镇静催眠药 sedative-hypnotic drugs pharmacological department, school of basic medicine, peking...

镇静催眠药 sedative-hypnotic drugs

Pharmacological department , school of basic medicine , Peking union medical college

叶菜英


Definition :

Drugs which can selectively inhibit CNS and cause sedation and hypnosis .


Inhibit CNS in a dose-dependent manner Low dose : relief patients’ irritability, sedation Suitable increment : Induce sleep.

sleep → deepen and extend the role of hypnosis . Large dose ： deepen Central inhibition

→ anticonvulsant anesthesia.

poisoning dose → central inhibition death.

The physiological significance of sleep

Apperception and sleep are to maintain physiological function of the body .

People must study and work in the wake - a clear head , high efficiency

The body must have sufficient sleep - to relief the body from fatigue , get rest

The physiological significance of sleep

Promote the development of brain function Maintain energy of brain function Consolidation of memory and ensure the

best brain functions Promote the growth of the body, resist

aging Enhance the body's immune function


categories

苯二氮卓类 Benzodiazepines ：安定 Diazepam ，硝基安定等

巴比妥类 Barbiturates: 异戊巴比妥 amobarbital 等其他类：水合氯醛 chloral hydrate 等

苯二氮卓类 benzodiazepines

N

C N

O

OHCl

H

地西泮（安定）地西泮（安定）DiazepamDiazepam

奥沙西泮奥沙西泮OxazepamOxazepam

三唑仑三唑仑TriazolamTriazolam

鎮静、催眠和抗焦虑药

苯二氮卓类 Benzodiazepines

Advantages ： Efficacy, safe, fewer side effects

categorise Long-acting ：（ T1/220hr ） Middle-acting ：（ T1/26-20hr ） Short-acting ：（ T1/26hr ）


Long-acting ：（ T1/220hr ）安定 Diazepam 、氯氮卓 chlordiazepoxide （利眠灵）氟胺安定 flurazepam ( 氟安定）


Middle-acting ：（ T1/26-20hr ）硝基安定（硝西泮）去甲羟基安定（舒宁） Short-acting ：（ T1/26hr ）甲基三唑氯安定 Trizolam （三唑仑 )


Physiological process Oral, injection absorption→ binding to plasma pro

tein → distribution in the brain, blood-rich organizations →metabolised by liver enzyme , and metabolin can bind to glucuronic acid directly → eliminated from the kidney

Some enter hepatoenteral circulation→ effects last → accumulation

几种苯二氮卓类药代动力学比较药名生物利

用度血浆蛋白结合率

分布容积

口服吸收

T1/2 蓄积代谢活性代谢物

安定 100 98 1.1 快 20-100

易产生氧化去甲安定、去甲羟基安定

利眠灵

100 97 0.3 快 7-28 易产生氧化去甲氯氮卓、去甲羟安定

氟胺安定

100 97 2.2 快 20-100

易产生氧化 N- 脱烷基氟安定

硝基安定

78 87 1.9 慢 15-20

不易氧化去甲安定

去甲羟基安定

88 90 1.0 慢 5-18 不易结合去甲安定

甲基三唑氯安定

55 90 1.1 慢 1.5-5 无氧化 α- 羟三唑安定


Pharmacokinetic characteristics ： The speed of Absorption and the extent of plasma binding ar

e in equilibrium with liposolubility . More than 90 % bind → absorbed quickly, such as diazapam

, etc.

Liver metabolism : metabolised to a range of active substances by liver drug enzyme , t1 / 2 longer than the mother nuclide .

Demethyldiazapam is metabolised to a wide range of active metabolins, t1/2 20-100 hr.

苯二氮卓类 Benzodiazepines Pharmacokinetic

characteristicsLong-acting ： slow elimination ， long t1/2 ，repeated administration → accumulation

The majority of drugs are oxygenized in the body (such as diazapam) ——affected by many factors , Such as drinking , liver disease → t1 / 2 extended

苯二氮卓类 Benzodiazepines Pharmacological actions

Anti-anxiety and anticonvalsantSedation and hypnosisCNS inhibition

Central muscle relaxantLapsus memoriae

Abstinent symptom


Pharmacological actions and clinical applications

Anti-anxiety and anticonvulsant effect Advantages : high selectivity , wide safety margin ,

slow elimination , lasting effects ,low dependence and light withdrawal symptoms.

Clinical applications : anxiety with obsessive-compulsive disorder , gastrointestinal neurosis ,heart neurosis . Strychnine and other drugs cause seizures.

苯二氮卓类 BenzodiazepinesPharmacological actions and clinical applications Sedation and hypnosis :

Clinical applications ： Narcotic administration —— calm

Treat insomnia —— difficult to fall asleep , wake up easily and early.

苯二氮卓类 BenzodiazepinesPharmacological actions and clinical applications Central inhibition ： strengthen the inhibition

of central inhibitors （ such as ethanol , barbiturates ） .

Central muscle relaxant:

Clinical applications: muscle cramps , cerebral vascular accident , spinal cord injuries and lumbar muscle strain


Lapsus memoriae ： damage in recent memory (reversible)

Withdrawal symptoms ： psychological and physiological dependence after long-term use . Sudden withdrawal symptoms ： nervous , trembling , appetite lose and sleep disorders.

鎮静、催眠和抗焦虑药苯二氮卓类

GABA— 中枢抑制递质（ 2α 、 2β 、 γ2 组成） GABA 与 R 结合与 Cl- 通道相偶联→ Cl- 升高→突触后膜超极化→中枢抑制 BZ 与 GABA-R 分布相似，存在功能联系，组成 GABA.R.BZ-R.cl- 复合物

苯二氮卓类 Benzodiazepines【 Mechanism of action 】 At present , it is thpught that the central role of

BZ is possibly closely related to the drug effects on the γ-aminobutyric acid (GABA) receptor in different parts of the brain .

The receptor is a comples macromolecule ,which is a ligand-gated Cl-channel .

GABA is central suppressive neurotransmitter which is related to sedation , hypnosis , anticonvulsant and emotional stability .

苯二氮卓类 Benzodiazepines【 Mechanism of action 】 GABA neuron ending release GABA ， agitate GABAA

receptors on postsynaptic membrane . GABAA receptor is constructed by two αsubunits and two βsubunits . GABA binds to GABAA receptorβsubunit and open Cl channel ， resulting in Cl － inflow , postsynaptic neurons potential decline and membrane hyperpolarization . The cell is hard to be excited .

When GABA exhausted ， the role of the drugs disappear ， indicating that the role depends on GABA but not the receptor 。

苯二氮卓类 Benzodiazepines【 Mechanism of action 】 On the GABA neuron ending there are specific point

s with high affinity to BDZ . The binding point exists in the cortex , mid brain ,co

rnu ammonis , spinal cord and so on , consistent with the distribution of GABAA receptors .

Recent years studies indicate the binding of BZ to GABAA receptor αsubunit can not open Cl- channel directly . But it can enhance the binding of GABA to GABAA receptor βsubunit , which can increase the frequency of the Cl- channel openness .

苯二氮卓类 Benzodiazepines【 Mechanism of action 】 In short ， the binding of BZ with GABAA receptorαs

ubunit can enhance the binding GABA with GABAA receptors , increase the neurotransmitter function of GABA and synaptic inhibition effect ； It can also function by increasing the frequency of C1 － channel openness .

It is generally believed that GABAA receptors in amygdala and cornu ammonis play a role in anti-anxiety of BZ ， while the sedation and hypnosis effect is related to receptors in the brain stem.


Adverse effects ： Therapeutic dose ： drowsiness ， dizziness ,

fatigue , Memory decline . Large dose ： ataxia overdose →intoxation →coma , respiratory depr

ession death Long term use ： tolerance ， addiction Ethanol strengthen toxicity Through the placenta : teratogenicity role

巴比妥类 Barbiturates[ 化学结构 ] ╱NH2 HOOC╲ ╱NH—OC╲ ╱HO═ C CH2→O═C (2) (5)C ╲NH2 HOOC╱ ╲NH—OC╱ ╲H

Barbituric acid is a condensed by urea and malonate . Barbituric acid does not have hypnotic effect itself ， C5 is substit

uted by different groups . C5-two H substituted ——barbiturates

C5-benzene ring——anticonvulsant ， phenobarbital

C5-side chain has branches——amobarbital C2-O substituted by S——thiopentalthiopental

鎮静、催眠和抗焦虑药巴比妥类

巴比妥类 barbiturates

长效：长效：苯巴比妥苯巴比妥 ((phenobarbitalphenobarbital ））作用维持作用维持 6~8 h6~8 h

中效：中效：异戊巴比妥异戊巴比妥（（ amobarbitalamobarbital ）） 3~6 h3~6 h

短效：短效：司可巴比妥（司可巴比妥（ secobarbital)secobarbital) 2~3 h 2~3 h

超短效：超短效：硫喷妥硫喷妥（（ thiopentalthiopental ）） 0.5 h0.5 h

巴比妥类 barbiturates[Physiological process] Oral and intramuscular injection absorption→distributi

on all over the body , body fluid →brain High liposolubility （ metabolised by liver drug enzym

e ）→ eliminated in urine （ short maintenance time ）

Low liposolubility→ eliminated in original form （ long maintenance time ）

巴比妥类作用快慢与消除比较

Main drugs liposolubility effect time eliminated way

Phenol low slow some destroyed in liver ，barbital some eliminated from kidney

amobarbitalamobarbital slightly low slightly faster destroyed in liver

secobarbitalsecobarbital higher faster destroyed in liver

thiopentalthiopental highest fastest Store fat ， destroyed in liver

巴比妥类 barbiturates[Characteristics of pharmacological action] Barbiturates generally inhibit the CNS . It has sedative ,

hypnotic , anticonvulsant , antiepileptic and anaesthetic effect at different doses from low to large , respectively .

Inhibit cardiovascular system at large dose . 10 times of hypnosis dose can cause respiratory paralysi

s and death . Poor safety ， easy to cause dependence . The applicatio

n has been declining and is mainly used for anticonvulsant , antiepilepsia and anaesthesia .


[Pharmacological actions and clinical application] Sedation & hypnosis

Low dose —— sedation

middle dose—— hypnosis , shorten time to fall asleep , extend sleeping time

Long term use —— rebound phenomenon , dependence , addiction.

巴比妥类 barbiturates[Pharmacological actions and clinical application] Anticonvulsant and antiepilepsia strong action for tetanus , children with high fe

ver , eclampsia , meningitis , encephalitis and convulsion caused by central stimulants .

Preanesthetic medication and anesthesia Thiopental : intravenous anesthesia ， inducti

on of anesthesia .

Phenolbarbitol ： anesthetic medication

巴比妥类 barbiturates[Pharmacological actions and clinical application]

Enhance the function of central depressant Barbiturates of sedative dose combined with an

tipyretic analgesic drugs can augment the analgesic effect of the latter .

巴比妥类 barbiturates[Mechanism of action] The centrol role is related to the activation of GABAA

receptors . Barbiturates can function as GABA in the absence of G

ABA , which can increase the permeability of Cl － channel , leading to the cell membrane hyperpolarization . Different from BZ drugs which increase Cl － channel opening frequence ， barbiturates mainly extend the Cl － channel opening time .

In addition ， barbiturates can weaken or block the excited reaction resulted from depolarization caused by the glumatic acids and inhibit the CNS .


[Adverse effects] After effect :dizziness , drowsiness , fine uncoordinate mo

vement

Allergic response : nettle rash , angioneuroedema , erythema mlutiforme

Tolerance

Dependence

Acute intoxication :significant inhibit respiration center .


[Notes] The drug is a inducer of liver drug-metabolizing enzymes and p

romote metabolism of other drugs . The main cause of death of barbiturates is deep respiratory inhi

bition . In pregnant and lactant period , the thyroid function is low . Pat

ients who have fever , anaemia , hypotension , hemorrhagic shock , heart , liver , kidney dysfunction and old people with mental disease should take the drug with caution .

Patients with respiratory inhibition caused by bronchial asthma and head injury , severe liver dysfunction , uncontrolled diabetes and who is allergic are forbidden to take .

巴比妥类 barbiturates[Acute intoxation treatment] Intoxation : deep coma , high respiratory inhibitio

n , blood pressure drop , body temperature drop , shock and renal failure.

Breath maintenance , circulation , O2 , trachea cannula , artificial breathing , transfusion , central stimulants.

Gastric lavage ， alky drugs such as sodium bicarbonate , strong emictory , dialysis .

其他类 Other sedative-hypnotic drugs 水合氯醛 chloral hydrate

Hypnosis —— refractory insomnia Anti-convulsion —— tetanus , eclampsia . conv

ulsion of epilepsia gravior Toxic dose —— inhibit respirate and blood pre

ssure , large dose can cause anesthesia . Take 10% solution orally or per rectum genera

lly in order to reduce stimulate .

水合氯醛 chloral hydrate

【 Adverse effects 】 Gastrointestinal reaction : strong stimulation of gastric

mucous membrane causes nausea , vomit and epigastric discomfort .

Large dose can inhibit myocardial contraction and shorten the cardiac muscle refractory peroid .

Overdose cause damage to heart , liver and kidney . So patients with liver or kidney disease are forbidden to take .

Allergic reactions occur occasionally , such as erythema, urticaria, dermatitis, and so on.

鎮静、催眠和抗焦虑药

The central effect of The central effect of

ethanol in bloodethanol in blood

Thanks!

镇静催眠药 sedative-hypnotic drugs pharmacological department, school of basic medicine, peking...

Documents