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?