Download - Treatment of psychosis
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DRUG TREATMENT OF PSYCHOSIS
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Psychiatric illness
Psychosis Neurosis
OCDPhobiaAnxiety
PTSD
Schizophrenia
Mania Depression Bipolar
Psychosis: Pt is not aware of illness and refers to treatmentNeurosis: Less serious and insight present
(Obsessive compulsive disorder, Post traumatic stress disorder)
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Psychosis• Psychosis is a thought disorder
characterized by :• Disturbances of reality and perception• Impaired cognitive functioning• Inappropriate or diminished affect (mood)
• Psychosis denotes many mental disorders. Schizophrenia is a type of functional
psychosis in which severe personality changes and thought disorders
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• Earlier: termed as major tranquilizers • USA: Antipsychotics• Europe: Neuroleptics (both antipsyo + EPS)
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Schizophrenia
• Pathogenesis is unknown.• Onset of schizophrenia is in the late teens early
twenties.• Genetic predisposition -- Familial incidence. • Multiple genes are involved.• Afflicts 1% of the population worldwide.• May or may not be present with anatomical
changes.
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Schizophrenia• It is a thought disorder.• The disorder is characterized by a divorcement from
reality in the mind of the person (psychosis).
• Symptoms positive or negative.• Positive:
– visual and auditory hallucinations– Delusions– Thought disorders – Irrational conclusions – Control by external forces (paranoia),
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• Negative– Poor socialization– Emotional blunting– Introvert behaviour – Lack of motivation – Congnitive deficits (lack of attention and loss of memory)
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Psychosis Producing Drugs
1) Levodopa2) CNS stimulants
a) Cocaine b) Amphetaminesc) Khat, cathinone, methcathinone
3) Apomorphine 4) Phencyclidine
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Role of DA in psychosis • Positron emission tomographic (PES) DA receptor density
• Postmortem DA density
• Inc DA by L Dopa , Amphetamine, Apomorphin precipitate
the symptoms
• Most antipsychotic drugs blocking D2 in CNS Mesolimbic,
frontal
• Inc Homovalinic acid (HVA)
• Drug should absolutely rather then partially, ineffective
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Central Dopaminergic pathway
• Ultra short Periglomular cells in olfactory bulb
• Intermediate Ventral hypothalamus role in prolactin release, Hypothalamic-hypophyseal functions
• Long : most IMP. Cover SN, Ventral Tegmental areas to Limbic system, amygdala, Caudate, Putamen
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Parkinson’s dec. DA in basal ganglia
Scizopherenia Over activity of DA in Mesolimbic Mesocortical Mesofrontal
There are four major pathways for the dopaminergic system in the brain:I. The Nigro-Stiatal Pathway: Voluntary movementsII. The Mesolimbic Pathway.: BehaviourIII. The Mesocortical Pathway: Behaviour IV. The Tuberoinfundibular Pathway: Prolactin release
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• 5HT2 agonist visual hallucinations and sensory disturbance , which are similar to psychosis
• 5HT has a modulator role on DA pathway• After has fall off because • 5HT Visual • Schizo Auditory predominate
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Glutamate
• Glutamate exerts excitatory, while DA exerts inhibitory role over GABA ergic striatal neurons which projects to thalamus and serves as sensory gate.
• Inc Glu, or Dec DA disturbed the Gate t allow uninhibited sensory inputs to cortex.
• Hallucination and thought disorders.
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Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine
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Antipsychotic treatments In 1940’s Phenothiazenes were isolated and were
used as pre-anesthetic medication, but quickly were adopted by psychiatrists to calm down their mental patients.
In 1955, chlorpromazine was developed as an antihistaminic agent by Rhone-Pauline Laboratories in France.
In-patients at Mental Hospitals dropped by 1/3.
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Antipsychotic/Neuroleptics
Three major groups :1. Phenothiazines 2. Thioxanthine3. Butyrophenones
OLDER DRUGS
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Antipsychotic/Neuroleptics
1) Phenothiazines
Chlorpromazine Thioridazine FluphenazineTrifluopromazine Piperacetazine Perfenazine
Mesoridazine Acetophenazine
Carphenazine
Prochlorperazine
Trifluoperazine
• Aliphatic Piperidine Piperazine*
* Most likely to cause extrapyramidal effects.
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Antipsychotic/Neuroleptics
2) ThioxanthinesThiothixeneChlorprothixene
Closely related to phenothiazines
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Antipsychotic/Neuroleptics
3) ButyrophenonesHaloperidolDroperidol*
*Not marketed
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Atypical Antipsychotic
PimozideAtypical Antipsychoitcs
LoxapineClozapine
OlanzapineQuetiapine
IndolonesSertindole
ZiprasidoneOlindone
MolindoneRisperidone
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Classification of antipsychotic drugs:
Atypical Antipsychotic Drugs:Clozapine,Olanzapine, Risperidone, Ziprasidone
Typical Antipsychotic Drugs:Phenothiazines:
Chlorpromazine, Thioridazine ,Trifluperazine, Fluphenazine.Butyrophenones:
Haloperidol Benperidol.Thioxanthenes:
ThiothixeneOthers:
Pimozide Loxapine
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Antipsychotics/Neuroleptics
• The affinities of most older “classical” “Typical” agents for the D2 receptors correlate with their clinical potencies as antipsychotics
Dopamine Synapse
DA
L-DOPA
Tyrosine
Tyrosine
dopamine
receptor
antagonist
D2
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Typical
• 1st generation • Agitation, Acute mania• More extrapyramidal
symptom• Less efficacy • addicitive • Difficulty to discontinue • Slow excret
Atypical
• 2nd generation • Depression, bipolar, mania• Less extrapyramidal
symptom• Efficacy is more• Less addicitive • Easier discontinue • Fast excret (relapse)
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Antipsychotics/Neuroleptics
Presynaptic EffectsBlockade of D2 receptors
Compensatory Effects
Ý Firing rate and activity of nigrostriatal and mesolimbic DA neurons.
Ý DA synthesis, DA metabolism, DA release.
Postsynaptic EffectsDepolarization Blockade
Inactivation of nigrostriatal and mesolimbic DA neurons.
Receptor Supersensitivity
The acute effects of antipsychotics do not explain why their therapeutic effects are not evident until 4-8 weeks of treatment.
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Antipsychotic/Neuroleptics
Chlorpromazine: 1 = 5-HT2 = D2 > D1 > M > 2
Haloperidol: D2 > D1 = D4 > 1 > 5-HT2 >H1>M = 2
Clozapine: D4 = 1 > 5-HT2 = M > D2 = D1 = 2 ; H1
Quetiapine: 5-HT2 = D2 = 1 = 2 ; H1
Risperidone: 5-HT2 >> 1 > H1 > D2 > 2 >> D1
Sertindole: 5-HT2 > D2 = 1
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Thioridazine
• Least incidence of EPS • Low D2 blocking preset central anticholinergic
activity– Interferes male sexual by inhibiting ejaculation – It can cause cardical arry. (Prolong QT interval)– Retinal damage limits long term admnistration
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Trifluperazine, fluphenazine, Haloperidol • High potency drugs and have least α blocking,
anticholinergic , sedative, Cause jaundice,
• Penfluridol: long acting anti psychotic • Pimozidine : Selective D2, long duration, inc QT
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A typical antipsychotics
• Unique receptor profile• Effective against the negative as well as
positive schizophrenia• Lesser liability for inducing Extra pyramidal • Effectiveness in patient refractoru to typical
neuroleptics
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• 5HT2, and D4 high affinity• Besides α1, M1, H1, D2• No singal receptor action best predict
Clozapine 5-HT2 >H1=M1= 1 =D4>D2=D1olanzapine 5-HT2 >H1=M1=D4> 1 =D2=D1Risperidone 5-HT2 > 1 = D2>D4>H1>D1Quetiapine 1 =H1>D2=5-HT2 =M1>D1
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Clozapine: • weak D2 blocking action• 5HT2, α, D4 • Positive and negative schizophrenia • Dyskinesia rare• Reserve drug,(Risk of precipitation of seizures and agranulocytosis)
• Risk of EPS• Risks of intestinal dysfunction, weight gain,
uncontrol BP, hyperlipidemia,
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Risperidone: 5HT2, α, D2• EPS at high dose , less precipitation of seizuresOlanzapine: 5HT2, α, D2, M more action • Anti cholinergic side effects• Can cause seizures, weight gain,• Mania, bipolar disorder Ziprasidone: Inc QT, arrhythmias Quetiapine : Cataract formation , short half life Aripiprazole: partial agonist 5HT1a, D2, antagonist at
5HT2a/. DA, 5HT stabilizer
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PK
• Oral BV vary largely• IM inj 10 fold inc BV• IM Oil depot longer acting • Highly lipophilic• Highly protein binding• Metab cyto p-450
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Non psychotics Uses
• Antiemetics:D2 block in CTZ• Preanaesthetic (Promethazine) Anti H, Anti
Choli, Antiemetic • Huntington’s disease (Haloperidol)
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Antipsychotic/Neuroleptics
Clinical Problems with antipsychotic drugsinclude:
1) Failure to control negative effect2) Significant toxicity
a) Neurological effectsb) Autonomic effectsc) Endocrine effectsd) Cardiac effects
3) Poor Concentration
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Neurological effects
• Acute dystonia- Spasms of muscles of tongue, neck and face (ACh)IM anticholinergic
• Akasthisia – Uncontrolled motor restlessness• Parkinsonism• Neuroleptic Mallignant Syndrome dantrolene, Diazepam
• Rabbit syndrome (perioral tremors)Anti choliner• Tardive dyskinesia
PiperazinesButyrophenones
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Tardive Dyskinesia (TD)
• Repetitive involuntary movements, lips, jaw, and tongue
• Choreiform quick movements of the extremities• As with Parkinson’s, movements stop during
sleep• May get worse when medications
discontinued, No effective treatment
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ADR/Anticholinergic
Some antipsychotics have effects at muscarinic acetylcholine receptors:
• Dry mouth• Blurred vision• Urinary retention• Constipation
ClozapineChlorpromazine
Thioridazine
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ADR/CVS
Some antipsychotics have effects at -aadrenergic receptors:
ChlorpromazineThioridazine
Postural hypotension, Palpitation, Inhibition of ejaculations, Q-T prolongation ( Tiori)Excess cardiovascular mortality Phenothiazine
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ADR/CNS
Drowsiness, Lethargy, confusion (typical) Other side effects are increased appetite Sedation (RAS) Weight gain Aggravation of seizures
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ADR/ Endocrinal
Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration
Galactorrhea in females Males Gynaeocmastia Dec FSH, LH amenorrhoea
Riseridone
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ADR/ Metabolic
Elevation of blood sugar (insulin resistance) Triglyceride levels
Low potency drug high risk
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Antipsychotics/Neuroleptics
• Antipsychotics produce catalepsy (reduce motor activity).– BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.
• Antipsychotics reverse hyperkinetic behaviors (increased locomotion and stereotyped behaviour).
– BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.
• Antipsychotics prevent the dopamine inhibition of prolactin release from pituitary.
– BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
hyperprolactinemia
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• Postural hypotension (α blocking)• Weight again ( except haloperidol)• Retinal damage ( Thioridazine)• Agranulocytosis ( Clozapine)• Cataract formation ( Quetiapine)• Cholestatic jaundice ( Chlorpormazine) • Dryness mouth, blurred vision(max thioridazine )
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THANK Q
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Etiology of Schizophrenia
IdiopathicBiological Correlates1) Genetic Factors2) Neurodevelopmental abnormalities.3) Environmental stressors.