Download Chapter 14 Sedative

Chapter 16 Sedatives and Hypnotics
 Graded dose-dependent depression of central
nervous system function is a charicteristic of
sedative-hypnotics.
 Classification of drugs
 Benzodiazepines are the most important
sedative-hypnotics.
 Barbiturates
 Other agents
Sub-classify of Benzodiazepines
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Short-acting(t1/2<6 hours)
Triazolam（三唑仑）
intermediate -acting(t1/2 6~24 hours)
Oxazepam(奥沙西泮），nitrazepam（硝基安定）
long-acting(t1/2>24 hours)
Diazepam(地西泮,安定）,flurazepam（氟西泮，氟
安定）,and chlordiazepoxide（氯氮卓）
Benzodiazepines
Diazepam(地西泮）
[Pharmacological effects and clinical uses]
• 1. Antianxiety
• Diazepam reduces anxiety at doses that do not produce
sedation.
• This action is related to selective inhibition of neuronal
circuits in the limbic边缘 system of the brain.
• 2. Sedative and hypnosis
• It shortens the latency潜伏期 of sleep onset,decreases
intermittent awakening and prolongs the duration of
sleep.
Benzodiazepines
• 3. Anticonvulsant effects and antiepileptic effects
Benzodiazepines are capable of inhibting the
development and spread of epileptic form activity
in the central nervous system.
• 4.Muscle relaxation
• The mechanism is that it exerts inhibitory effects on
polysynaptic reflexes and internuncial
transmission,and at high doses may depress
transmission at the skeletal myoneural junction.
Benzodiazepines
Therapeutic applications
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Anxiety disorders
Insomnia失眠
Anticonvulsion and antiepilepsy
Muscle disorders
[Mechanism of actions]
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Benzodiazepines
GABAA receptor has a structure comprised of multiple
subunits( alpha, beta,gamma, etc). Combinations of the three
major subunits appear to be essential for normal physiologic
and pharmacologic function of the macromolecule.
GABA binds to receptor sites on the beta subunits and that
this interaction initiates gating of the chloride channel current.
The benzodiazepine receptor sites are probably located on
alpha subunits. Benzodiazepine drugs can binds to these
sites,but they don’t substitute for GABA. They appear to
enhance GABA’effects without directly activating GABA
receptors or opening the associated chloride channels.
The enhancement in chloride ion conductance induced by the
interaction of benzodiazepines with GABA takes the form of
an increase in the frequency of channel opening events.
This effect may be due in part to enhanced receptor affinity
for GABA.
安定的作用机制
安定
BZ受体
GABA受体调控蛋白变构
GABA激活GABAA受体
Cl-通道开放
Cl-内流
细胞超极化
Benzodiazepines
[Adverse effects]
• Many of the common adverse effects of drugs in this
class are those resulting from dose-related depression
of central nervous system functions.
• Relatively low doses may lead to drowsiness思睡,
impaired judgment,and diminished motor skills etc.
• At toxic doses,sedative-hypnotics can produce
significant respiratory and cardiovascular depression.
• Physical and psychological dependence can develop
when diazepam is taken for a long period. Rebound
and abstinence signs include anxiety, insomnia,
tension, tremor震颤 and seizure.
Barbiturates
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long-acting
Phenobarbital 苯巴比妥（鲁米那）
intermediate –acting
Pentobarbital戊巴比妥，Amobarbital异戊巴比妥
Short-acting
Secobarbital 司可巴比妥
Ultra- short-acting
Thiopental 硫喷妥钠
Barbiturates
Pharmacological effects and
Therapeutic applications
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As the dose increases, Barbiturates have :
Sadation and hypnosis
Anticonvulsion and antiepilepsy
Anaesthesia and pre-anaesthesia medication.
Barbiturates
[Mechanism of actions]
• Barbiturates also facilitate the actions of GABA at
multiple sites in the central nervous system. But in
contrast to benzodiazepines, on different site ,
Barbiturates prolong the duration of the GABA-gated
channel (chloride channels) openings.
• Barbiturates can reduce glutamate induced
depolarization and inhibit Na+and K+ channel at
higher concentrations.
• Barbiturates depress the reticular ascending activating
system at sedative-hypnotic concentrations.
Barbiturates
[Adverse effects]
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Hangover宿睡
Drug tolerance-dependence
Acquired hypersensitivity
Poisoning
Other agents
• Chloral hydrate（水合氯醛）