Transcript 镇静催眠药sedative-hypnotic drugs

镇静催眠药
sedative-hypnotic drugs
Pharmacological department , school of basic medicine ,
Peking union medical college
叶菜英
镇静催眠药
sedative-hypnotic drugs
Definition
:
Drugs which can selectively inhibit CNS
and cause sedation and hypnosis .
镇静催眠药 sedative-hypnotic drugs
Inhibit CNS in a dose-dependent manner
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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
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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
镇静催眠药sedative-hypnotic drugs
categories
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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
鎮静、催眠和抗焦虑药
苯二氮卓类 benzodiazepines
地西泮（安定）
Diazepam
奥沙西泮
Oxazepam
三唑仑
Triazolam
苯二氮卓类 Benzodiazepines
Advantages：Efficacy, safe, fewer side effects
categorise
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Long-acting：（T1/220hr）
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Middle-acting：（T1/26-20hr）
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Short-acting：（T1/26hr）
苯二氮卓类 benzodiazepines
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Long-acting：（T1/220hr）
安定 Diazepam、
氯氮卓chlordiazepoxide （利眠灵）
氟胺安定flurazepam (氟安定）
苯二氮卓类 benzodiazepines
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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)
苯二氮卓类 Benzodiazepines
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Physiological process
Oral, injection absorption→ binding to plasma
protein → 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 血 浆 蛋 分布 口服 T1/2
用度
白 结 合 容积 吸收
率
蓄积
安定
100
98
1.1
快
20100
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
20100
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
代谢 活性代谢物
苯二氮卓类Benzodiazepines
Pharmacokinetic characteristics：
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The speed of Absorption and the extent of plasma binding are
in equilibrium with liposolubility .
More than 90 % bind → absorbed quickly, such as
diazapam , etc.
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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
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Pharmacokinetic characteristics
Long-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
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Pharmacological actions
Anti-anxiety and anticonvalsant
Sedation and hypnosis
CNS inhibition
Central muscle relaxant
Lapsus memoriae
Abstinent symptom
苯二氮卓类Benzodiazepines
Pharmacological actions and clinical applications
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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 obsessivecompulsive
disorder
,
gastrointestinal
neurosis ,heart neurosis . Strychnine and other
drugs cause seizures.
苯二氮卓类Benzodiazepines
Pharmacological actions and clinical applications
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Sedation and hypnosis :
Clinical applications：
Narcotic administration —— calm
Treat insomnia —— difficult to fall asleep ,
wake up easily and early.
苯二氮卓类Benzodiazepines
Pharmacological 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
苯二氮卓类Benzodiazepines
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Lapsus memoriae ：damage in recent
memory (reversible)
Withdrawal symptoms ： psychological
and physiological dependence after longterm 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 Clchannel .
 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
points with high affinity to BDZ .
 The binding point exists in the cortex , mid
brain ,cornu 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
receptorαsubunit 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 antianxiety of BZ ，while the sedation and hypnosis
effect is related to receptors in the brain stem.
苯二氮卓类Benzodiazepines
Adverse effects：
 Therapeutic dose ：drowsiness ，dizziness ,
fatigue , Memory decline .
 Large dose ：ataxia
overdose →intoxation →coma , respiratory
depression
death
 Long term use ：tolerance ，addiction
 Ethanol strengthen toxicity
 Through the placenta : teratogenicity role
巴比妥类 Barbiturates
[化学结构]
O═ C
╱NH2
╲NH2
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╱NH—OC╲ ╱H
CH2→O═C (2)
(5)C
HOOC╱
╲NH—OC╱ ╲H
HOOC╲
Barbituric acid is a condensed by urea and malonate .
Barbituric acid does not have hypnotic effect itself，C5
substituted by different groups .
C5-two H substituted ——barbiturates
C5-benzene ring——anticonvulsant ，phenobarbital
C5-side chain has branches——amobarbital
C2-O substituted by S——thiopental
is
鎮静、催眠和抗焦虑药
巴比妥类
巴比妥类 barbiturates
长效：苯巴比妥 (phenobarbital） 作用维持6~8 h
中效：异戊巴比妥（amobarbital）
3~6 h
短效：司可巴比妥（secobarbital)
2~3 h
超短效：硫喷妥（thiopental）
0.5 h
巴比妥类barbiturates
[Physiological process]
 Oral
and
intramuscular
injection
absorption→distribution all over the body , body
fluid →brain
 High liposolubility（metabolised by liver drug
enzyme ） → 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
amobarbital slightly low slightly faster destroyed in liver
secobarbital higher
faster
destroyed in liver
thiopental
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
paralysis and death .
 Poor safety，easy to cause dependence . The
application has been declining and is mainly used for
anticonvulsant , antiepilepsia and anaesthesia .
巴比妥类barbiturates
[Pharmacological actions and clinical application]
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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
fever , eclampsia , meningitis , encephalitis and
convulsion caused by central stimulants .
 Preanesthetic medication and anesthesia
Thiopental : intravenous anesthesia ， induction
of anesthesia .
Phenolbarbitol ：anesthetic medication
巴比妥类barbiturates
[Pharmacological actions and clinical application]
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Enhance the function of central depressant
Barbiturates of sedative dose combined with
antipyretic 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
GABA , 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 .
巴比妥类barbiturates
[Adverse effects]
After effect :dizziness , drowsiness , fine uncoordinate
movement
Allergic response : nettle rash , angioneuroedema ,
erythema mlutiforme
Tolerance
Dependence
Acute intoxication :significant inhibit respiration center .
巴比妥类barbiturates
[Notes]
 The drug is a inducer of liver drug-metabolizing enzymes and
promote metabolism of other drugs .
 The main cause of death of barbiturates is deep respiratory
inhibition .
 In pregnant and lactant period , the thyroid function is low .
Patients 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]
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Intoxation : deep coma , high respiratory
inhibition , 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
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Hypnosis —— refractory insomnia
Anti-convulsion —— tetanus , eclampsia .
convulsion of epilepsia gravior
Toxic dose —— inhibit respirate and blood
pressure , large dose can cause anesthesia .
Take 10% solution orally or per rectum
generally in order to reduce stimulate .
水合氯醛 chloral hydrate
【Adverse effects】
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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
ethanol in blood
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