Transcript What is schizophrenia

Antipsychotic Drugs
Department of pharmacology
Classification
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Antipsychotic Drugs
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Antimanic drugs
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Antidepressants
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anxiolytics
Antipsychotic Drugs
Contents
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Overview
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Introduction of Schizophrenia
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Classification of antipsychotic drugs
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Chlorpromazine
Overview
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Antischizophrenic,neuroleptic drugs
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These agents are prescribed for
treating schizophrenia or
management of psychotic symptoms
Overview
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What is schizophrenia ?
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There appears to be a genetic
component to schizophrenia.
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There is also evidence for changes in
brain structure.
Schizophrenia
schizophrenia
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Clinical Manifestations
Characteristics-- perturbations affecting:
language
perception
thinking
volition
Behavior
social activity
size of ventricles
Unaffected twin
Schizophrenic twin
MRIs of monozygotic twins show marked enlargement
of the lateral ventricle in the twin with schizophreniz
Schizophrenia
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Syndrome overview:
Typically begins in late
adolescence
Insidious onset.
Poor outcome.
Social withdrawal /perceptual
distortions lead to chronic
delusions /hallucinations.
Schizophrenia
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Positive Symptoms:
Conceptual disorganization
Delusions
Hallucinations
Schizophrenia
Negative Symptoms:
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Anhedonia
Decreased emotional expression
Impaired concentration
Diminished socialization
The Nature of Schizophrenia
• Incidence is about 70% of
hospital patients mental health
hospital, with a strong, but not
invariable, hereditary
component.
The Nature of Schizophrenia
• Dopamine overactivity hypothesis
(especially in left hemisphere).
• There is some evidence for involvement
of 5-HT, and possibly other mediators,
such as glutamate.
【pathogenesis of schizophrenia】
Relevance of pathogenesis of
schizophrenia to dopaminergic
nerve in CNS:
Pathogenesis of schizophrenia
1.DA increases in the brain of the
patient.
2.DR increases in the brain of the
patient.
3.Functions of dopaminergic neurons
increase.
【pathogenesis of schizophrenia】
4.Promotion of DA release induces
episode of schizophrenia.
5.Blocking DR inhibit episode of
schizophrenia.
Four pathway of dopaminergic
neurotransmission
1.limbic system- mesencephalic
pathway
emotion
2.cortico- mesencephalic pathway
thinking and motion
Four pathway of dopaminergic
neurotransmission
3.nigrostriatum pathway
motion
4.hypothalamo-hypophysis
pathway
endocrine
Mechanism of action
Antagonism of dopaminergic
receptors (D2) in CNS.
1.to block dopamine receptors in
limbic
system-mesencephalic
pathway to improve emotion
Mechanism of action
2.to block dopamine receptor in
cortico- mesencephalic pathway to
restore thinking and motion
1 and 2 are therapeutic effects of
drugs
Mechanism of action
3.to block dopamine receptor in
nigrostriatum pathway to cause
extrapyramidal symptoms ----the adverse effects of drugs
Mechanism of action
4.to bock dopamine receptor in
hypothalamo-hypophysis
pathway to cause endocrine
dysfunction ----- the adverse
effects of drugs
Classification of antipsychotic
drugs
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Phenenothiazines
(Chlorpromazine)
Thioxanthenes
(Tardan)
Butyrophenones
(Haloperidol)
Atypicals
(Clozapine)
Available Medications
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Typical medications
 Low potency agents - Chlorpromazine
(sedation)
 High potency agents - Haloperidol (motor
problems – extrapyramidal effects)
“Atypical” agents
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Clozapine - great
Olanzapine - good
Risperidone – good
Aripiprazole – partial agonist
Typical Antipsychotics
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Good ability to treat hallucinations and
delusions in most people within
approximately 2 months
Typical Antipsychotics
Limited effect on negative symptoms
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Flat affect
Avolition
Anhedonia
Attentional impairment (Cognition)
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Chlorpromazine
Pharmacologic effects
1.effects on CNS
(1) antipsychotic effect
(2) sedation and synergism with other
CNS depressives
(3) antiemetic effects
(4) effects on temperature-regulating
mechanisms
2.altering endocrine
3.peripheral effects
1.effects on CNS
1) antipsychotic effects
(1) tranquilization:
• to make animals docile and friendly,
rapidly to control manic states of
psychotic patients and make them quiet
(calming effect) and peaceful;
• to make patients feel indifferent, then
induce sleep
in few days.
1.effects on CNS
antipsychotic effects
(2)
intellect restoration, emotional
quieting, reducing psychomotor
excitement of the patient
in few weeks.
(3) to eliminate hallucination and
illusion of the patient
in few months.
• (4) For normal person to induce
sedation
Action mechanism
Blocking dopamine D2 receptor
in limbic systemmesencephalic and corticomesencephalic pathways.
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Dopamin receptor: two type, five
subtype
- DA1 (D1-like receptor): D1,D5
- DA2 (D2-like receptor): D2,D3, D4
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D2 receptor activation  motor
activity  aggravates schizophrenia
D2 receptor blockade  alleviation of
schizophrenia
2) sedation and synergism with other
CNS depressives
analgesics, sedative-hypnotics,
anesthetics.
Pharmalogical effects
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3)Antiemetic effect.
-This is a results of blocking DA2
receptor.
-In low doses, blocking DA2 receptor
in chemoreceptor trigger zone(CTZ).
-In high doses, chlorpromazine may
directly
depress
the
medulla
vomiting center.
Pharmalogical effects
4)effect on temperature-regulating
mechanism
 to inhibit temperature-regulating
center in hypothalamus to induce
poikilothermia
(hypothermia,
hyperthermia).
4)effect on temperature-regulating
mechanism
in a cold climate it decrease
temperature in body
 in a hot climate they can cause
hyperthermia
Pharmalogical effects
(2) Autonomic nervous system effects
a) Hypotensive effects
 receptor blockade, postural hypotension
b) Anticholinergic effects---- Blocking Mreceptor
dry mouth, constipation, blurred vision, urinary
retention, etc.
Pharmalogical effects
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Endocrine system effect
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Increasing the lactogenic hormone.
Increased levels of prolactin may lead to
galactorrhea .
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Phenothiazines decrease FSH and ACTH.
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Decreasing release and secretion of pituitary
growth hormone.
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Prolactin
FSH
ACTH
growth hormone.
Therapeutic uses
 1. Psychotic disorders, all kind of
schizophrenia.
Therapeutic uses
 2. Nausea and vomiting.(except
carsickness).
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ineffective for vomiting induced by
stimulating vestibules of ears (motion
sickness).
effective for nausea and vomiting,
Therapeutic uses
 3.Artificial hibernation*
Artificial hibernation therapy can be
used in serious patients with toxic
infection, toxication and trauma etc.
CPZ + pethidine + promethazine
Artificial hibernation therapy
physical reduction of body temperature
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body temperature↓+ central depression(sleep)
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irritability to pathologic reaction↓;
basal metabolism↓→ O2 consumption↓;
vasodilation→to improve microcirculation
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to protect the important organs from
damage to gain enough time for effective
etiological treatment by other drugs.
Therapeutic uses
4.antipruritics:
blocking).
promethazine
(H1
5. intractable hiccup: chlorpromazine.
Adverse effects
1.general adverse effects
central depression,
M-receptor blockage
Adverse effects
2.Extrapyramidal effects:Duo to DA
receptor block:
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a) Parkinsonism
b) Akathisia
c) Acute dystonia
treated by central muscarinic
antagonists
Duo to supersensitive to DA:
Tardive dyskinesia
Adverse effects
2.extrapyramidal effects
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acute dystonic reaction (facial
grimacing and torticollis)
tardive dyskinesia (sucking the
lips and other involuntary
facial movements).
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patient display sucking of the
lips and other involuntary facial
movement. (The dyskinesia may
persist for after discontinuation
of the therapy).
Adverse effects
33.cardiovascular
effects:
orthostatic
hypotension
(First choice NA or AD?),
syncope
and
reflex
tachycardia.
Adverse effects
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4.Inducing psychosis by drug
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5.acute toxication
po. large dose: 1~2 g / time，
clinical symptoms：
narcoma ，Bp shock，
cardiac damage, arrhythmia……
Adverse effects
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6.allergic reaction
skin
reactions,
leukopenia,
obstructive jaundice
Adverse effects
7 Endocrine disorder:
 Hyperprolactinemia--causes:
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For women: Amenorrhea(abnormal
suppression or absence of menstrual
flow), galactorrhea , infertility
For men: impotence infertility,diminished
libido
For children: decreasing growth.
Drug interaction:
1)Increasing CNS inhibition with ethanol,
sedative-hypnotics, morphine.
2)Inhibiting the of L-Dopa (agonist of the
doparmin-receptor).
3)Increase the dose with phentoin and
carbamazepine.
Antipsychotic drugs
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Contraindications
epilepsy
coma
elderly with CVS disorders
severe hepatic and renal dysfunction
Atypical antipsychotic drugs
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Clozapine and Risperidone
selectively inhibit D4 and 5-HT2receptors.
Risperidone selectively inhibit D2
and 5-HT2-receptors.
Atypical antipsychotic drugs
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Sulpiride selectively inhibit D2receptors in the mesolimbic and
mesocortical areas of the brain.
Sulpiride ,Clozapine and
risperidone have low risk of extrapyramidal adverse reaction.
Atypical antipsychotic drugs
Sulpiride
 Selectively inhibit D2-receptors in
the mesolimbic and mesocortical
areas of the brain.
 Producing low extra-pyramidal
adverse reaction.
Summary for chlorpromazine
1. blocking 3 types of receptors
• DR
• MR
• αR
2. effect on 3 systems
• CNS
• endocrine system
• Autonomic nervous system
3. 3 main clinical uses
• psychotic disorders
• nausea and vomiting,
• artificial hibernation
4. 3 main adverse reactions
• central depression
• extrapyramidal effects
• cardiovascular effects
Antimanic drug
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Lithium carbonate
Pharmacodynamics
Possible mechanisms of action:
-effects on electrolyte/ion transport
neurotransmitter
-neurotransmitter release modulation
influence on second messengers.
Lithium salts how to affect second
messengers?(learning by yourself)
Antidepressants
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Overview
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Classification
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TCA Antidepressants
Overview
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Depression is an alteration of mood
characterized by sadness, worry, and
anxiety.
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The patient may suffer from losses of
weight, libido, and enthusiasm.
Depression
Clinical depression is a syndrome that may
include:
 Sustained mood disturbances
 Impaired memory and concentration
 Disturbed sleep
 Reduced energy level
 Reduced libido
 Impaired sleep.
Depression
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Patient complaints suggestive of
depression may include:
Pain (headaches, body aches)
A mood of apathy, anxiety, or
irritability
Sexual complaints
low energy, excessive tiredness
reduced capacity for enjoyment.
Classification of
Antidepressant Drugs
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Five of antidepressant
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Tricyclic antidepressants (TCA)
Monoamine oxidase inhibitors (MAO)
NA reuptake inhibitors
Serotonin-specific reuptake inhibitors
(SSRIs)
Serotonin and NA-specific reuptake
inhibitors
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Most antidepressants are believed to
improve by increasing NT
 Catecholamine
 5-HT stores
Tricyclic antidepressant TCAs
Imipramine
Pharmalogic effects
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CNS
-In the depressed patients , an
elevation of mood occur 2-3 weeks
after administration begins, the
latency period can be as long as 4
weeks.
-The imipramine blocks the re-uptake
of serotonin and NA
Pharmalogic effects
Autonomic nervous system
Blocking M-receptor
Pharmalogic effects
Cardovascular effect:
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Hypotensin (blocking α receptor)
Tachycardia
Mechanism of TCA:
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Blocking re-uptake of
neurotransmitter
(NA)
(5-HT)
Clinic use
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1) depression
2)enuresis
3) anxiety and
phobic-anxiety syndromes
4)Obsessive-compulsive
neurosis companied by
depression
Untoward effects
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1)anticholinergic effect
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2)cardiac arrhythmas
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3)manic excitement can occur in
patient with bipolar manic-deprssive
illness
Untoward effects
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4)The combination of a MAO inhibtor
with tricyclic antipressants should
not be avoided ,since hyperpyrexia,
convulsions and coma can result
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Selective
Serotonin reuptake
inhibitors (SSRI)
A.Fluoxetine
B.Paroxetine
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Summary for antidepressant
Drugs
Antidepressant Drugs
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1. Pharmacological effects
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(1) Central effects
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Inhibiting
reuptake
of
monoamine
transmitters
Improving patient’s mood after 2 weeks
Sedative effects in normal subjects
Antidepressant Drugs
1. Pharmacological effects
 (2) Autonomic effects
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Muscarinic blocking effects
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(3) Cardiovascular effects
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-blocker,
arrhythmia
Hypotension,
tachycardia,
Antidepressant Drugs
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2. Clinical uses
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(1) Treatment of depression
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Endogenous, melancholic, etc.
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(2) Treatment of enuresis
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(3) Anxiety and panic disorder
Chlorpromazine caused
blurred vision, tachycardia,
and dry mouth, constipation is
due to the blocking:
A dopamine (DA) receptor
B a adrenaline receptors
C ß adrenaline receptors
D M receptor
E N receptor
The role of chlorpromazine in normal
person is:
A restlessness
B be in high spirits
C nervous insomnia
D sedation
E above are not
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1.How are agents in this chapter
classified?
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2.Describe
the
pharmacological
effects of Chlorpromazine.
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3 What are the major differences
between the TCA and SSRIs?
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4 Could adrenaline be used in the
hypotension induced by
chlorpromazine? Why?