Transcript 抗精神失常药

Drugs used in the Treatment
of Psychological Disorders
 Antipsychotic drugs
 Antidepressant and antimanic drugs
 Anxiolytics
2012.5.14
5.8
5.9
周二
周三
周一
5.14
8:00-8:45
情绪的脑机制
1
周煜东
8:50-9:35
精神分裂症的病因学
1
周煜东
9:50-10:35
精神分裂症的神经生物学
1
周煜东
8:00-8:45
精神分裂症的主要临床表现
1
李惠春
8:50-9:35
精神分裂症的诊断标准
1
李惠春
9:50-10:35
自杀、法律能力的评定
1
陈炜
13:15-16:40
CPR培训
4
张悦怡、王一红
8:00-8:45
成瘾的神经生物学机制
1
包爱民
9:50-10:35
精神药物治疗
1
陈忠
10:40-11:25
药物成瘾性的控制
1
陈忠
13:15-16:40
临床基本穿刺（胸穿、腰穿）练习
4
王一红
教学目标：
掌握：精神药物（抗精神病药、抗躁狂药、抗抑
郁药）分类及其代表药；以氯丙嗪为代表，抗
精神失常药的药理作用、临床应用和不良反应
特点；以丙米嗪(米帕明)为代表，抗抑郁药的
药理作用和作用机制(阻断NA和5-HT再摄取)、
临床应用。
了解：其他主要药物的特点。
Psychiatric Disorders (in general)
 Lifetime prevalence: about 1/3- 1/2 of
population
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Substance abuse: 16%
Schizophrenia: 1%
Affective Disorder: 8-10%
Anxiety Disorder: 15%
Epidemiology
• Incidence consistent worldwide
 1% general population
 10% siblings , parents / offspring, dizygotic twins
 50% monozygotic twins
• Environmental factors implicated

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Prenatal stress - infection, famine, war, death of
spouse
Season of birth - winter > summer
Urban setting > rural setting
• Age of onset


Men 17 – 27, Women 17 - 37
Childhood onset extremely rare: 1 in 10,000100,000
• Duration – life
• Outcome
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10 % good - optimistic
80% remission without full recovery
10 % no remission
Signs & Symptoms

Positive symptoms
• Delusions (错觉)- fixed false belief outside cultural
norm (bizarre vs. non bizarre)
• Hallucinations (幻觉)- perceptual (hearing), have
no outside source
• “Like my voice”
• Not an illusion (幻想，a mistaken perception for which
there is an actual external stimulus)
• Disorganization - pattern of speech or behavior,
making up words without a meaning (neologisms)
Signs & Symptoms

Negative symptoms
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•
•
•
•
•
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Affective flattening情感冷淡
Avolition / Amotivation (decreased motivation)
Autistic behaviors (social withdrawal )
Anhedonia (inability to experience pleasure )兴致缺乏
Ambivalence (coexistence of opposing attitudes or
feelings)
Anosognosia (impaired awareness of illness )
Cognitive deficit
Criteria
A) Symptoms (positive and negative)
B) Social and occupational decline
C) Duration - longer than 6 months
Exclusions
Not another psychiatric condition, e.g. mood
Not another medical condition, e.g. sarcoidosis
Not drug abuse
Not a pervasive developmental disorder全身性发
育迟缓
DA学说
DA／5HT平衡障碍学说
NMDAR功能低下学说
其发病与遗传、社会环境、
躯体生化代谢等因素有关
Classification of antipsychotics
Typical:
 Phenothiazines (吩噻嗪类): chlorpromazine
 Thioxanthenes (硫杂蒽类): chlorprothixene氯普噻吨（泰尔登）
 Butyrophenones (丁酰苯类): haloperidol氟哌啶醇
Atypical:
 Clozapine, olanzapine奥氮平, risperidone利培酮
Available Medications
 Typical medications (D2 receptor antagonists)
 Low potency agents - Chlorpromazine (sedation)
 High potency agents - Haloperidol (motor problems –
extrapyramidal effects)
 Atypical agents
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Clozapine – 5-HT2 and D4 receptor antagonist, great efficacy
Olanzapine （奥氮平）– 5-HT2, D1, D2, M, H, αreceptor
antagonist, good
Risperidone （利培酮）– 5-HT2 and D2 receptor antagonist,
good
Aripiprazole （阿立哌唑） – partial agonist of D2 and 5-HT1
receptor
A. Antipsychotic drugs
1. The dopamine hypothesis of schizophrenia
2. The serotonin hypothesis of schizophrenia
3. The glutamate hypothesis of schizophrenia
中脑-皮层通路
结节-漏斗通路
黑质-纹状体通路
A. Antipsychotic drugs
Phenothiazines（吩噻嗪类）
Chlorpromazine
氯丙嗪
• Chlorpromazine (氯丙嗪) made in 1950 in
S
N
(CH 2)3
Cl
France, used to treat pre-operative anxiety; 1952
Delay and Deniker published the first report of
Chlorpromazine's efficacy in psychosis
• 1963 Carlsson and Lindquist report that
Haloperidol and Chlorpromazine result in
accumulation of DA metabolites
N(CH3)2 • D hypothesis (excessive dopaminergic activity
2
plays a role in the disorder) - 1976 Seeman et. al.
and Creese et. al. report that “potency” of DA
antagonism at D2 related to efficacy
A. Antipsychotic drugs
Good & Gilman
A. Antipsychotic drugs
(1) Central effects:
Blocking central D2 dopamine
receptors
a) Antipsychotic effects (neuroleptic effects)
镇静和抗精神病作用
 for treatment of schizophrenia
 controlling excitation and then hallucinations
(weeks to months)
b) Antiemetic effects 镇吐作用
 inhibiting chemoreceptor trigger zone (CTZ)
dopaminergic function
A. Antipsychotic drugs
c) Poikilothermic effects 体温调节作用
 hypothermic anesthesia
 artificial hibernation
d) Extrapyramidal effects 椎体外系作用
 primary adverse effects
e) Potentiating the effects of central depressants
 sedative-hypnotics, analgesics, general anesthetics,
ethanol
A. Antipsychotic drugs
(2) Autonomic nervous system effects
a) Hypotensive effects
  receptor blockade, postural hypotension
b) Anticholinergic effects
 dry mouth, constipation, blurred vision,
urinary retention, ect.
(3) Endocrine effects
 prolactin 
 ACTH, growth hormone 
A. Antipsychotic drugs
2. Clinical uses
(1) Treatment of schizophrenia
(2) Treatments of emesis (呕吐)and hiccough(呃逆)
 used for emesis and hiccough
 but ineffective on motion sickness
(3) Hypothermic anesthesia and artificial hibernation
 combined with lowering room temperature
A. Antipsychotic drugs
3. Adverse effects
(1) Side effects
 central depression
 peripheral effects: postural hypotension,
dry mouth, and other effects resulting from
muscarinic and  receptor blockade
A. Antipsychotic drugs
(2) Extrapyramidal effects
 Due to DA receptor block:
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
a) Parkinsonism
b) Akathisia (静坐不能)
c) Acute dystonia (急性肌张力障碍)

attenuated by central muscarinic antagonists
 Due to supersensitive to DA:
 Tardive dyskinesia (迟发性运动障碍)
A. Antipsychotic drugs
(3) Other central reactions药源性疾病
 neuroleptic maglinant syndrome (神经阻滞药恶性综合征）
(NMS, induced by excessive blocking of DAergic system): high fever,
hypertension, tonus, autonomic system disorder, even death
Treatment: DA agonists (eg bromocriptine),
DA releasers (eg amantadine),
and muscular relaxants (eg scoline)
 psychotic reactions
 epilepsy and convulsion: lowering seizure threshold
(4) Allergic and hemological reactions
 skin reactions, leukopenia, obstructive jaundice,
liver damage
A. Antipsychotic drugs
(5) CVS reactions
 arrhythmia
 hypotension: treated by  receptor agonists
 sudden death (elderly with CVS diseases)
(6) Endocrine reactions
 hyperplasia of mammary glands (乳腺增生),
galactorrhea (溢乳), amenorrhea (闭经 ),
 child growth retard
A. Antipsychotic drugs
(6) Acute intoxication
 severe CNS depression, coma, severe hypotension
(7) Contraindications
 epilepsy
 coma
 elderly with CVS disorders
 severe hepatic and renal dysfunction
A. Antipsychotic drugs
Other phenothiazines
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perphenazine 奋乃静
fluphenazine 氟奋乃静
trifluoperazine 三氟拉嗪
thioridazine 硫利达嗪
 more potent therapeutic effects and
extrapyramidal effects
A. Antipsychotic drugs
Thioxanthenes
(硫杂蒽类)：结构与三环类抗
抑郁药相似
 Chlorprothixene 氯普噻吨（泰尔登）
 Used for the patients with symptoms of
depression and anxiety
A. Antipsychotic drugs
Butyrophenones（丁酰苯类）
 Haloperidol
氟哌啶醇
 Droperidol 氟哌利多（氟哌啶）
Combined with fentanyl（芬太尼）:
neuroleptanalgesia（神经安定 [镇痛] 麻醉术）
A. Antipsychotic drugs
Others
 Penfluridol
五氟利多
 Longer duration of action, taking once weekly
 Sulpride
舒必利
 selectively acts on mesolimbic D2 receptors
 few extrapyramidal reactions
 Clozapine
氯氮平
 Blocking D4 and 5-HT receptors
 Risperidone 利培酮
 Blocking D2 and 5-HT2 receptors
Disorders of Mood
Disorders of mood (affective disorders 情感障碍) are
extremely common in medical practice. The
severity of these conditions covers an
extraordinarily broad range, from normal
grief reactions and dysthymia to severe,
incapacitating illness that may result in death.
Emotion（情绪）refers to transient responses to
environmental, internal, and cognitive stimuli,
while mood （心境）refers to the predominant
emotional state over time.
Disorders of Mood
The symptoms of depression are intense feelings of
sadness, hopelessness, despair, and inability to
experience pleasure in usual activity.
Mania is characterized by the opposite behavior,
that is, enthusiasm, rapid thought and speech
patterns, and extreme self-confidence and impaired
judgment.
Anxiety, a state characterized by arousal, vigilance,
physiologic preparedness, and negative subjective
states, may share certain critical circuits with fear.
B. Antidepressant Drugs
Monoamine hypothesis（单胺假说）
5-HT  — genetic basis of depression & mania
NE  — depression
NE  — mania
Modulation of monoamines in the synaptic space
and/or the related post-synaptic receptors is of
therapeutic importance
Modulation of monoamines
(NE and 5-HT) in the
synaptic space and/or the
related post-synaptic
receptors is of therapeutic
importance
Long-term adaptations to antidepressant treatment
Molecular pharmacology
Model of the neurotrophic
hypothesis of
antidepressant treatments and
stress-related disorders
B. Antidepressant Drugs
Enhancement of monoamine (5-HT, NE)
transmitter function
Inhibition of monoamine reuptake
Inhibition of monoamine degradation
May decrease the number and sensitivity of NE and 5-HT receptors
B. Antidepressant Drugs
Tricyclic/polycyclic antidepressants
Monoamine oxidase inhibitor
NE reuptake inhibitor (NARIs)
Selective 5-HT reuptake inhibitors (SSRIs)
NE and 5-HT reuptake inhibitor (SNRIs)
Noradrenergic and specific serotonergic antidepressants
(NaSSAs)
B. Antidepressant Drugs
Imipramine
丙咪嗪（米帕明）
Tricyclic
structure
N
CH 3
CH 2CH 2CH 2N
CH 3
B. Antidepressant Drugs
1. Pharmacological effects
(1) Central effects
 Inhibiting reuptake of monoamine transmitters
include NA and 5-HT
 Improving patient’s mood after 2 weeks
 Sedative effects in normal subjects (1 and H1 receptor)
 Extrapyramidal effects (D2 receptor)
(2) Autonomic effects
 Muscarinic blocking effects
(3) Cardiovascular effects ( receptor)
 Hypotension, tachycardia, arrhythmia
B. Antidepressant Drugs
2. Clinical uses
(1) Depression
 Endogenous depression (内源性抑郁),
 melancholic depression (更年期抑郁), etc.
(2) Enuresis (遗尿)
(3) Anxiety, panic disorder (惊恐障碍) and
obsession (强迫症)
B. Antidepressant Drugs
3. Adverse effects
(1) Antimuscarinic effects
 dry mouth, constipation, intraocular pressure increase,
blurred vision, urinary retention, ect.
 Contraindicated in prostatauxe and glaucoma
(2) CNS reactions
 dizzy or delirium（谵妄）, depression-mania (bipolar
patients)
(3) CVS reactions
 Postural hypotension, sinus tachycardia, potential of
arrhythmia
B. Antidepressant Drugs
4. Drug interactions
(1) Plasma protein binding
 displacement by phenytoin, aspirin, scopolamine,
phenothiazines, ect.
(2) MAO inhibitors
 potentiating the effects of TCA,
 contraindicated for combination with MAOIs
(3) Potentiating the effects of CNS depressant drugs
B. Antidepressant Drugs
Interaction of TCA with other types of drugs
B. Antidepressant Drugs
Other tricyclic antidepressants
 amitriptyline (阿米替林)
 clomipramine (氯米帕明、氯丙咪嗪)
 doxepin (多塞平)
B. Antidepressant Drugs
NE reuptake inhibitors (NRIs)
 Selective norepinephrine reuptake inhibits
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rapid actions

weaker sedative, anticholinergic and hypotensive effects
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desipramine (地昔帕明)
maprotiline (马普替林)
nortriptyline (去甲替林)
protriptylin (普罗替林)
amoxapine (阿莫沙平)
B. Antidepressant Drugs
Selective 5-HT reuptake inhibitors
 Selective serotonin reuptake inhibits (SSRIs)
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weaker sedative effects
with anti-anxiety effects
fluoxetine (氟西汀，百忧解)
paroxetine (帕罗西汀)
sertraline (舍曲林)
B. Antidepressant Drugs
5-HT/NE reuptake inhibitors
 Mixed serotonin/norepinephrine reuptake inhibits
(SNRIs)

rapid action

less affinity with receptors

higher safety
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venlafaxine (文拉法辛)
milnacipram (米那普仑)
lofepramine (洛夫帕明)
B. Antidepressant Drugs
Noradrenergic and specific serotonergic
antidepressant (NaSSA) mirtezapine (米氮平)
 blocking presynaptic (auto- or hetero-) 2 receptor
on both
norepinephrine and serotonin (5-HT) presynaptic axons
- increasing NE and 5-HT release;
 stimulating postsynaptic 1 receptors on serotonergic cell bodies
- increasing the firing rate of serotonergic neurons
 potently blocking postsynaptic 5-HT2A, 5-HT2C and 5-HT3
receptors – attenuating 5-HT2C-mediated anxiety
 The net outcome of these effects is increased noradrenergic
activity together with specific increased serotonergic activity,
especially at 5-HT1A receptors
NE & 5-HT release 
5-HT neuron firing 
Blocking 5-HT2,
5-HT3 receptors
Mirtazapine:
NE release 
5-HT release 
5-HT1A ; 5-HT2/3 
B. Antidepressant Drugs
Monoamine oxidase inhibitors (MAOIs)
 selective for central MAO-B, less selective for enteric
MAO-A;
 used in treatments of depression (non-sensitive to
TCAs) and Parkinson disease
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phenelzine (苯乙肼): non-selective
selegiline (司来吉兰): also used in Parkinson disease
C. Antimanic Drugs
 Lithium carbonate
 Carbamazepine
 Chlorpromazine
 Other related antiepileptic
and antipsychotic drugs
C. Antimanic Drugs
Lithium carbonate
碳酸锂
1. Pharmacological effects and clinical uses
 Mood-stabilizing agent
 (1) Inhibiting NE and DA release
 (2) Interfering phosphatidylinositol (PI) metabolism
C. Antimanic Drugs
2. Adverse effects
 Related to the serum concentration of Li+
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
0.8 – 1.5 mmol/L: therapeutic level
1.6 – 2.0 mmol/L: GI reactions
> 2.0 mmol/L: CNS toxicity
 Monitoring serum concentration of Li+ if
possible
C. Antimanic Drugs
(1) Side effects
 Nausea, vomiting, abdominal pain, diarrhea, sedation,
finger tremor, polyuria, etc.
(2) Acute intoxication
 Mental confusion, coma, hyperreflexia, gross tremor,
dysarthria, seizures, kidney failure, death, etc.
(3) Others
 Benign thyroid enlargement, renal damage
D. Anxiolytic drugs
1. Benzodiazepines see details in Sedative-Hypnotic Drugs
2. Buspirone（丁螺环酮）
 5-HT1A receptor selective partial agonist, lowering
5-HT release
 Fewer sedative, hypnotic, memory-deficient effects
 No cross tolerance to benzodiazepines, and less
potential of dependence