1. Institute of Pharmacology
Sedative-Hypnotic Drugs
Zhang Bin
Institute of Pharmacology
School of Medicine
Shandong University

2. Insomnia Symptoms of insomnia： 1. have trouble falling asleep
指尽管有充分的睡眠条件和环境却存在对睡眠时间和质量不满足，并影响到白天社会功能的一种主观体验。
Symptoms of insomnia：
1. have trouble falling asleep
2. have trouble staying asleep
3. early morning waking
4. daytime drowsiness (嗜睡), fatigue or difficulty concentrating

3. Potential complications of insomnia
World Sleep Day

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

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

6. Classifications
Benzodiazepines (BZ，苯二氮卓类):
Barbiturates (巴比妥类)
Others some are popular

7. 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

8. Ratio of lethal dose to effective dose for phenobarbital and diazepam

9. *2. Different influences on sleep phases
3. Tolerance
4. Dependence
Physiological dependence
withdrawal symptoms
Psychological dependence

10. Phases of sleep 1. NREMS (non rapid eye movement sleep, 非快动眼睡眠)
SWS ( slow wave sleep，慢波睡眠)
Stages 1- 4 (入睡期、浅睡期、中度睡眠期、深度睡眠期)
Characterists:
Play roles in eliminating the fatigue and promote
growth
night-waking（夜惊）, sleep-walking（梦游, somnambulism）
occur in stage 3 and 4
shorten stage 3 and 4 will clean up night-waking
and sleep-walking.

11. 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。
2. REMS ( rapid eye movement sleep, 快动眼睡眠）
FWS ( fast wave sleep，快波睡眠 )
Characterists:
Play roles in brain and intellectual development.
Rapid eye movement, dream, muscle relaxation,
fast breathing et al.
Long-term shorten will induce “rebound （反跳）” after
withdrawal, significantly increase the frequency and
duration of REMS, cause dreaminess, nightmare,
aggravate anxiety and insomnia, finally lead 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。

12. Phases of sleep 4-5 cycles of alternating REMS and NREMS NREM REM
80-120min
20-30min
Sleep latency
4-5 cycles of alternating REMS and NREMS 8h 2h
25% 5% 4h
50%
10%
﹤2h
10%

13. 睡眠时间(h) 1 2 3 儿童
青壮年
老年人 4 5 6 7

14. Section 1 Benzodiazepines
(BZ，苯二氮卓类)

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

16. Diazepam (地西泮，安定） 【Pharmacological actions and clinical uses】
1. Antianxiety
at the lowest effective doses
relieve the anxiety state induced by
various causes
Uses: For anxiety

17. decrease sleep-induction time decrease the number of awakenings
2. Sedation and Hypnosis
decrease sleep-induction time
decrease the number of awakenings
increase the duration of sleep
prolong stage Ⅱ of NREMS
shorten stage Ⅲ，Ⅳ of NREMS
(reduce night-waking and sleep-walking， deep sleep)
* seldom effect on REMS (little rebound)

18. Uses:
Premedication (术前给药）: an adjunct in anesthesia
For insomnia (not for depression)

19. 3. Anticonvulsant and antiepileptic effects
Uses: For 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

20. 4. Central muscle relaxation
Uses: For skeletal muscle spasms
Spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy
Spasticity from cerebral vascular accident and spinal cord injury
Spasticity from anxiety
Skeletal muscle spasms caused by local disease such as lumbar muscle strain(腰肌劳损)

21. 5. Amnesia (遗忘): anterograde amnesia
Uses: Endoscopy (内窥镜检查)
Electric defibrillation(电除颤)
6. Effects on respiration and cardiovascular
function
Respiratory depression
Cardiovascular depression
larger dose→side effect

22. 【 Mechanisms of action 】
Sites of action:
Mainly acts on limbic system（边缘系统） and brainstem reticular formation（网状结构）

23. 【 Mechanism of action 】 GABA GABA Barbiturates BZs + + - - Cl-
GABAA 受体
GABA
Barbiturates
BZs + + - -
Cl-

24. 【 Mechanism of action 】

25. 【 Mechanism of action 】

26. 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.

27. 【 Mechanism of action 】
Increase the efficiency of GABAergic synaptic inhibition
1. Bind with BZ site on the GABAA receptor
2. Enhance the affinity of GABAA receptor for GABA ，
promote GABA binding to GABAA receptor.
3. Increase the frequency of Cl- channel opening
4. Enhance hyperpolarization and further inhibit neural
excitability
5. not substitute for GABA, but appear to enhance
GABA’s effects

28. 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

29. 【 Adverse Reactions 】 1. CNS depression
Hangover (宿醉）： residual effect, most common
drowsiness（嗜睡）, exhaustion（乏力）,
dizziness（头晕）, memory decay（记忆力下降）
Diminished motor skills, impaired judgment, ataxia
→ impact on driving ability
iv. too quick →inhibit respiratory and cadiovascular
fuction

30. 【 Adverse reactions 】 2. Tolerance and dependence (addiction)
Tolerance 1-2w
Dependence
Physiological dependence
withdrawal symptoms
Psychological dependence

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

32. Advantages of BZs 1. higher therapeutic index, great margin of safety,
no anesthesia and coma in large dose
2. little influences on REMS, little rebound , less dependence and withdrawal syndrome
3. shorten stage Ⅲ，Ⅳ of NREMS，reduce night-waking and sleep-walking
4. little effects on hepatic microsomal drug-metabolizing enzymes（肝药酶）
5. Less general adverse reactions

33. Section 2 Barbiturates

34. 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)
Ultra-short-acting:
thiopental sodium (硫喷妥钠)

35. 【Pharmacological actions and clinical uses】
dose-dependent effects
1. Sedation and hypnosis （not for routinely use ）
shorten REMS→ “rebound”
Easy to produce tolerance and dependence
Hepatic enzyme inducer (肝药酶诱导剂）
more adverse reactions , severe intoxication

36. 【Pharmacological actions and clinical uses】
2. Anticonvulsant and antiepileptic effects
Phenobarbital（苯巴比妥）：
generalized tonic-clonic seizure (大发作)
3. Anesthesia
4. Enhance the effects of other CNS depressants
Adverse reaction: respiration center paralysis

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

38. Detoxifcation（中毒解救） Alkalization of the urine （碱化尿液）
often aids in the elimination of phenobarbital
—iv. NaHCO3

39. Section 3 Other sedative-hypnotics

40. Other sedative-hypnotics
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)
Zolpidem (唑吡坦 , 思诺思)
Zopiclone (佐匹克隆)
Zaleplone (扎来普隆)
Melatonin (褪黑素)
Ramelteon（雷美尔通）

41. Chloral hydrate（水合氯醛）
1. Hypnosis :
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, etc.
3. gastic mucosal irritation: not used for gastritis and ulcer patients oral: dilute (10%), rectal administration
4. toxicity on heart, liver, kidney
5. Tolerance and dependence
Low therapeutic index

42. Zolpidem (唑吡坦,思诺思Stilnox,舒睡晨爽)
非苯二氮卓类GABAA-R agonist
1. only has sedative-hypnotic effects
2. almost does not change the normal sleep
phase
3. little residual effects, tolerance and dependence
4. detoxification: flumazenil

43. Zopiclone (佐匹克隆,忆梦返,唑吡酮) Eszopiclone (艾司佐匹克隆, Lunesta)
增强GABAA受体功能，具抗焦虑、镇静催眠、抗惊厥和肌松作用。不影响REM,依赖性轻，无明显后遗效应。

44. 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

45. Melatonin（褪黑素,MT,美乐通宁）
Mechanism:
activate MT-R on suprachiasmatic nucleus(视交叉上核), enhance the function of GABA
Clinical uses：sleep- wake rhythm disorders
used for adults and the elderly
can not be used by teenagers

46. Ramelteon (雷美尔通, 拉米替隆)
selective agonist at the MT1 and MT2 subtypes of
melatonin receptors
mainly decrease sleep latency
no dependence or withdrawal effects, long-term use
4. can not be used by teenagers

47. The basic principles of drug therapy for insomnia
1. begin at the lowest effective doses
2. best used intermittently（2 - 4 times/week）
3. short-term use（less than weeks）
4. gradual discontinuation

48. “Ideal” hypnotics 1. induce sleep rapidly
2. does not affect normal sleep phases 3. there is no residual effects the next day
4. long-term use does not cause drug dependence 5. no interaction with alcohol and other drugs
卓别林
（ ）

49. Thank you!