Sedative-Hypnotic Drugs

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

2. 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

3. Normal EEG and brain wave pattern

5. Wakefulness and Sleep

6. 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

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

8. NREM NREM NREM NREM Normal sleep pattern 80-120min 20-30 min REM REM REM 4-5 REM and NREM 的交替循环 0 1 2 3 4 Sleep latency NREM REM 4 1 3 sws 2 dream REM sws sws Night-walking and somnambulism

9. Phases of sleep • 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-termshorten will induce “rebound” after withdrawal, significantly increase the frequency and duration of REM, causedreaminess, nightmare,anxiety and insomnia, finally leading to dependence.

10. 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 thefatigue and promote growth • Shorten SWS 3、4 phase will clean up night-walking and somnambulism

11. 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

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

13. 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

14. 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

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

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

17. 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

18. 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

19. 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

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

21. 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

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

23. Section 1 Benzodiazepines

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

25. 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)

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

27. 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…..

28. 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）

29. 心理治疗的疗效是肯定的对焦虑症的心理治疗不可忽视心理治疗的疗效是肯定的对焦虑症的心理治疗不可忽视

30. 2. Sedationand Hypnosis 【Pharmacological actions】 • 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)

31. 【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

32. 【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)

33. 【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

34. 5. For muscle relaxation in specific neuromuscular disorder skeletal muscle spasticityin cerebral vascular accidentand spinal cord injury

35. 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； 癫痫持续状态：5-10mg/次，再发作时可反复应用

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

37. GABAA receptor

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

39. 【 Mechanisms of action 】

40. 【 Mechanisms of action 】

41. 【 Mechanisms of action 】 Benzodiazepine

42. GABA Benzodiazepine Entry of Cl- hyperpolarizes cell making it more difficult to depolarize and therefore reduces neural excitability. Receptor binding GABA Receptor empty (no agonists) Receptor binding GABA and benzodiazepine 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

43. 【 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

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

45. 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

46. 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

47. 【 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

48. GABA BZs Flumazenil - 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

49. 氟马西尼 （ Flumazenil ，安易醒） DIAZEPAM FLUMAZENIL

50. 【 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)