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镇静催眠药

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					               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
 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
    镇静催眠药sedative-hypnotic drugs

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
鎮静、催眠和抗焦虑药

   苯二氮卓类 benzodiazepines




 地西泮(安定)     奥沙西泮       三唑仑
 Diazepam    Oxazepam   Triazolam
    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)
苯二氮卓类 benzodiazepines
   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

   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
   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         蓄积   代谢 活性代谢物
     用度  白 结 合 容积 吸收
         率
安定   100   98   1.1   快   20-     易产生 氧化 去甲安定、去
                          100            甲羟基安定
利眠   100   97   0.3   快   7-28    易产生 氧化 去甲氯氮卓、
灵                                        去甲羟安定
氟胺   100   97   2.2   快   20-     易产生 氧化 N- 脱 烷 基 氟
安定                        100            安定
硝基   78    87   1.9   慢   15-20 不易     氧化 去甲安定
安定
去甲   88    90   1.0   慢   5-18    不易   结合 去甲安定
羟基
安定
甲基   55    90   1.1   慢   1.5-5   无    氧化 α-羟三唑安定
三唑
氯安
定
    苯二氮卓类Benzodiazepines
    Pharmacokinetic characteristics:
   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.

   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 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
   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
   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Benzodiazepines
Pharmacological 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

   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
  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 anti-
  anxiety 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]
        ╱NH2     HOOC╲              ╱NH—OC╲ ╱H
O═ 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
    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
  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]
    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]


   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]
   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

   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】
    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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