Treatment of psychosis
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TREATMENT OF PSYCHOSIS

TREATMENT OF PSYCHOSIS

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Treatment of psychosis Presentation Transcript

  • 1. DRUG TREATMENT OF PSYCHOSIS
  • 2. Psychiatric illness Psychosis Neurosis OCD Phobia Anxiety PTSD Schizophrenia Mania Depression Bipolar Psychosis: Pt is not aware of illness and refers to treatment Neurosis: Less serious and insight present (Obsessive compulsive disorder, Post traumatic stress disorder)
  • 3. 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
  • 4. • Earlier: termed as major tranquilizers • USA: Antipsychotics • Europe: Neuroleptics (both antipsyo + EPS)
  • 5. 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.
  • 6. 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),
  • 7. • Negative – Poor socialization – Emotional blunting – Introvert behaviour – Lack of motivation – Congnitive deficits (lack of attention and loss of memory)
  • 8. Psychosis Producing Drugs 1) Levodopa 2) CNS stimulants a) Cocaine b) Amphetamines c) Khat, cathinone, methcathinone 3) Apomorphine 4) Phencyclidine
  • 9. 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
  • 10. 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
  • 11. 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 movements II. The Mesolimbic Pathway.: Behaviour III. The Mesocortical Pathway: Behaviour IV. The Tuberoinfundibular Pathway: Prolactin release
  • 12. • 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
  • 13. 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.
  • 14. Dopamine Synapse DA L-DOPA Tyrosine Tyrosine
  • 15. 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.
  • 16. Antipsychotic/Neuroleptics Three major groups : 1. Phenothiazines 2. Thioxanthine 3. Butyrophenones OLDER DRUGS
  • 17. Antipsychotic/Neuroleptics 1) Phenothiazines Chlorpromazine Thioridazine Fluphenazine Trifluopromazine Piperacetazine Perfenazine Mesoridazine Acetophenazine Carphenazine Prochlorperazine Trifluoperazine • Aliphatic Piperidine Piperazine* * Most likely to cause extrapyramidal effects.
  • 18. Antipsychotic/Neuroleptics 2) Thioxanthines Thiothixene Chlorprothixene Closely related to phenothiazines
  • 19. Antipsychotic/Neuroleptics 3) Butyrophenones Haloperidol Droperidol* *Not marketed
  • 20. Atypical Antipsychotic Pimozide Atypical Antipsychoitcs Loxapine Clozapine Olanzapine Quetiapine Indolones Sertindole Ziprasidone Olindone Molindone Risperidone
  • 21. Classification of antipsychotic drugs: Atypical Antipsychotic Drugs: Clozapine, Olanzapine, Risperidone, Ziprasidone Typical Antipsychotic Drugs: Phenothiazines: Chlorpromazine, Thioridazine , Trifluperazine, Fluphenazine. Butyrophenones: Haloperidol Benperidol. Thioxanthenes: Thiothixene Others: Pimozide Loxapine
  • 22. 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
  • 23. 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)
  • 24. Antipsychotics/Neuroleptics Presynaptic Effects Blockade of D2 receptors  Compensatory Effects  Firing rate and activity of nigrostriatal and mesolimbic DA neurons.  DA synthesis, DA metabolism, DA release. Postsynaptic Effects Depolarization 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.
  • 25. 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
  • 26. 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
  • 27. 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
  • 28. 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
  • 29. • 5HT2, and D4 high affinity • Besides α1, M1, H1, D2 • No singal receptor action best predict Clozapine 5-HT2 >H1=M1= 1 =D4>D2=D1 olanzapine 5-HT2 >H1=M1=D4> 1 =D2=D1 Risperidone 5-HT2 > 1 = D2>D4>H1>D1 Quetiapine 1 =H1>D2=5-HT2 =M1>D1
  • 30. 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,
  • 31. Risperidone: 5HT2, α, D2 • EPS at high dose , less precipitation of seizures Olanzapine: 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
  • 32. 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
  • 33. Non psychotics Uses • Antiemetics:D2 block in CTZ • Preanaesthetic (Promethazine) Anti H, Anti Choli, Antiemetic • Huntington’s disease (Haloperidol)
  • 34. Antipsychotic/Neuroleptics Clinical Problems with antipsychotic drugs include: 1) Failure to control negative effect 2) Significant toxicity a) Neurological effects b) Autonomic effects c) Endocrine effects d) Cardiac effects 3) Poor Concentration
  • 35. 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 Piperazines Butyrophenones
  • 36. 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
  • 37. ADR/Anticholinergic  Some antipsychotics have effects at muscarinic acetylcholine receptors: • Dry mouth • Blurred vision • Urinary retention • Constipation Clozapine Chlorpromazine Thioridazine
  • 38. ADR/CVS  Some antipsychotics have effects at - adrenergic receptors: Chlorpromazine Thioridazine Postural hypotension, Palpitation, Inhibition of ejaculations, Q-T prolongation ( Tiori) Excess cardiovascular mortality Phenothiazine
  • 39. ADR/CNS  Drowsiness, Lethargy, confusion (typical)  Other side effects are increased appetite  Sedation (RAS)  Weight gain  Aggravation of seizures
  • 40. ADR/ Endocrinal  Blockade of D2 receptors in lactotrophs in breast increase prolactin concentration  Galactorrhea in females  Males Gynaeocmastia  Dec FSH, LH  amenorrhoea Riseridone
  • 41. ADR/ Metabolic  Elevation of blood sugar (insulin resistance)  Triglyceride levels  Low potency drug high risk
  • 42. 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
  • 43. • 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 )
  • 44. THANK Q
  • 45. Etiology of Schizophrenia Idiopathic Biological Correlates 1) Genetic Factors 2) Neurodevelopmental abnormalities. 3) Environmental stressors.