Sedative-Hypnotic Drugs

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Sedative-Hypnotic Drugs

Lou haiyanLou haiyanInstitute of PharmacologyInstitute of Pharmacology

School of MedicineSchool of MedicineShandong UniversityShandong University

[email protected]@sdu.edu.cn

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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

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Normal EEG and brain wave pattern

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波形分类频率振幅出现条件皮层意义

α 波 8-13 Hz 20-100mV 清醒、安静、闭目；枕叶显著安静状态

β 波 14-30 Hz 5-10 mV

睁眼或接受其它刺激（或快波睡眠时相）额叶和顶叶显著；

安静闭目时只在额叶出现

紧张状态

θ 波 4-7 Hz 100-150 mV 困倦抑制

δ 波 0.5-3 Hz 20-200 mV 睡眠，极度疲劳或麻醉时抑制

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Wakefulness and Sleep

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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

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Normal Sleep Patterns

There are two major types of sleep:Non-rapid eye movement (NREM) sleepRapid eye movement (REM) sleep

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Normal sleep pattern

NREMNREM REMREM

4-5 REM and NREM 4-5 REM and NREM 的交替循环的交替循环

80-120min80-120min 20-30 min20-30 minNREMNREM NREMNREM NREMNREMREMREM REMREM

REMREMNREMNREMSleep latency

0 1 2 3 4

sws1 2 3

sws

4sws

Night-walking and somnambulismNight-walking and somnambulism

dreamdreamREMREM

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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。

Phases of sleep

Play roles in brain and intellectual development long-term shorten will induce “reboundrebound” after withdrawal,

significantly increase the frequency and duration of REM,

cause dreaminess, nightmare, anxiety and insomnia,

finally leading to dependence.

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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。

2. NREMS (non rapid eye movement sleep,

非快动眼睡眠 )

SWS ( slow wave sleep ，慢波睡眠 )

Play roles in eliminating the fatigue and promote

growth Shorten SWS 3 、 4 phase will clean up night-walking

and somnambulism

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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

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What Happens if We are Deprived of Sleep?

Lack of alertness Fatigue Memory problems Irritability Depression Lack of motivation Accidents

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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

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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

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Insomnia

Symptoms of insomniaSymptoms of insomnia ：：1. difficulty falling asleep

2. difficulty staying asleep

3. early morning waking

4. daytime drowsiness, fatigue or difficulty concentrating

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Insomnia

Causes of insomnia:Causes of insomnia:

1. Psychological problems: anxiety

2. Medical problems

3. Medication

4. Sleep disorders

anxiety: the most common cause

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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

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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

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CNS depression (dose-dependent)

Its major therapeutic use is to cause sedation (with concomitant relief of anxiety)

— small dose

encourage sleep — large dose

Definition of sedative-hypnotic drugsDefinition of sedative-hypnotic drugs

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Benzodiazepines (BZ ，苯二氮卓类 )

Barbiturates ( 巴比妥类 )

Others

Classifications

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1. Graded dose-dependent depression of CNS function

Characteristics Characteristics

Dose-response curves for two hypothetical sedative-hypnotics

Drug A: barbiturates

Drug B: benzodiazepines and certain newer hypnotics

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*2. Different influences on sleep phases

3. Tolerance and dependence Physiologic dependence

Psychologic dependence

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Section 1 Benzodiazepines

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Chemical Structure

1,4-benzodiazepines (1,4- 苯并二氮卓）

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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 )

Classifications

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1. Antianxiety

【 Pharmacological actions 】

at the lowest effective doses relieve the anxiety state induced by

various causes

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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… ..

焦虑反应、焦虑症

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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）

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心理治疗的疗效是肯定的对焦虑症的心理治疗不可忽视

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2. Sedation and Hypnosis

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)


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3. Anticonvulsant and antiepileptic effects


4. Central muscle relaxation

5. Others

Anterograde amnesia ( 顺行性记忆缺失 ) Respiratory depression

Cardiovascular depressionlarger dose→side effect

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【 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 )

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【 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

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5. For muscle relaxation in specific

neuromuscular disorder

skeletal muscle spasticity in cerebral

vascular accident and spinal cord injury

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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

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【 Mechanisms of action 】

1. Sites of action:

2. Interaction with GABAA receptor

Mainly acts on limbic system and midbrain

reticular formation.

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GABAA receptor

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Molecular MechanismGABA

+

-

+

-

GABA and GABA agonist

BZsBarbituratespicrotoxin

Cl-

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Benzodiazepine

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Binding of GABA is enhanced by

benzodiazepine,resulting in a greater entry of chloride ion.

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

Binding of GABA causes the chloride ion channel to open

Empty receptor isinactive, and the coupled chloride channel is closed.

Empty receptor isinactive, and the coupled chloride channel is closed.

Receptor empty (no agonists)

Cl-Cl-Cl-Cl-Cl-Cl-

Receptor binding GABAReceptor binding GABA and benzodiazepine

Cl-Cl-

Cl-Cl-

Cl-Cl-

Cl-Cl-

Cl-Cl-

Cl-Cl-Cl-Cl-

Cl-Cl-Cl-Cl-

Entry of Cl- hyperpolarizes cell makingit more difficult to depolarize and thereforereduces neural excitability.

GABA receptorBenzodia

zepinereceptor

Benzodiazepine

GABA

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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


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oral absorption is rapid and complete

im: absorption is slow and irregular

iv: acute

【 Pharmacokinetics 】1. Absorption

high plasma protein binding rate high lipid solubility→cross BBB and

placental barrier

2. Distribution diazepam

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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

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Biotransformation of benzodiazepines地西泮

* :active metabolite

Boldface: drugs available for clinical use

奥沙西泮

氯氮卓普拉西泮

三唑仑

劳拉西泮氟西泮

阿普唑仑

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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

【 Adverse Reactions 】

2. Tolerance and dependence withdrawal symptom

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Washing stomach Symptomatic treatment Benzodiazepine specific antagonist

Flumazenil ( 氟马西尼，安易醒） :

short t1/2, repeated administration

3. toxic reaction and detoxifcation

GABABZs

Flumazenil-

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氟马西尼（ Flumazenil ，安易醒）

DIAZEPAM FLUMAZENIL

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【 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 )

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Alcohol and other CNS depressants

Enzyme induction

sodium phenobarbital or phenytoin,

carbamazepine( 卡马西平 ), rifampicin( 利福平）

shortern t1/2

Enzyme inhibition

cimetidine

prolong t1/2

【 Drug interactions 】

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Intermediate acting—nitrazepam （硝西泮）：特点：口服吸收好， 30 分起效，维持睡眠 6 ～ 8 小时 ; 醒后无明显后遗效应 ; 兼抗癫痫作用

Short acting— 艾司唑仑（ estazolam ，舒乐安定 )

特点：吸收快，口服后 20 ～ 60 分钟入睡，维持 5 ～8 小时 ; 副作用小；兼抗癫痫、抗惊厥作用

Long acting—flurazepam （氟西泮）

特点：与地西泮相似，镇静催眠作用较强。代谢物 ( 去烷基氟西泮）有活性，作用持久（ t1/2 40-100h ）

Similar drugs

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Short acting —triazolam （三唑仑）

BDZ 类中代谢最快、作用最强的药物 ; 速效、强效（ 45-100 倍）、极少蓄积为突出优点。临床上曾广泛用于各种类型的失眠，现因依赖性少用。

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Section 2 Barbiturates

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Classifications

thiopental sodium ( 硫喷妥钠 )

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 , seconal)

Ultra-short-acting:

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1. Sedation and hypnosis

shorten REMS→ “rebound” Easy to produce tolerance and dependence

Hepatic enzyme inducer

more adverse reactions , severe intoxication

not sedative-hypnotics for routinely use

【 Pharmacological actions and clinical uses 】

dose-dependent effects

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3. Anesthesia and premedication

eg. thiopental sodium （硫喷妥钠） onset (30s), duration (15min)

4. Enhance the effects of other CNS depressants

【 Pharmacological actions and clinical uses 】

2. Anticonvulsant and antiepileptic effects

generalized tonic-clonic seizure ( 大发作 )

and status epilepticus

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【 Mechanisms 】

GABA mimetic (high dose activate

GABA receptor)

Extend opening time of Cl- channel

inhibit excitatory neurotransmitter

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Pharmacokinetics

1. Absorption: po,im

2. Hepatic enzyme inducer

3. Urine pH affects excretion

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Alkalization of the urine often aids in the

elimination of phenobarbital—iv. NaHCO3

Detoxifcation

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Adverse reactions

Hangover

Tolerance and dependence

Respiratory depression ：

深度的呼吸抑制死亡原因

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Advantages of BZs

1. Higher therapeutic index, no anesthesia in large dose

2. Prolong stage 2 sleep, shorten stage 3, 4 sleep, little influences on REMS

3. Do not induce hepatic enzyme

4. Less rebound and dependence

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Section 3 Other hypnotic agents

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Newer drugs for anxiety and sleep disorders

Buspirone ( 丁螺环酮 )

Zolpidem ( 唑吡坦 , 思诺思 )

Zopiclone ( 佐匹克隆 )

Older sedative-hypnotics

Chloral hydrate ( 水合氯醛 )

Meprobamate ( 甲丙氨酯，眠尔通 )

Other hypnotic agents

more selective

Non-GABAergic system

Zaloplone ( 扎来普隆 )

Melatonin ( 褪黑素 )

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Chloral hydrate （水合氯醛）1. Hypnosis :

strong, 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 ( 小儿高热惊厥 )

3. oral: need to dilute (10%), rectal administration

(gastic mucosal irritation: not used for gastritis and ulcer patients)

4. Inhibit cardiac contractility (contraindicated to patients with severe

heart, liver, kidney disease)

5. Tolerance and dependence

6. Low therapeutic index

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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

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Melatonin （褪黑素 ,MT ）作用：调节生物节律、神经内分泌、应激反应，抑制肾上腺、性腺、甲状腺分泌，

抗炎、镇痛、镇静、催眠、抗氧化、清除

自由基。机制：激活视交叉核上的 MT － R 增强 GABA 的功能用途：成年和老年人的睡眠障碍 , 不宜用于未成年人

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催眠药应用原则：

1. 消除诱因：环境、生活习惯、药物、疾病等

2. 药物：健康人暂时性或老年人间断性失眠，用最低

有效量、短期应用、交替应用

3. 长期失眠用非药物治疗（心理疗法），辅以药物

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“理想的”安眠药

1. 迅速诱导睡眠，服后 30min 内即可入睡。2. 不引起睡眠结构紊乱。3. 没有宿醉作用，第二天无药物残留作用。4. 无呼吸抑制5. 长期使用不引起药物依赖性。6. 与乙醇和其他药物无相互作用。

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药物治疗失眠的基本原则

1. 应用最小有效剂量 2. 间断用药（每周 2-4 次） 3. 短期用药（不超过 3-4 周） 4. 逐渐停药

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Summary

1. The pharmacological effect , mechanism

of action, clinical use and adverse

reactions of Benzodiazepines 2. Compare Benzodiazepines and

Barbitals

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Thank you!

Sedative-Hypnotic Drugs

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