Antipsychotic Drugs
Department of pharmacology
Classification Antipsychotic Drugs
Antimanic drugs
Antidepressants
anxiolytics
Antipsychotic Drugs
Contents Overview
Introduction of Schizophrenia
Classification of antipsychotic drugs
Chlorpromazine
Overview
Antischizophrenic,neuroleptic drugs
These agents are prescribed for treating schizophrenia or management of psychotic symptoms
Overview What is schizophrenia ?
There appears to be a genetic component to schizophrenia.
There is also evidence for changes in
brain structure.
Schizophrenia schizophrenia
Clinical Manifestations Characteristics-- perturbations affecting: language perception thinking volition Behavior social activity
size of ventricles
MRIs of monozygotic twins show marked enlargement MRIs of monozygotic twins show marked enlargement of the lateral ventricle in the twin with schizophrenizof the lateral ventricle in the twin with schizophreniz
Unaffected twinUnaffected twin Schizophrenic twinSchizophrenic twin
Schizophrenia Syndrome overview:
Typically begins in late adolescence
Insidious onset. Poor outcome. Social withdrawal /perceptual
distortions lead to chronic delusions /hallucinations.
Schizophrenia Positive Symptoms:
Conceptual disorganization Delusions Hallucinations
Schizophrenia
Negative Symptoms:
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.
• Dopamine overactivity hypothesis
(especially in left hemisphere).
• There is some evidence for involvement of 5-HT, and possibly other mediators, such as glutamate.
The Nature of Schizophrenia
【 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.
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
Four pathway of dopaminergic neurotransmission
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 therapeutic effects of drugsdrugs
Mechanism of action
3.to block dopamine receptor in nigrostriatum pathway to cause extrapyramidal symptoms ----- the adverse effects of drugsthe adverse effects of drugs
Mechanism of action
4.to bock dopamine receptor in hypothalamo-hypophysis pathway to cause endocrine dysfunction ----- the adverse the adverse effects of drugseffects of drugs
Classification of antipsychotic drugs
Phenenothiazines (Chlorpromazine) Thioxanthenes
(Tardan) Butyrophenones
(Haloperidol) Atypicals
(Clozapine)
Available Medications• Typical medications
Low potency agents - Chlorpromazine (sedation)
High potency agents - Haloperidol (motor problems – extrapyramidal effects)
• “Atypical” agents Clozapine - great Olanzapine - good Risperidone – good Aripiprazole – partial agonist
Typical Antipsychotics
• Good ability to treat hallucinations and delusions in most people within approximately 2 months
Typical Antipsychotics
Limited effect on negative symptoms Flat affect Avolition Anhedonia Attentional impairment (Cognition)
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 CNS1) 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 CNSantipsychotic 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 system- mesencephalic and cortico-mesencephalic pathways.
Dopamin receptor: two type, five subtype
- DA1 (D1-like receptor): D1,D5
- DA2 (D2-like receptor): D2,D3, D4
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 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
(2) Autonomic nervous system effects
a) Hypotensive effects receptor blockade, postural hypotension
b) Anticholinergic effects---- Blocking M-receptor
dry mouth, constipation, blurred vision, urinary retention, etc.
Pharmalogical effects
Pharmalogical effects Endocrine system effect Increasing the lactogenic hormone. Increased levels of prolactin may lead to
galactorrhea .
Phenothiazines decrease FSH and ACTH.
Decreasing release and secretion of pituitary growth hormone.
Prolactin FSH ACTH growth hormone.
Therapeutic uses
1. Psychotic disorders, all kind of schizophrenia.
Therapeutic uses
2. Nausea and vomiting.(except carsickness).
ineffective for vomiting induced by stimulating vestibules of ears (motion sickness).
effective for nausea and vomiting,
3.Artificial hibernation* Artificial hibernation therapy can be
used in serious patients with toxic infection, toxication and trauma etc.
CPZ + pethidine + promethazineArtificial hibernation therapy
Therapeutic uses
physical reduction of body temperature↓
body temperature↓+ central depression(sleep)↓
irritability to pathologic reaction↓;
basal metabolism↓→ O2 consumption↓; vasodilation→to improve microcirculation
↓ to protect the important organs from
damage to gain enough time for effective etiological treatment by other drugs.
Therapeutic uses
4.antipruritics: promethazine (H1 blocking).
5. intractable hiccup: chlorpromazine.
Adverse effects
1.general adverse effects
central depression, M-receptor blockage
2.Extrapyramidal effects:2.Extrapyramidal effects:Duo to Duo to DA receptor block:DA receptor block:
a) Parkinsonisma) Parkinsonism b) Akathisiab) Akathisia c) Acute dystoniac) Acute dystonia treated by central treated by central
muscarinic antagonistsmuscarinic antagonists
Duo to supersensitive to DA:Duo to supersensitive to DA: Tardive dyskinesiaTardive dyskinesia
Adverse effects
acute dystonic reaction (facial grimacing and torticollis)
tardive dyskinesia (sucking the lips and other involuntary facial movements).
Adverse effects2.extrapyramidal effects
patient display sucking of the lips and other involuntary facial movement. (The dyskinesia may persist for after discontinuation of the therapy).
33.cardiovascular effects: orthostatic hypotension (First choice NA or AD?), syncope and reflex tachycardia.
Adverse effects
4.Inducing psychosis by drug
5.acute toxication
po. large dose: 1~2 g / time ， clinical symptoms ： narcoma ， Bp shock ， cardiac damage, arrhythmia……
Adverse effects
6.allergic reaction skin reactions, leukopenia, skin reactions, leukopenia,
obstructive jaundiceobstructive jaundice
Adverse effects
7 Endocrine disorder: Hyperprolactinemia--causes: For women: Amenorrhea(abnormal
suppression or absence of menstrual flow), galactorrhea , infertility
For men: impotence infertility,diminished libido
For children: decreasing growth.
Adverse effects
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.
ContraindicationsContraindications epilepsyepilepsy comacoma elderly with CVS disorderselderly with CVS disorders severe hepatic and renal severe hepatic and renal
dysfunctiondysfunction
Antipsychotic drugsAntipsychotic drugs
Atypical antipsychotic drugs Clozapine and Risperidone
selectively inhibit D4 and 5-HT2-receptors.
Risperidone selectively inhibit D2 and 5-HT2-receptors.
Sulpiride selectively inhibit D2-receptors in the mesolimbic and mesocortical areas of the brain.
Sulpiride ,Clozapine and risperidone have low risk of extra-pyramidal adverse reaction.
Atypical antipsychotic drugs
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• αR2. effect on 3 systems• CNS• endocrine system• Autonomic nervous system3. 3 main clinical uses• psychotic disorders• nausea and vomiting,• artificial hibernation4. 3 main adverse reactions• central depression• extrapyramidal effects• cardiovascular effects
Antimanic drug
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
Overview
Classification
TCA Antidepressants
Overview Depression is an alteration of mood
characterized by sadness, worry, and anxiety.
The patient may suffer from losses of weight, libido, and enthusiasm.
DepressionClinical depression is a syndrome that may
include: Sustained mood disturbances Impaired memory and concentration Disturbed sleep Reduced energy level Reduced libido Impaired sleep.
Depression 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 Five of antidepressant Tricyclic antidepressants (TCA) Monoamine oxidase inhibitors (MAO) NA reuptake inhibitors Serotonin-specific reuptake inhibitors
(SSRIs) Serotonin and NA-specific reuptake
inhibitors
Most antidepressants are believed to improve by increasing NT
Catecholamine 5-HT stores
Tricyclic antidepressant TCAs
Imipramine
Pharmalogic effects
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: Hypotensin (blocking α receptor) Tachycardia
Mechanism of TCA:
Blocking re-uptake of neurotransmitter
(NA) (5-HT)
Clinic use
1) depression 2)enuresis 3) anxiety and
phobic-anxiety syndromes 4)Obsessive-compulsive
neurosis companied by
depression
Untoward effects 1)anticholinergic effect
2)cardiac arrhythmas
3)manic excitement can occur in patient with bipolar manic-deprssive illness
Untoward effects 4)The combination of a MAO inhibtor
with tricyclic antipressants should not be avoided ,since hyperpyrexia, convulsions and coma can result
Selective Serotonin reuptake inhibitors (SSRI)
A.Fluoxetine B.Paroxetine
Summary for antidepressant antidepressant DrugsDrugs
1. 1. Pharmacological effectsPharmacological effects
(1) Central effects(1) Central effects Inhibiting reuptake of monoamine Inhibiting reuptake of monoamine
transmitterstransmitters Improving patientImproving patient’’s mood after 2 s mood after 2
weeksweeks Sedative effects in normal subjectsSedative effects in normal subjects
Antidepressant DrugsAntidepressant Drugs
1. 1. Pharmacological effectsPharmacological effects (2) Autonomic effects(2) Autonomic effects Muscarinic blocking effectsMuscarinic blocking effects
(3) Cardiovascular effects(3) Cardiovascular effects -blocker, Hypotension, tachycardia, -blocker, Hypotension, tachycardia,
arrhythmiaarrhythmia
Antidepressant DrugsAntidepressant Drugs
2. 2. Clinical usesClinical uses
(1) Treatment of depression(1) Treatment of depression Endogenous, melancholic, Endogenous, melancholic, etc.etc.
(2) Treatment of enuresis(2) Treatment of enuresis
(3) Anxiety and panic disorder(3) Anxiety and panic disorder
Antidepressant DrugsAntidepressant Drugs
Chlorpromazine caused blurred vision, tachycardia, and dry mouth, constipation is due to the blocking:A dopamine (DA) receptorB a adrenaline receptorsC ß adrenaline receptorsD M receptorE N receptor
The role of chlorpromazine in normal person is:A restlessnessB be in high spiritsC nervous insomniaD sedationE above are not
1.How are agents in this chapter classified?
2.Describe the pharmacological effects of Chlorpromazine.
3 What are the major differences between the TCA and SSRIs?
4 Could adrenaline be used in the hypotension induced by chlorpromazine? Why?
