Antipsikosis

PSYCHOTROPICPSYCHOTROPIC

SS

dr. Agung Wiwiek Indrayani, M.Kesdr. Agung Wiwiek Indrayani, M.Kes

Department of Pharmacology Department of Pharmacology

Faculty of Medicine Faculty of Medicine

Udayana UniversityUdayana University

- Antipsychotics- Antipsychotics

- Antineurotics- Antineurotics

- Antidepressants- Antidepressants

- Psychotomimetics- Psychotomimetics

PSYCHOTROPICSPSYCHOTROPICS

Psychiatric

disorders

Organic : CNS infections, intoxication, tumor etc.

Psychogenic

Mental deficiency

Psychosis

Psychosomatics

Psychoneurosis

Psychopath

SchizophreniaParanoidPsychosis affective

Personality disorders

Sociopath

Sex-deviation

Addiction

Others

ANTIPSYCHOTIC

S

Effective in controlling many Effective in controlling many manifestations of psychotic illnessmanifestations of psychotic illness

*thought disorder*thought disorder

*emotional withdrawal*emotional withdrawal

*hallucinations, delusions*hallucinations, delusions

ANTIPSYCHOTICS

CLASSIFICATIONCLASSIFICATION

PharmacokineticsPharmacokinetics

- - Lipophylic, and bound to the proteinLipophylic, and bound to the protein tends to be accumulated in the SNCtends to be accumulated in the SNC

- - Gastrointestinal absorption often irraticsGastrointestinal absorption often irratics much better result if be given by i.m. injectionmuch better result if be given by i.m. injection

- - Long half life Long half life the dose once a daythe dose once a day

(flufenazine : once every 2 weeks)(flufenazine : once every 2 weeks)

MECHANISM OF ACTIONMECHANISM OF ACTION

Neurochemical theoryNeurochemical theory

1. 1. Dopaminergic receptor theoryDopaminergic receptor theory

proposed by Carlsson (awarded a Nobel Prize 2000)proposed by Carlsson (awarded a Nobel Prize 2000)

** amphetamine cause dopamine release in the brainamphetamine cause dopamine release in the brain

can produce a syndrome resemble to schizophrenia.can produce a syndrome resemble to schizophrenia.

** in animal dopamine releasing drugs may cause in animal dopamine releasing drugs may cause

a stereotypic repetitive behaviour resemble to aa stereotypic repetitive behaviour resemble to a

schizophrenia schizophrenia

D-receptor theory D-receptor theory psychosis psychosis

1. Most antipsychotics block r-D1. Most antipsychotics block r-D22 mesolymbic mesolymbic

2. Drugs which are the2. Drugs which are the dopaminergic activity dopaminergic activity

* levodopa * levodopa : precusor of dopamine : precusor of dopamine

* amphetamine* amphetamine : dopamine release: dopamine release

* apomorphine * apomorphine : r-D: r-D2 2 agonistagonist

trigger a schizophrenia attacktrigger a schizophrenia attack

elicit symptoms of schizophreniaelicit symptoms of schizophrenia

3. Postmortem study3. Postmortem study

* r-D* r-D22 population in schizophrenia patient who population in schizophrenia patient who

received antipsychotics than those who did notreceived antipsychotics than those who did not

received the drugs received the drugs up regulation up regulation

4. Using PET4. Using PET (positron emission tomography) (positron emission tomography)

schizophrenic patients (under therapy or not)schizophrenic patients (under therapy or not)

r-Dr-D22 population (density) more than normal population (density) more than normal

D-receptor theoryD-receptor theory

5. Homovalynic acid 5. Homovalynic acid (dopamine metabolite) (dopamine metabolite) concentrationconcentration

in the cerebrospinal fluid, blood and urine ofin the cerebrospinal fluid, blood and urine of

schizophrenic patients who is improved by a drugschizophrenic patients who is improved by a drug

therapy higher than those before therapytherapy higher than those before therapy

homeostatic mechanismhomeostatic mechanism

in the dopaminergic nerve activity in the dopaminergic nerve activity


PSYCHOSISPSYCHOSIS

Neurochemical theoryNeurochemical theory

2. 2. Glutamate theoryGlutamate theory

proposed by Goff and Coyle (2001)proposed by Goff and Coyle (2001)

** glutamate NMDA (N-methyl-D-asparate) receptorglutamate NMDA (N-methyl-D-asparate) receptor

antagonist such as phencyclidine, ketamine andantagonist such as phencyclidine, ketamine and

dizocilpine produce psychotic symptomsdizocilpine produce psychotic symptoms

** postmortem studies in schizophrenic patients showedpostmortem studies in schizophrenic patients showed

that glutamate concentration and glutamate receptorsthat glutamate concentration and glutamate receptors

less than those of non schizophrenialess than those of non schizophrenia


r-Dr-D22 plays an important role in the plays an important role in the

pathophysiological of schizophreniapathophysiological of schizophrenia(conventional antipsychotics showed strong affinity to r-D(conventional antipsychotics showed strong affinity to r-D22))

butbut * * antipsychotics which is not r-Dantipsychotics which is not r-D22 selective selective

showed a very effective for schizophreniashowed a very effective for schizophrenia there are must be other mechanismthere are must be other mechanism

glutamate theory, theory involves r-5HTglutamate theory, theory involves r-5HT2 2 ??

PSYCHOSISPSYCHOSIS

Block the r-DBlock the r-D22 (dopaminergic-2 receptors)(dopaminergic-2 receptors)

r-D subtyping :r-D subtyping :- r-D- r-D11 postsynaptic postsynaptic

- r-D- r-D22 pre and postsynaptic pre and postsynaptic

- r-D- r-D33 (homolog D (homolog D22))



Limbic D5

ventral striatum D3

cortex frontal D4

amigdala D4

hypocampus D4

D1, D2, D4

D4

1. Transmitter synthesis2. Transmitter release3. Postsynaptic receptor

G : guanine nucleotide proteinG-GTP and G-GDP :G-protein which is bound to GTP(guanosinetriphosphate) or GDP (guanosine diphosphate)

PSYCHOSISPSYCHOSIS

* * Block r-DBlock r-D

- in mesolombics - in mesolombics antipsychotic effectsantipsychotic effects

- in basal ganglia- in basal ganglia parkinsonism, choreaparkinsonism, chorea

** Block peripheral r-MBlock peripheral r-M

- dry mouth etc.- dry mouth etc.

* * Block r-Block r-- hypotension- hypotension

Causative Causative for organic psychosis for organic psychosis

* Treat the intoxication* Treat the intoxication

* Antibiotics and chemotherapeutics* Antibiotics and chemotherapeutics

* Surgery* Surgery

Drug therapy of psychosis

- - Most psychosis Most psychosis * * the causes is not known the causes is not known ignota ignota

AntipsychoticsAntipsychotics

Drug therapy of psychosis

Side effects ofSide effects of PSYCHOSISPSYCHOSIS

Parkinsonism, chorea athetoidParkinsonism, chorea athetoid

(caused by blockade of r-D in(caused by blockade of r-D in basal ganglia) basal ganglia)

dry mouth

cycloplegia

constipation

hypotension, tachycardia r-blockage

r-M blockage

Type A

Side effects of Side effects of PSYCHOSISPSYCHOSIS

Type B Type B

- bone marrow depression

- hepatic malfunction

* jaundice

* steatosis

- renal malfunction

Receptor affinity Side effects

Drugs D1 D2 H1 M 5-HT ESP Sed Hypot

Classical

1. Chlorpromazine

2. Thioridazine

3. Haloperidol

4. Flupenthixol

Atypical

1. Sulpiride

2. Clozapine

3. Risperidone

4. Sertindole

5. Quetiapine

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Side effects of some antipsycotics

ToxicityToxicity

Reversible neurologic effectsReversible neurologic effects Tardive dyskinesiasTardive dyskinesias Autonomic effectsAutonomic effects Endocrine and metabolic effectsEndocrine and metabolic effects Neuroleptic malignant syndromeNeuroleptic malignant syndrome SedationSedation Overdosage toxicityOverdosage toxicity

Lithium & Other

Drugs Used in

Bipolar Disorder

PharmakokineticsPharmakokinetics

Lithium absorbed rapidly & completelyLithium absorbed rapidly & completely Half life 20 hoursHalf life 20 hours Therapeutic plasma concentration 0.6-Therapeutic plasma concentration 0.6-

1.4 meq/L1.4 meq/L Plasma levels of drug altered by Plasma levels of drug altered by

changes body waterchanges body water dehydration/diureticsdehydration/diureticstoxic levelstoxic levels Theophylline increase renal clearenceTheophylline increase renal clearence

Mechanism of ActionMechanism of Action

Not well definedNot well defined Inhibits the recycling of neuronal Inhibits the recycling of neuronal

membrane phosphoinositides involved membrane phosphoinositides involved in the generation in the generation inositol triphosphate inositol triphosphate (IP3) and diacylglycerol (DAG)(IP3) and diacylglycerol (DAG)

Decrease CaDecrease Ca2+2+ intraceluler intraceluler

Decrease hyperactivityDecrease hyperactivity

Clinical UseClinical Use

•Bipolar Affective Disorder (Bipolar Affective Disorder (manic depresive manic depresive

diseasedisease))

•Alternative drugsAlternative drugs

carbamazepine, clonazepam, gabapentin, carbamazepine, clonazepam, gabapentin,

valproic acidvalproic acid

ToxicityToxicity TremorTremor SedationSedation AtaxiaAtaxia AphaxiaAphaxia Thyroid enlargementThyroid enlargement Reversible nephrogenic diabetes Reversible nephrogenic diabetes

insipidusinsipidus EdemaEdema Pregnancy: congenital cardiac anomaliesPregnancy: congenital cardiac anomalies Contraindicated in nursing mothersContraindicated in nursing mothers

Antipsikosis

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