Transcript Antipsychotropic drugs

CHAPTER 20
ANTIPSYCHIATRIC DRUGS
Psychotic Disorders
1.Schizophrenia (thinking disorder)
2.Mania (mood disorder)
3.Depression (mood disorder)
4.Anxiety
Antipsychiatric Drugs
1.Antipsychotic drugs
2.Antimanic drugs
3.Antidepressive drugs
4.Antianxiety drugs
Section 1
Antipsychotic Drugs
Schizophrenia
Personality change and behavior disorders
with environment
Positive symptoms: thinking disorder,
cognition disturbance, hallucination,
paranoia, delusion(妄想）
Negative symptoms: disturbance of
feeling, discommunication
Natures of Schizophrenia

Dopamine theory of schizophrenia
pathogenesis

overactivity of the meso-limbic
dopaminergic neurons
Natures of Schizophrenia
raphetamine：promote DA release and
induce Schizophrenia.
 decrease
synthesis and storage of
DA can improve the condition

DA-R increase in putamen and
nucleus accumbens septi
Antischizophrenic Agents

Phenothiazines（吩噻嗪类）

Thioxanthenes(硫杂蒽类）

Butyrophenones(丁酰苯类）

Others
The Main Pathways of DA
and Functions in Brain
1.Nigra-striatum （黑质-纹状体） DA system
From A9 of meso-nigrosubstantia
to caudate nucleus, putamen.
Extrapyramidal function
（regulation of movement ）
Decrease - PD
Augmentation - Chorea （舞蹈症）
(irregular,involuntary mucle jerks and impair
voluntary activity)
The Main Pathways of DA
and Functions in Brain
2. Meso-limbic（中脑-边缘叶）DA system
the center of emotion and feeling
The Main Pathways of DA
and Functions in Brain
3. Meso-cortical（中脑皮层）DA system
Cognition, thinking and consciousness
System 2 and 3 augmentation
-schizophrenia
4.Tubero-infundibular (结节-漏斗 ) DA system
Regulate pituitary hormone release
The Main Pathways of DA
and Functions in Brain
5.Area postrema of medulla
DAergic system:
Central vomitting
(chemoreceptor trigger zone,CTZ)
The Subtypes of DA Receptor

In the early, DA receptors are
classified to four subtypes: D1-4

According to protein structure,
transmembrane signaling
mechanisms, effect properties and
sites of receptors, DA receptor
classified to D1 and D2 subtypes.
The Subtypes of DA Receptor

D1 is GS coupling receptor，AC，
cAMP  in brain.

D2 is Gi coupling receptor，AC，
cAMP  in brain.
The Subtypes of DA Receptor



分子克隆技术证实脑内存在D1，D2，D3，
D4，D5亚型受体。
D1-like receptors：D1和D5的分子同源性
超过80%，与GS偶联，药理学特性符合
D1。
D2-like receptors：D2、D3、D4同源性
45%，与Gi偶联，药理学特性符合D2。
The Subtypes of DA Receptor

Migro-striatal system： D1-like receptors
(D1,D5) and D2-like receptors(D2、D3、D4).

Meso-cortical and mesolimbic system
D2-like receptors(D2、D3、D4).

Tubero-infundibular system: D2.
Mechanisms of
Antipsychotic Drugs
1.Block Meso-limbic and Mesocortical DA receptor
2.Block 5-HT receptor
Phenothiazines（吩噻嗪类）






Dimethylamine derivatives
二甲胺类
Piperazine derivatives
哌嗪类
Piperidine derivatives
哌啶类
Chlorpromazine(氯丙嗪)
（Wintermine, 冬眠灵）

History

Originally
developed
as
an
antihypertensive agent.

In 1952 chlorpromazine was used to
treat schizophrenia in France
Chlorpromazine(氯丙嗪)
（Wintermine, 冬眠灵）
1.Blocks D2 receptor in the mesolimbic
and Meso- cortical
2. Block α-R
3. Block M-R
Pharmacological Actions
1. Effets on CNS
(1)
Behavioral and psychological effects
a. for animals: docile and friendly.
b. for normal person: sedation, induce
to sleep.
Pharmacological Actions
c. for schizophrenia patients:
Antipsychotic effect (neuroleptic effect):
6 wks - 6 ms to Emax.
Mechanism:
Block D2 receptor in the mesolimbic
and meso-cortical pathways of brain.
Chlorpromazine
(2)Antiemetic action
Blocks D2 receptor of CTZ on area
postrema of medulla (IV ventricule)
Large doses inhibit the vomiting
center directly.
Chlorpromazine
(3) On temperature regulation
inhibit temperature-regulating center in
hypothalamus to poikilothermia
a. The temperature changed dependent
with environment temperature.
cold environment ,T (hypothermia)
hot environment, T
(hyperthermia)
Chlorpromazine
(4) Potentiate the effects of CNS
depressants
sedation and synergism with other
CNS depressants
( analgesics,sedative-hypnotics,
anesthetics)
Chlorpromazine
(5)On extrapyramidal system
Block DA receptors on Nigrastriatal DA system
Pharmacological Actions
2. Autonomic nervous system
(1) Block α-R result in orthostatic
hypotension.
(2) Block M-R induce atropine-like
effects.
Pharmacological Actions
3. Endocrine system
Tuberoinfundibular DA pathway blockade.
a. ↓prolactin release-inhibiting factor.
b. ↓corticotropin and growth hormone.
Pharmacological Actions
3. Endocrine system
c. ↓luteinizing hormone-releasing factor.
d.↓follicl-stimulating hormone-releasing factor
Pharmacokinetics
1. Absorption
slow and unpredictable
after oral administration
2. Distribution
PPBR >90%
3. lipid solubility plays a major role
Clinical Uses
1. Schizophrenia
mania, paraniod states, schizophrenia
and psychoses with chronic alcoholism.
2.Vomiting and intractable hiccups
3. Artificial hibernation
Lyticcocktail (chlorpromazine plus
dolantin plus promethazine)
Adverse Reactions
1. Common adverse reactions
Excessive sedation
M block effects
Adverse Reactions
2. Extrapyramidal reactions
(1) Parkinson’s syndrome
(2) Akathisia
(3) Acute dystonia
facial grimacing and torticollis
block DA receptors in the nigrostriatum
artane
Adverse Reactions
(4) Tardive dyskinesia
sucking and macking of the lips and
other involuntary facial movements .
3. Psychotic Disorders
Adverse Reactions
4.Convulsion and epilepsy
5. Allergic reactions
6.Cardiovascular and Endocrine system
7.Acute intoxation
Contraindictions
1.Epilepsy and Convulsion
2.Glaucoma
3.Cyclomastopathy and breast carcinoma
4. Coronary heart disease
吩噻嗪类抗精神病作用比较
药物 抗精神病
副作用
剂量（mg/d) 镇静 锥体外作用 降压作用
氯丙嗪 300-800
++
++
+++(iv)
++(po)
氟奋乃静 1-20
+
+++
+
三氟拉嗪 6-20
+
+++
+
奋乃静
8-32
++
+++
+
硫利达嗪200-600
+++
+
+
Thioxanthenes(硫杂蒽类)
Chloprothixene
(氯普噻吨，tardan, 泰尔登)
1. Stronger sedative action.
2. Weak anti-depressant effect.
Butyrophenones(丁酰苯类)
Haloperidol(氟哌啶醇)
1. More effects in antipsychotic, to treat
the schizophrenia and the mania.
2. The extrapyramidal reaction is
very severe.
3. Strong antiemetic activity.
Other Antipsychotic Drugs
Clozapine(氯氮平)

It is an atypical antipsychotic agent.
1. Low affinity for D2, high affinity for
D4 and 5-HT2A.
2. More effective for positive and
negative symptoms of schizophrenia
Clozapine
3. Onset rapidly: a week
4. Lacking in extrapyramidal adverse
effects
5. Major adverse effect is
agranulocytosis (粒细胞缺乏）
Sulpiride
1. Stronger antipsychotic and
antiemetic activity.
2. Having antidepressant efficacy.
3. The extrapyramidal reaction is
slight.
Risperidone（利培酮）
1. Effective against negative as well
as positive symptoms
2. Improve the cognition disturbance
3. Few adverse reactions
New Theory of Psychosis
D1 function↓, D2 function↑
New drugs(by Jin Guo-zhang)
l-stepholidine
(l-SPD, 左旋千金藤啶碱）
Stimuli D1, block D2
Section 2
Antimanic Drugs

Manic-depressive disorder (bipolar
affective), emotional disorders

Biochemical bases: amine theory
Mania
5-HT↓ NE↑
Depression
5-HT↓ NE↓
Lithium carbonate(碳酸锂)
“Mood-stabilizing” agent
1. Effects on neurotransmitters and their
release.
↓NE and DA release from synapse in the
brain, ↑those reuptake.
Lithium carbonate(碳酸锂)
2.Effects on second messengers that
mediate transmitter action
a.inhibits the transformation of inositol
monophosphate (IP) to PIP2, leads to a
reduction of PIP2 , then IP3 and DAG
decrease.
b. inhibits AC
Lithium Carbonate

Clinical Uses
1. mania
2. manic-depressive psychosis
Lithium Carbonate

Adverse reactions
Lithium toxicity due to overdose:
nausea, vomit, abdominal pain,
profuse diarrhea, and ataxia
more severe: mental confussion,
hyper-reflexia, tremor, convulsion
Lithium Carbonate

Intoxication can be usually be reversed
by osmotic diuresis or in more cases by
dislysis.

Use Nacl by intravenous to treat

Serum concentration is carefully
maintainted between 0.8 and 1.5mmol/L.
Section 3
Antidepressant Agents
1.Tricyclic agents
Non-selective monoamine reuptake
inhibitors
Imipramine(丙米嗪, 米帕明)
Doxepin(多塞平)
Antidepressant Agents
2. Norepinepherine reuptake inhibitors
Desipramine(地昔帕明)
3. 5 –HT reuptake inhibitors
Fluoxetine(氟西汀)
4.Others
Imipramine(丙米嗪, 米帕明)

Pharmacological effects and mechanism
1. CNS effects
Elevating the mood that is depressed.
It blocks the reuptake of NE or 5-HT.
onset is slow and requires 2~3w.The
latency period can be as long as 4w.
Imipramine
2. Autonomic nervous system
Anticholinergic activity
3. Cardiovascular system
Tachycardia, arrhythmias,
orthostatic hypotension
quinidine-like action
Imipramine
Clinical Uses
1. Depression
2. Enuresis（遗尿）
3. Anxiety and phobia（恐怖症）
Adverse reactions
 1. Atropine-like action
 2. Cardiovascular reaction
New developed antidepressants

Maprotiline(马普替林)

A “tetracyclic drug; ” reduce
reuptake of NA
New developed antidepressants

Fluoxetine(氟西汀)

Selectively inhibits reuptake
of 5-HT

Less adverse reactions