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Psychosis and Anti-psychotic Drugs

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  1. 1. Chetan Rastogi M.Pharm 1st Year Pharmacology 1
  2. 2. Psychosis Psychosis refers to a variety of mental disorders characterized by one or more of the following symptoms: diminished and distorted capacity to process information and draw logical conclusions.  hallucinations, delusions, marked loosening of associations. disorganized behavior, and aggression or violence. 2
  3. 3. Psychosis Psychosis: Psychosis can be broadly Categorized in to 2 groups: 1 ORGANIC 2 FUNCTIONAL 3
  4. 4. 1. Acute and chronic organic brain syndromes (cognitive disorders) such as, Delirium and dementia, prominent features of confusion, disorientation, defective memory and disorganized behavior. 2. Functional disorders such as, memory and orientation mostly retained by emotion, thought, reasoning and behavior are altered. 3. Schizophrenia (split mind) i.e. splitting of perception and interpretation from reality- hallucination, inability to think coherently. Schizophrenia is often described in terms of positive or negative (deficit) symptoms.. 4. Paranoid state i.e. fixed delusions (false beliefs) and loss of insight in to abnormality. 4
  5. 5. Schizophrenia It is a thought disorder. The disorder is characterized by a divorcement from reality in the mind of the person (psychosis). It may involved visual and auditory hallucinations, delusions, intense suspicion, feelings of persecution or control by external forces (paranoia), depersonalization, and there is attachment of excessive personal significance to daily events, called “ideas of reference”. 5
  6. 6. Schizophrenia Positive Symptoms Hallucinations, delusions, paranoia, ideas of reference. Negative Symptoms Apathy, social withdrawal, anhedonia, emotional blunting, Poor speech –Cognitive impairment , extreme inattentiveness or lack of motivation to interact with the environment. These symptoms are progressive and non-responsive to medication . 6
  7. 7. Psychosis Producing Drugs 1) Levodopa 2) CNS stimulants a) Cocaine b) Amphetamines c) Khat, cathinone, methcathinone 3) Apomorphine 4) Phencyclidine 7
  8. 8. Dopamine Theory of Schizophrenia Dopamine Correlates: • Antipsychotics reduce dopamine synaptic activity. • These drugs produce Parkinson-like symptoms. • Drugs that increase DA in the limbic system cause psychosis. • Drugs that reduce DA in the limbic system (postsynaptic D2 antagonists) reduce psychosis. • Increased DA receptor density (Post-mortem, PET). • Changes in amount of homovanillic acid (HVA), a DA metabolite, in plasma, urine, and CSF. 8
  9. 9. Dopamine Theory of Schizophrenia Evidence against the hypothesis Antipsychotics are only partially effective in most (70%) and ineffective for some patients. Phencyclidine, an NMDA receptor antagonist, produces more schizophrenia-like symptoms in non-schizophrenic subjects than DA agonists. Atypical antipsychotics have low affinity for D2 receptors. Focus is broader now and research is geared to produce drugs with less extrapyramidal effects. 9
  10. 10. Dopamine System There are four major pathways for the dopaminergic system in the brain: The Nigro-Stiatal Pathway. II. The Mesolimbic Pathway. III. The Mesocortical Pathway. IV. The Tuberoinfundibular Pathway. I. 10
  11. 11. 11
  12. 12. Catecholamines Tyrosine ⇓ Tyrosine hydroxylase L-Dopa ⇓ Dopa decarboxylase Dopamine (DA) ⇓ Dopamine β hydroxylase Norepinephrine (NE) (Noradrenaline) Phenylethanolamine⇓ -N-methyltransferase Epinephrine (EPI) (Adrenaline) 12
  13. 13. Tyrosine L-DOPA DA Dopamine Synapse
  14. 14. Dopamine System DOPAMINE RECEPTORS There are at least five subtypes of receptors: Receptor D1 D2 D3 D4 D5 14
  15. 15. 15
  16. 16. Dopamine System DOPAMINE RECEPTORS      Receptor D1 D2 D3 D4 D5 2o Messenger System ⇑cAMP ⇓cAMP,⇑K+ ch.,⇓Ca2+ch. ⇓cAMP,⇑K+ ch.,⇑Ca2+ch. ⇓cAMP ⇑cAMP 16
  17. 17. Dopamine Reuptake System 17
  18. 18. ANTIPSYCHOTICS Antipsychotic drugs are also known as Neuroleptics, Ataractic, Major Tranquilizer and AntiSchizophrenic drugs. A first generation of antipsychotics, known as Typical antipsychotics, was discovered in the 1950s. Most of the drugs in the second generation, known as Atypical antipsychotics, have been developed more recently. 18
  19. 19. CLASSIFICATION A. Typical Antipsychotics: (traditional/older) 1. Phenothiazines: a. Aliphatic side chain: Chlorpromazine, Triflupromazine b. Piperidine side chain: Thioridazine c. Piperazine side chain: Trifluoperazine, perphenazine Fluphenazine 2. Butyrophenones: Haloperidol, Trifluperidol, Penfluridol, droperidol, domperidone 19
  20. 20. 3. Thioxanthenes: Flupenthixol 4. Other heterocyclics: Pimozide, Loxapine, molindone, sulpiride, amisulpiride, penfluridol, Remoxipride, metoclopramide B. Atypical/newer antipsychotics: Clozapine, Risperidone, Olanzapine, Quetiapine, Aripiprazole, Ziprasidone, paloparidone 20
  21. 21. Low potency Chlorpromazin e Thioridazine Thiothixene High potency Haloperidol, Fluphenazine,Trifl uoperazine,Perph ennazine, Pimozide Extrapyramidal Extrapyramidalsymptoms MORE, LESS AntiCh LESS NEWER Clozapine Olanzapine Quetiapine Aripiprazole Risperidone Ziprasidone 21
  22. 22. Traditional ⇓ Vs. Atypical ⇓ Mainly DA DA and 5HT Mainly D2 D2+D4+5HT Treat mostly POSITIVE Treat POSITIVE and symptoms More adverse effects Less useful in refractory disease NEGATIVE symptoms Lesser adverse effects Useful in refractory disease 22
  23. 23. Mechanism of Action: -Antipsychotic blocks D₂ receptors in the brain's Dopaminergic pathway. -Some also block or partially block serotonin receptors (particularly 5HT2A, C and 5HT1A receptors) -But antipsychotic drugs can also block wide range of receptor targets. 24
  24. 24. In the Mesolimbic- Mesocortical and Nigrostriatal pathway Antipsychotic blocks: 25
  25. 25. In the Tuberoinfundibular pathway Antipsychotics block: Dopamine released at this site regulates the secretion of prolactin from anterior the pituitary gland. Antipsychotics blocks D₂ receptor at this site. 26
  26. 26. Antipsychotic blocks D₂ receptors Some also block or partially block serotonin receptors 27
  27. 27. Pharmacology of Antipsychotics: Typical Antipsychotics Phenothiazine Absorption Concentration Metabolism Vd Dose Chlorpromazine (CPZ) More Highly bound to consistent plasma and tissue effect in IV and protein IM administration Metabolized in liver by CYP2D6 enzyme Large 20 L/kg Acute single dose lasts 6-8 hours t⅟₂ is 18-30 hrs Triflupromazine More potent than CPZ -- -- -- Thioridazine Low potency with anticholinergic action -- -- -- Trifluoperazine, Fluphenazine High potency with Autonomic action -- -- -- Depot IM inj every 2-4 weeks (25 mg/ml ) 28
  28. 28. Butyrophenones Potency t⅟ ₂ Haloperidol Potent antipsychotic Produces few autonomic effects 24 hours. Trifluperidol Similar to Haloperidol but slightly more potent -- Penfluridol Exceptional long acting neuroleptic, used for chronic Schizophrenia, affective withdrawl and social maladjustment -- Dose -- -- 20-60 mg , once weekly 29
  29. 29. Thioxanthenes Flupenthixol Less sedative than CPZ, indicated for Schizophrenia and other Psychoses. t⅟ ₂ Other heterocyclics Pimozide Specific DA antagonist with little adrenergic or cholinergic blocking activity. Used in Gilles de la Tourett’s syndrome and ticks. Long Duration of action. 48-60 hrs. (after single dose) 30
  30. 30. Atypical Antisychotic drugs These are newer 2nd Generation antipsychotics that have weak D₂ receptor blocking but potent 5-HT₂ antagonistic activity. They May improve the impaired Cognitive function in psychotics. 31
  31. 31. Atypical Clozapine Blocking activity A very potent antipsychotic D₂, D₄, 5HT₂, α receptors Combination of D₂+5HT₂ , High affinity for α₁, α₂ and H₁ receptors Metabolism (Enzyme) By CYP3A4 Risperidone -- Olanzapine Potent antipsychotic Broader spectrum of efficacy Monoaminergic (D₂, 5HT₂, α₁, α₂) as well as muscarinic and H₁ receptors By CYP1A2 and Glucuronyl transferase Quetiapine New short- acting antipsychotic 5HT₁А, 5HT₂, D₂, α₁, α₂ and H₁ receptor By CYP3A4 Aripiprazole Unique antipsychotic which is partial agonist at D₂ and 5HT₁А 5HT₂ Ziprasidone Latest antipsychotic , moderately potent inhibitor. Combination D₂+5HT₂A/₂C +H₁ + α₁, Na reuptake -- By CYP2D6 and CYP3A4 -- t⅟ ₂ and Dose t⅟₂ - 12 hours Dose - Low dose <6 mg/day t⅟₂ 24-30 hours -- t⅟₂ - 3days t⅟₂ - 8 hours 32
  32. 32. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS Anticholinergic (antimuscarinic) side effects: Dry mouth, blurred vision, tachycardia, constipation, urinary retention, impotence 33
  33. 33. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS Antiadrenergic (Alpha-1) side effects: Orthostatic hypotension w/ reflex tachycardia sedation 34
  34. 34. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS Antihistamine effect: sedation, weight gain 35
  36. 36. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Increased prolactin secretion (common with all; from dopamine blockade) Weight gain (common, antihistamine effect?) Photosensitivity (v. common w/ phenothiazines) Lowered seizure threshold (common with all) Leucopenia , agranulocytosis (rare; w/ phenothiazines) Retinal pigmentopathy (rare; w/ phenothiazines) 37
  37. 37. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Chlorpromazine and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine). Haloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked. 38
  38. 38. MANAGEMENT OF EPS Dystonia and parkinsonism: anticholinergic antiparkinson drugs Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive Akathisia: benzodiazepines, propranolol Tardive dyskinesia: increase neuroleptic dose; switch to clozapine 39
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