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Antipsychotics - drdhriti

A compiled Power point presentation on "Antipsychotic drugs" suitable for Undergraduate level medical students and also PG students in the subject of Pharmacology.

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Antipsychotics - drdhriti

  1. 1. Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
  2. 2. • • Drugs having primary effects on Psyche (mind) and – osis (diseased or abnormal condition) – overall the mental process and used for treatment of Psychiatric disorders History of psychopharmacology: – – – – – • • Treatment – to “Dope” 1952 – Chlorpromazine (Reserpine - research) TCA and MAOI – 1957 Benzodiazepines – 1960 1980 onwards – novel drugs The disease - often imprecise, overlap and depends on predominant symptoms – to decide drug therapy types Types of disorders: DSM IV and ICD 10 Psychoses (Disorder of thought, behaviour and to comprehend reality) 2. Affective disorders (Disorder of Mood) 3. Neuroses (less serious) – no loss of comprehending of reality 1.
  3. 3. • • Defn.: These are serious Psychiatric illness with serious distortion of thought, behaviour, capacity to recognize reality and of perception (delusion and hallucinations) - Misperception and misevaluation (Loss of contact with reality - loss of ability to comprehend reality) Classification: 1. 2. Acute and chronic Brain syndromes (cognitive): Delirium and Dementia. Toxic or pathological basis is present - Brain tumor, Drugs etc. Confusion, disorientation and defective memory and disorganized behaviors. Functional disorders: No underlying cause   Schizophrenia (split mind): splitting of perceptions and interpretations from reality – inability to think coherently and auditory hallucinations Paranoid states: Paranoid individuals constantly suspect (persecutory) the motives of those around them, and believe that certain individuals, or people in general, are "out to get them."
  4. 4. – – – Delusion: These are fixed, false beliefs that are outside patient`s culture firmly held. Types – grandeur/persecutory etc. Hallucinations: Abnormal sensations. It is a sensory perception without a source in the external world. May be visual, auditory, olfactory and tactile etc. Illusion: It is a mistaken or false interpretation of a real sensory experience
  5. 5. False Belief Delusion of Persecution
  6. 6. Pic. 1 Pic. 2
  7. 7. Little Voice Inside My Brain.
  8. 8. The real shadow of the hallucinating person transforms into the corporal image.
  9. 9.  Disorders of Mood  Mania: elation or irritable mood, reduced sleep, hyperactivity, uncontrollable thought and speech. Associated with violent behaviour  Depression: sadness, loss of interest and pleasure, worthlessness, guilt, physical and mental slowing, self-destructive ideation   Bipolar Unipolar
  10. 10.  Less severe and ability to comprehend reality is not lost: (mild disorder - anxiety, depression, or hypochondria) Anxiety – unpleasant emotional state - concern for future 2. Phobic states – fear of specific persons/objects/situations 3. Obsessive-compulsive – limited abnormality of thoughts and behaviour, but recurrent intrusive thoughts or ritual like behaviour 4. Reactive depression – physical illness/loss 5. Post-traumatic stress disorder – war, riots, earthquakes and tsunami 6. Hysterical (Neurotransmitters of mental Illness: Dopaminergic and NA and 5-HT) 1.
  11. 11. 1. Phenothiazines (S(C6H4)2NH.) :    1. Butyrophenones:  1. 2. 3. Aliphatic side chains: Chlorpromazine (CPZ), Triflupromazine Piperidine side chain: Thioridazine and Mesoridazine Piperazine side chain: Trifluoperazine, Fluphenazine and Perphenazine Haloperidol, Trifluperidol Thioxanthenes: Flupenthixol Other heterocyclics: Pimozide, Loxapine, Clozapine Atypical antipsychotics: Risperidone, Olanzapine, Quetiapine, Aripiprazole and Ziprasidone  chondrium
  12. 12. • Tricyclic structure – 2 Benzene rings are linked by a sulfur and a nitrogen atom • Nature of substitute at position 10 influences pharmacological activity • Divided into 3 groups on the basis of substitution at position 10
  13. 13.    Effect of CPZ and Reserpine on laboratory animals and psychiatric patients Differ in Normal and psychotic individuals In Normal: (Neuroleptic syndrome)  Effects are appreciated as neutral or unpleasant (different from typical Barbiturate action)  Indifference to surroundings, paucity of thoughts, psychomotor slowing, emotional quietening, and tendency to go off to sleep (easily aroused)  Minimized spontaneous movements, but no ataxia or slurring of speech
  14. 14.  In psychotics:  Typical Psychotic patients – less agitated, more communicative and responsive  Aggressive and impulsive behaviour diminishes  Over a period of days – hallucinations/delusions and others come to normal  Neuroleptics – emotional quietening with neurological effects – tremor, rigidity, bradykinesia etc.  Ataxia and dysarthria do not develope in normal doses  Tranquilizers – major and minor (!)
  15. 15.  All phenothiazines, Butyrophenones and Thioxanthenes have same antipsychotic efficacy – but potency differs in equieffective doses  1. Antipsychotic effects: Low potency – more sedation      1. 2. 3. 4. Low potency (Aliphatic and piperidines) and high potency (others) Prompt sedative action (tolerance develops) Antipsychotic effects take weeks to develop, but no tolerance Valuable in early treatment - added value in agitated psychotic patients But, not used as anxiolytic or sedative Performance and intelligence are unaffected relatively, but impaired vigilance – high potency drugs Extrapyramidal effects: More with high potency drugs (less in thioridazone and atypical ones) Lowers seizure threshold – low potency drugs (piperazines - lower propensity) Loss of temperature control: High doses – Poikilothermic, medullary and other vital centres Antiemetic action – all except thioridazine
  16. 16. Drugs Sedative Extrapyramidal Hypotensive Aliphatic side chain +++ ++ +++ Piperidine +++ + +++ Piperazine + +++ + Haloperidol + +++ + • Low Potency: Fewer EPS H1, α1, and muscarinic • High Potency: Higher EPS but lower H1, α1, and muscarinic
  17. 17.  Behavioural Effects:  Conditioned avoidance response inhibited (Remember, what is it ??)
  18. 18.  Dopamine Hypothesis: Dopamine theory of schizophrenia       Over activity of DA in limbic area Drugs which increase dopaminergic activity (amphetamines, levodopa and bromocriptine etc.) – induce or exacerbate schizophrenia Density of Dopamine receptors in post mortem of untreated – increased PET in treated and untreated – untreated increased Homovanillic acid (HMV) – changed in treated patients in CSF and urine Most antipsychotics block postsynaptic D2 receptors in CNS except clozapine like atypical ones      Site of action being limbic system and mesocortical areas But, initial rise in firing of DA neurones and DA activity increases initially Followed by tolerance to increased activity of DA in Basal ganglia – Parkinson like effect But, no such effect in limbic area - continued blockade Hypothesis - Not complete, several atypical ones do not interact with D2 – other receptors - serotonin
  19. 19.  ANS: α-blocking activity  CPZ = Tflprmzn > thioridazine > clozapine > fluphenazine > haloperidol  More potent compounds – lesser alpha-blocking property - weak anticholinergic property  Additionally, Phenothiazines - Weak H1 and anti5HT property α-blocking, anticholinergic, weak H1 and anti-5HT  Local anaesthetic action  Skeletal muscle – no prominent action, spinal reflexes are not affected  Reduce action) certain types of spasticity (Basal ganglia
  20. 20. Drugs CPZ Receptors blocked α1, D2 and H1 Haloperidol, Fluphenazine D2 only and Thioxanthenes Promethazine D2 and H1 Clozapine, Risperidone Serotonin
  21. 21.  CVS: Postural hypotension –  By central and peripheral action  Almost equal to α-blocking drugs  Less prominent in psychotics  Endocrine: Increase in release of prolactin – galactorrhoea and Gynaecomastia  Reduction in gonadotropin secretion  ACTH release in response to stress decreased  GH release reduced  Decreased ADH release
  22. 22.         Absorbed orally, but unpredictable and parenterally better Bioavailability low – enterohepatic circulation Long biological half life Bound to plasma protein and tisue protein - Large Vd – 20 L/kg (higher CNS entry than plasma) Metabolized by liver by hydroxylation Cumulation action – once a day dose maintenance Excreted in urine and Bile (6 to 12 months) Available as tablets 10, 25, 50 and 100 mg tabs, Syr. and injections
  23. 23. 1. CNS:     1. 1. Drowsiness, lethargy and mental confusion Increased appetite and weight gain Aggravation of seizures Postural hypotension, palpitation, inhibition of ejaculation – more with thioridazine and low potency drugs CVS: Anticholinergic:   1. Dry mouth, constipation, blurring of vision and urinary hesitancy - more common with thioridazone Hypersalivation - clozapine Endocrine: Hyperprolactinemia. Lowers Gn hormones but infertility, amenorrhea and gynaecomastia is uncommon
  24. 24. 5. Extrapyramidal disturbances: Parkinsonism – rigidity, tremor, hypokinesia (1-4 wks)    Acute muscular dystonia (acute onset) – grimacing, tongue thrusting, torticollis and locked jaw etc. – initial therapy – resolve spontaneously Akathisia (1-8 weeks): 20% cases- restlessness, agitation, compulsive desire to move about      Dose reduction or anticholinergics rabbit syndrome – years after therapy Anticholinergics/Propranolol - stoppage Tardive dyskinesia: constant chewing, pouting, lip licking etc. – accenuated by anticholinergics – uncommon with newer ones Malignant neuroleptic syndrome – Rare, high doses of potent agents – rigidity, tremor, immobility, semiconsciousness, fluctuation in BP and Myoglobinemia – must stop, Dantrolene 6. Weight gain: risk of diabetes worsening – clozapine, less with Haloperidol. Blue pigmentation of exposed skin, lenticular opacities and degeneration
  25. 25. 7. Hypersensitivity reactions:  Cholestatic jaundice – common with CPZ  Skin rash, urticaria, photosensitivity etc.  Agrannulocytosis – clozapine  Myocarditis - clozapine
  26. 26. Triflupromazine: More potent than CPZ, used mainly as antiemetic 1.  Thioridazone: Marked Anticholinergic action, but less EPS 1.  1. causes muscle dystonia in children cardiac arrhythmia and sexual function retardation Trifluoperazine and fluphenazine: High potency, less sedation, more EPS effect
  27. 27.          Butyrophenone derivative, Potent antipsychotic Strong D2 blocker Preferred in acute schizophrenia in highly agitated patients Less autonomic effects, no weight gain and less epiletogenic Marked EP effects to produce parkinsonism Irreversible toxic encephalopathy – used along with lithium Orally 1.5 mg to 7.5 mg and 2 – 10 mg IV and repeated every Hrly upto 30 mg Available as 0.5 mg, 1.5 mg and 5 mg tablets E1/2 is 24 hrs
  28. 28. • Better control of positive symptoms than negative symptoms  Positive scale        Delusions Conceptual disorganization Hallucinations Hyperactivity Grandiosity Suspiciousness/persecution Hostility Relieved by Antipsychotics  Negative scale        Blunted affect Emotional withdrawal Poor rapport Passive/apathetic social withdrawals Difficulty in abstract thinking Lack of spontaneity and flow of conversation Stereotyped thinking Less Relieved by Antipsychotics
  29. 29.    Cognitive, affective and Motor disturbances – relieved overall Little improvement in judgment, memory and orientation Some patients do not respond (90% responds) Only symptomatic relieve, does not remove the cause – lifelong treatment may require  Choices of Drugs: Patient dependent, empirical and guided by presenting symptoms  Individual patients differ in response to different drugs
  30. 30. Symptoms Agitated and violent Drugs CPZ, Thioridazine and Haloperidol Withdrawn and apathetic Trifloperazine and Fluphenazine Negative symptoms Clozapine and olanzapine, risperidone and aripiprazole Mood elevation Haloperidol, fluphenazine and olanzepine
  31. 31.   Mania: CPZ or Haloperidol – IM or IV Organic Brain Syndromes:  Not very effective, used as short term therapy  Acute cases to control aggression  As adjunct to nonsedatives to control exacerbations of violent behaviour  TCAs in depressed ones   Antiemetic and anti-anxiety Other Uses: Potentiation of anaesthetics, Intractable Hiccough, Tetanus and Alcoholic hallucinations
  32. 32.  Pharmacological actions, Mechanism of action and Adverse effects of CPZ /Haloperidol