical Sciences, Zhejiang Universitychenzhong@zju.edu.cn 医学院科研楼B402-420，88208228 2013.6

  2. 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）

  3. Anxiety • 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. 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.

  4. 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 • 神经性睡眠障碍 What’s the mechanism? Receptor? Neurotransmitter? Neuropeptide? stimulator pathway? When should start drug treatment? Why ethanol produce dual effect?

  5. Stage 3 & 4, 统称为慢波睡眠 Molecular Neuropharmacology

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

  7. Circadian rhythm & Circadian control SCN: suprachiasmatic nucleus 视交叉上核

  8. Sedative-Hypnotic Drugs • Benzodiazepines (BZ / BDZ, 苯二氮卓类) • Barbiturates (巴比妥类) • Others

  9. 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

  10. 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 benzodiazepinesenhances the affinity of GABA receptor for this neurotransmitter, resulting in a more frequent opening of adjacent chloride channels.- coagonist This in turn results inenhanced hyperpolarization（超极化）and further inhibition of neuronal firing.

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

  12. Action of the central inhibitory transmitter GABA on Cl- influx and the action sites of benzodiazepines (BDZs)

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

  14. 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（作用于脑干） at relatively larger doses, no anesthetic effect; not remarkably affect on REM used forinsomnia（失眠）andpreanesthetic medication

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

  16. A. Benzodiazepines (3) Antiepileptic and anticonvulsant effects Convulsion due various causes; status epilepticus(i.v.) (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. (5) Others Amnesia (短暂性记忆缺失, i.v.） Respiratory and CVS effects

  17. A. Benzodiazepines 3. Adverse effects (1) Central depression Most common: drowsiness and confusion (potentiated by ethanol or other central depressants). Ataxia (共济失调); cognitive impairment Antagonized by BZ receptor antagonist flumazenil（氟马西尼） (2) Tolerance and dependence Withdrawal syndrome: central excitation

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

  19. 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

  20. B. Barbiturates Phenobarbital 苯巴比妥

  21. 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。

  22. 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

  23. 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

  24. C. Others • Chloral hydrate 水合氯醛 Sedative-hypnotic effects 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

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

  26. 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！ 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

  27. Central stimulants • Psychomotor stimulants • Respiratory center stimulants

  28. 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

  29. A Psychomotor stimulants Caffeine 咖啡因

  30. 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

  31. 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)

  32. 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.

  33. B Respiratory center stimulants Nikethamide 尼可刹米

  34. 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

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

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