Sedative-Hypnotic Drugs

CHEN Zhong CHEN Zhong 陈 忠陈 忠

Department of Pharmacology, Department of Pharmacology,

College of Pharmaceutical Sciences, Zhejiang UniversityCollege of Pharmaceutical Sciences, Zhejiang University

chenzhong@zju.edu.cnchenzhong@zju.edu.cn

医学院科研楼医学院科研楼 B402-420B402-420 ，， 8820822888208228

Sedative-Hypnotic DrugsSedative-Hypnotic Drugs

2013.6

Sedatives Sedatives （镇静药）：（镇静药）：

能缓和激动，消除躁动，恢复安静情绪的药物能缓和激动，消除躁动，恢复安静情绪的药物

Hypnotics Hypnotics （催眠药）：（催眠药）：

能促进和维持近似生理睡眠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，故合称为等中枢抑制作用，故合称为镇静催眠药镇静催眠药（（ sedative-hypnoticssedative-hypnotics ））

- 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

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.

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?

Molecular Neuropharmacology

Stage 3 & 4, 统称为慢波睡眠

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

Circadian rhythm & Circadian control

SCN: suprachiasmatic nucleus

视交叉上核

Benzodiazepines Benzodiazepines

(BZ / BDZ, (BZ / BDZ, 苯二氮卓类苯二氮卓类 ))

Barbiturates (Barbiturates ( 巴比妥类巴比妥类 ))

OthersOthers

Sedative-Hypnotic Drugs

(5) Classification according to action duration

Short-acting:

triazolam, laorazepam, oxazepam, etc

Medium and long-acting:

nitrazepam, chlordiazepoxide, flurazepam etc

1. 1. ADMEADME

(1) Oral absorption

(2) Lipid solubility-dependent distribution, placcental penetrabbility

(3) Hepatic metabolism ---active metabolites

(4) Urinary excretion

A.A. Benzodiazepines Benzodiazepines

2. 2. Mechanisms of actionsMechanisms of actions

(1) Sites of action:(1) Sites of action: mainly acts on mainly acts on limbic systemlimbic system and and midbrain reticular formationmidbrain reticular formation..

(2) Interaction with GABA(2) Interaction with GABAAA receptor receptor

Benzodiazepines bind to specific, high affinity sites on the cell Benzodiazepines bind to specific, high affinity sites on the cell membrane, which are separate from but adjacent to the membrane, which are separate from but adjacent to the receptor for receptor for -aminobutyric acid (GABA).-aminobutyric acid (GABA).

The binding of benzodiazepinesThe binding of benzodiazepines enhances the affinity of GABA receptor for enhances the affinity of GABA receptor for this neurotransmitterthis neurotransmitter, resulting in a more frequent opening of adjacent , resulting in a more frequent opening of adjacent chloride channels.chloride channels. - - coagonistcoagonist

This in turn results inThis in turn results in enhanced hyperpolarizationenhanced hyperpolarization （（超极化超极化）） and further and further inhibition of neuronal firing.inhibition of neuronal firing.

A.A. Benzodiazepines Benzodiazepines

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

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

A.A. Benzodiazepines Benzodiazepines

Diazepam Diazepam 地西泮地西泮（安定）（安定）

N

NCl

CH3

O

R1

R2

R3

R4R7

1. 1. Pharmacological effects and clinical usesPharmacological effects and clinical uses

(1) Antianxiety(1) Antianxiety

at small dosesat small doses

acting on limbic systemacting on limbic system （（边缘系统边缘系统，，杏仁核、海杏仁核、海马马））

(2) Sedative-hypnotic effects(2) Sedative-hypnotic effects （（作用于作用于脑干）脑干） at relatively larger doses, no anesthetic effect; at relatively larger doses, no anesthetic effect;

not remarkably affect on REMnot remarkably affect on REM

used forused for insomniainsomnia （失眠）（失眠） andand preanesthetic preanesthetic medicationmedication

A.A. Benzodiazepines Benzodiazepines

NREM

Stages 3

Stages 3 and 4 are deep sleep.Growth hormone is released during these stages.

Slow wave sleep

BZs

(3) Antiepileptic and anticonvulsant effects(3) Antiepileptic and anticonvulsant effects

Convulsion due various causes; Convulsion due various causes; status epilepticusstatus epilepticus ((i.v.i.v.))

(4) Centrally acting muscle relaxant effect(4) Centrally acting muscle relaxant effect Relaxing the spasticity of skeletal muscle, probably by Relaxing the spasticity of skeletal muscle, probably by

increasing presynaptic inhibition in the spinal cord.increasing presynaptic inhibition in the spinal cord.

Used for the treatment of skeletal muscle spasms caused by Used for the treatment of skeletal muscle spasms caused by central or peripheral diseases.central or peripheral diseases.

(5) Others(5) Others Amnesia (Amnesia ( 短暂性记忆缺失短暂性记忆缺失 , i.v., i.v. ）） Respiratory and CVS effectsRespiratory and CVS effects

A.A. Benzodiazepines Benzodiazepines

3. 3. Adverse effectsAdverse effects

(1) Central depression(1) Central depression Most common: drowsiness and confusion (Most common: drowsiness and confusion (potentiated by potentiated by

ethanol or other central depressantsethanol or other central depressants). ).

Ataxia (Ataxia ( 共济失调共济失调 ); cognitive impairment); cognitive impairment

Antagonized by BZ receptor antagonistAntagonized by BZ receptor antagonist flumazenil flumazenil（氟马西尼）（氟马西尼）

(2) Tolerance and dependence(2) Tolerance and dependence Withdrawal syndrome: central excitationWithdrawal syndrome: central excitation

A.A. Benzodiazepines Benzodiazepines

(3) Others(3) Others local pain, respiratory and CVS reactions (i.v.)local pain, respiratory and CVS reactions (i.v.)

teratogenic effectsteratogenic effects （致畸效应）（致畸效应）

(4) Contraindications(4) Contraindications Myasthenia gravisMyasthenia gravis

Infants < 6 monthsInfants < 6 months

Pregnancy and lactation mothersPregnancy and lactation mothers

Elderly, heart/lung/liver/kidney dysfunctionElderly, heart/lung/liver/kidney dysfunction

A.A. Benzodiazepines Benzodiazepines

Other benzodiazepinesOther benzodiazepines

According to the metabolismsAccording to the metabolisms

Long-actingLong-acting ：： diazepamdiazepam, chlordiazepoxide (, chlordiazepoxide ( 氯氮卓氯氮卓 ), flurazepam (), flurazepam ( 氟西氟西

泮泮 ))

Intermediate-actingIntermediate-acting ：： Nitrozepam (Nitrozepam ( 硝西泮硝西泮 ), flunitrozepam (), flunitrozepam ( 氯硝西泮氯硝西泮 ), ),

oxazepam (oxazepam ( 奥沙西泮奥沙西泮 ), estazolam (), estazolam ( 艾司唑仑）艾司唑仑）

Short-actingShort-acting ：： triazolam (triazolam ( 三唑仑三唑仑 ))

A.A. Benzodiazepines Benzodiazepines

艹

Phenobarbital Phenobarbital 苯巴比妥苯巴比妥

C2H5

CO

NH

NH

CO

CO

C

C6H5

B.B. Barbiturates 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。

B.B. Barbiturates Barbiturates

2. 2. Pharmacological effects and clinical usesPharmacological effects and clinical uses

(1)(1) Sedative-hypnotic effectsSedative-hypnotic effects

可缩短可缩短 REMREM ，反跳明显；，反跳明显；

(2) Preanesthetic medication(2) Preanesthetic medication

(3) Antiepileptic and anticonvulsant effects(3) Antiepileptic and anticonvulsant effects

B.B. Barbiturates Barbiturates

3. 3. Adverse effectsAdverse effects

(1) Central depression:(1) Central depression: including after including after effect (hangover “effect (hangover “ 宿醉”宿醉” ))

(2) Tolerance and dependence:(2) Tolerance and dependence: long-term long-term usesuses

(3) Acute poisoning(3) Acute poisoning supporting therapiessupporting therapies

alkalizing urinealkalizing urine

hemodialysishemodialysis

B.B. Barbiturates Barbiturates

Chloral hydrate Chloral hydrate 水合氯醛水合氯醛 Sedative-hypnotic effectsSedative-hypnotic effects

Anticonvulsant effect:Anticonvulsant effect: usually used in childrenusually used in children

Hydroxyzine Hydroxyzine 羟嗪（安泰乐）羟嗪（安泰乐）

Meprobamate Meprobamate 甲丙氨酯（眠尔通）甲丙氨酯（眠尔通）

BuspironeBuspirone 丁螺环酮丁螺环酮

MethaqualoneMethaqualone 安眠酮安眠酮

C.C. Others Others

Antihistamines Antihistamines 抗组胺药抗组胺药

Ethanol Ethanol 乙醇乙醇

Melatonin Melatonin 褪黑素褪黑素

C.C. Others Others

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!

急性巴比妥中毒！自杀可能！

Central stimulantsCentral stimulants

Psychomotor stimulantsPsychomotor stimulantsRespiratory center stimulantsRespiratory center stimulants

Cortex stimulantsCortex stimulants

(mainly acting on cerebral cortex)(mainly acting on cerebral cortex)

Xanthines:Xanthines: caffeine caffeine 咖啡因咖啡因

Related drugsRelated drugs

Respiratory center stimulantsRespiratory center stimulantsDirect stimulation:Direct stimulation: 尼可刹米尼可刹米

Indirect stimulation (reflex)Indirect stimulation (reflex)

Spinal cord stimulantsSpinal cord stimulants ：士的宁：士的宁

A A Psychomotor stimulants Psychomotor stimulants

Caffeine Caffeine 咖啡因咖啡因

N

N N

N

H3C CH3�

CH3�

O

O

A A Psychomotor stimulants Psychomotor stimulants

1. 1. Pharmacological effectsPharmacological effects

(1) Central stimulation(1) Central stimulation

(2) CVS effects:(2) CVS effects: cardiac stimulation, dilatation of vesselscardiac stimulation, dilatation of vessels

(3) Relaxing smooth muscles:(3) Relaxing smooth muscles: airways, GIairways, GI

(4) Other effects:(4) Other effects: Gastric acid secretion, diuretic effectGastric acid secretion, diuretic effect

(5) Mechanisms of action(5) Mechanisms of action ：： inhibiting PDE- cAMP inhibiting PDE- cAMP ；；antagonizing A1 adenosine receptor & GABA receptorantagonizing A1 adenosine receptor & GABA receptor

A A Psychomotor stimulants Psychomotor stimulants

2. 2. Clinical usesClinical usesCentral depressionCentral depressionAdjuvant of migraineAdjuvant of migraine ( ( 偏头痛偏头痛 )) and antipyretic- and antipyretic-

analgesic drugsanalgesic drugs

3. 3. Adverse effectsAdverse effectsCentral excitationCentral excitationConvulsion (overdose)Convulsion (overdose)

A A Psychomotor stimulants Psychomotor stimulants

Methylphenidate Methylphenidate 哌甲酯（利他灵）哌甲酯（利他灵）

used for central depression caused by drugs or used for central depression caused by drugs or diseases; mild depression;diseases; mild depression; child hyperactivitychild hyperactivity; ; enuresis; enuresis; etc.etc.

Meclofenoxate Meclofenoxate 甲氯芬酯（氯酯醒）甲氯芬酯（氯酯醒）

Adjuvant of central depressive diseases; Adjuvant of central depressive diseases; enuresis; enuresis; etc.etc.

A A Psychomotor stimulants Psychomotor stimulants

Nikethamide Nikethamide 尼可刹米尼可刹米

N

C

C2H5

C2H5

N

O

B B Respiratory center stimulants Respiratory center stimulants

B B Respiratory center stimulants Respiratory center stimulants

1. 1. Pharmacological effectsPharmacological effects DirectDirect (respiratory centre)(respiratory centre) and indirectand indirect (reflex via (reflex via

chemoreceptor)chemoreceptor) stimulationstimulation

2. 2. Clinical usesClinical uses Respiratory failureRespiratory failure

3. 3. Adverse effectsAdverse effects Elevation of BP, tachycardia, tremor, Elevation of BP, tachycardia, tremor,

convulsionconvulsion

Dimefline Dimefline 二甲弗林 （回苏灵）二甲弗林 （回苏灵）

Direct stimulationDirect stimulation

LobelineLobeline 洛贝林（山梗菜碱）洛贝林（山梗菜碱）

Indirect stimulationIndirect stimulation

B B Respiratory center stimulants Respiratory center stimulants