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Pharmacotherapy of antipsychotics

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Antipsychotics with focus on atypical antipsychotic drugs.

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Pharmacotherapy of antipsychotics

  1. 1. ANTIPSYCHOTICS Dr. Manjeeta Gupta Department of Pharmacology MIMER Medical College 6/30/2014 1
  2. 2. Psychotic disorders (psychosis):  Severe psychiatric illness with distortion of thought and perception.  Classification of psychotic disorders:  Schizophrenia  Schizoaffective disorder – disorder of both thought and mood  Delusional disorder – includes paranoid psychosis  Substance-induced psychotic disorder – use/withdrawal of amphetamines, cocaine, alcohol, LSD  Cognitive disorder — organic brain syndrome
  3. 3. Schizophrenia Split mind – Highly disabling Chronic (relapsing & remitting) disorder of thought – Characterised by acute psychotic episodes • Typical feature – loss of touch with reality & selective attention deficit • Prevalence – 1% of population • Risk: 10% →1st degree relatives 10% → Dizygotic twins 50% → Monozygotic twins • Onset in adolescence/early adulthood
  4. 4. Schizophrenia —Split mind —Highly disabling chronic (relapsing and remitting) disorder of thought —Characterised by acute psychotic episodes • Typical feature – loss of touch with reality & selective attention deficit. • Prevalence – 1% of population • Risk — 10% in 1st degree relatives 10% in Dizygotic twins 50% in Monozygotic twins • Onset in adolescence/early adulthood
  5. 5. Etiology – unclear Genetic: No single schizophrenia gene Neuregulin – 1 (NRG – 1 mis-sense mutation) Dsybindin DISC-1 DAAO activator (G72) Environmental: Aberrant intrauterine brain development (infections, hypoxia?) – Cannabis consumption in adolescence 6/30/2014 5
  6. 6. Dysbindin (??, located pre and post synaptically, glutamate neurotransmission?) COMT (catechol-o-methyl transferase) Neuregulin1 (transmembrane protein many isoforms) Disc1 (neuronal migration, maturation, neurite outgrowth) 6/30/2014 6
  7. 7. Positive Symptoms Hallucinations Delusions Disorganized Thought Catatonia Negative Symptoms Blunted emotions Anhedonia Social withdrawal Cognition Attention Memory Mood Symptoms Loss of motivation Loss of insight Demoralization Suicide Schizophrenia - symptoms FUNCTION
  8. 8.  Hydrotherapy: “The pouring of cold water in a stream, from a height of at least four feet onto the forehead, is one of the most certain means of subsiding violent, maniacal excitement”... wrote an anonymous physician in the early 1800’s.  Dr Egas Moniz – Prefrontal lobectomy  In 1947, French surgeon Laborit discovered Promethazine used as anti-histaminic, had a calming effect on patients  In 1953, Delay & Denikar used Laborit’s observation to modify Promethazine structure into first effective anti- psychotic medication, Chloropromazine  In-patients at Mental Hospitals dropped by 1/3rd. 6/30/2014 8 History
  9. 9. Impact of Antipsychotics
  10. 10. Dopamine Hypothesis  Repeated administration amphetamine, induces psychosis resembling positive symptoms of schizophrenia  Carlson (1963) first proposed that drugs such as chlorpromazine & haloperidol alleviate schizophrenic symptoms by blocking DA receptors & thereby ↓ DA function  These antipsychotic medications, have been the main stay for treatment for nearly 50 years, have in common their ability to block D2 receptors.
  11. 11. 6/30/2014 12  ↑ DA receptor density (Post-mortem, PET)  ↑ Homovanillic acid (HVA) in plasma, urine & CSF 1.Mesolimbic – ↑ activity of D2 receptor → Positive symptoms 2.Mesocortical – ↓ activity of D1 receptors → Negative symptoms
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  14. 14. Dopamine tract Innervation Function D-antagonist effects Mesolimbic Limbic areas, Nucleus accumbens Arousal, memory, stimulus processing, behavior, spontaneity, motivation, assertively, self-confidence Psychosis relief Mesocortical Cortex – frontal and prefrontal Communication, cognition, social functions and stress response Psychosis relief Nigrostriatal Caudate nucleus, Putamen Extrapyramidal system and movement coordination Movement disorders Tubero infundibular Pituitary gland Prolactin secretion regulation Hyperprolactineamia, galactorhea, gynecomastia Dopaminergic systems in CNS
  15. 15. Serotonin Hypothesis  Correlation between DA affinity & antipsychotic efficacy has become weaker as a result of recently developed atypical antipsychotic medications that also show substantial affinity for 5HT2 receptors  The role of 5-HT in schizophrenia is based on the findings of LSD a central 5-HT agonist , produces hallucinations and sensory disturbances similar to psychosis.  Atypical neuroleptics like clozapine and olanzapine are potent 5-HT2A agonists.
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  18. 18. Glutamate Hypothesis  Preclinical as well as clinical studies provide evidence of hypofunction of NMDA receptors as a primary, or at least, a contributory process in the pathophysiology of schizophrenia  Several clinical trials with agents that act at the glycine modulatory site on the NMDA receptor have revealed consistent reductions in negative symptoms and variable effects of cognitive and positive symptoms  These studies also provide evidence that suggests the effects of clozapine on negative symptoms and cognition may be through activation of the glycine modulatory site on the NMDA receptor.
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  20. 20. Classification Typical /Classical Antipsychotics 1. Phenothiazines Aliphatic side chain: Chlopromazine, Triflupromazine Piperidine side chain: Thioridazine Piperazine side chain: Trifluoperazine, Fluphenazine 2. Butyrophenones: Haloperidol, Trifluperidol Penfluridol 3. Thioxanthenes: Flupenthixol 4. Other heterocyclics: Pimozide, Loxapine 6/30/2014 21 Low potency
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  22. 22. Chlopromazine  Prototype drug  Has D1 + D2 + α1, + H1 + 5-HT2A receptors blocking property  Potent local anaesthetic (irritant action)  Only helpful for positive symptoms  Highly plasma & tissue bound  Variable t1/2 - 18-30 hrs  Cumulative effect seen (OD maintenance dose)  Metabolised by CYP2D6 6/30/2014 23
  23. 23.  S/E: Marked EPS, Sedation, postural hypotension, reflex tachycardia, ↑ prolactin release, ↓ GH, ADH, ACTH & gonadotropins secretion  Lowers seizure threshold  Mild obstructive jaundice can occur, reversible on stopping treatment  Urticarial skin reactions are common but usually mild  Excessive sensitivity to ultraviolet light may also occur  Weight gain, impaired glucose tolerance, ↑serum TGs & QTc prolongation also seen  Tolerance develops to sedation & hypotension  Dose: 100-800 mg oral 6/30/2014 24
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  26. 26. Triflupromazine • Aliphatic side chain phenothiazine • More potent than CPZ • Use: Antiemetic • S/E: acute muscle dystonia in children • Dose: 50-200 mg oral 6/30/2014 27
  27. 27. Thioridazine • Low potency phenothiazine • Marked central anticholinergic action • Lowest incidence of EPS • S/E: Cardiac arrythmias, sexual dysfunction • Dose: 100-400 mg oral 6/30/2014 28
  28. 28. Trifluoperazine Fluphenazine • High potency piperzine side chain phenothiazine • Minimum autonomic actions • Marked EPS • Dose: 2-20 mg oral(Trifluoperazine) 1-10 mg oral(Fluphenazine)  Fluphanazine decanoate → given as depot intramuscular injection → ↑ compliance 6/30/2014 29
  29. 29. Haloperidol • Potent antipsychotic • Marked EPS • Fewer autonomic effects, Less epileptogenic • Does not cause weight gain • Uses: Acute schizophrenia Huntington’s disease Gilles de la tourette’s syndrome • Metabolised by CYP3A4 & CYP2D6 • Dose: 2-20 mg oral 6/30/2014 30
  30. 30. Trifluperidol • More potent than haloperidol • Similar actions • Dose: 1-8 mg oral 6/30/2014 31
  31. 31. Penfluridol • Long acting neuroleptic • Uses: Chronic schizophrenia Affective withdrawal Social maladjustment Dose: 20-60 mg oral 6/30/2014 32
  32. 32. Flupenthixol • Marked EPS • Infrequently used now a days • Uses: Schizophrenia with other psychosis • Dose: 3-15 mg oral 6/30/2014 33
  33. 33. Pimozide • Selective DA antagonist • Little α or cholinergic blocking action • Long t1/2 - 48-60 hrs • Uses: Maintenance therapy Gilles de la tourette’s syndrome Ticks • S/E: Arrythmias • Dose: 2-6 mg oral 6/30/2014 34
  34. 34. Loxapine • Dibenzoxapine derivative • MOA similar to CPZ • Rapid & short acting • Dose: 20-50 mg oral 6/30/2014 35
  35. 35. ARRIVAL OF ATYPICAL ANTIPSYCHOTIC • “German psychiatrists in the early 1960s opposed the theory that EPS and antipsychotic efficacy were linked. Their work led to introduction of Clozapine, an antipsychotic with no EPS.” • Clozapine was briefly marketed and quickly withdrawn for two reasons: – The embarrassment of not having any EPS, and – Agranulocytosis 6/30/2014 36
  36. 36. Atypical antipsychotics MARTA (multi acting receptor targeted agents) • Clozapine, Olanzapine, Quetiapine SDA (serotonin-dopamine antagonists) • Risperidone, Ziprasidone, Paliperidone, Lurasidone, sertindole Selective D2/D3 antagonists • Sulpiride, Amisulpiride Other newer drugs • Aripiprazole, Zotepine, Asenapine
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  38. 38. CLOZAPINE (1989) • 1st Atypical antipsychotic • Selectively blocks D4 receptors & has weak D2 blocking property • Also blocks α1 + α2 receptors & more strongly blocks 5-HT2 receptors in cortex • In addition has significant H1 blocking property • Useful for positive and negative symptoms and refractory cases • t1/2 -12 hrs • In 2002 FDA approved this drug for reducing suicidal risk in schizophrenia. • Used as RESERVE DRUG in RESISTANT SCHIZOPHRENIA
  39. 39. Side effects • Least extrapyramidal side effects • Major limitation is Agranulocytosis in 1-2 % • MC in 6th – 18th week of therapy • Risk ↑ when co-administered with carbamazepine, reversible on stopping drug (CYP3A4) • Orthostatic hypotension, sedation, weight gain, ↑ heart rate, paradoxical hypersalivation & ↑ risk for seizures (2-3%)
  40. 40. • Precipitates Diabetes, Myocarditis, urinary incontinence • Metabolised by CYP1A2, CYP2C19 & CYP3A4 • Interactions with SSRIs and valproic acid ↑ Clozapine levels • Dose: 100-300 mg oral
  41. 41. OLANZAPINE (1996) • Similar to clozapine ( blocks almost all receptors) • Broad spectrum efficacy covering Schizo-affective disorders & Mania • Also used in children with developmental CNS disorders & Tourette’s syndrome • t1/2 : 24 – 30 hrs • Lesser EPS • Metabolised by CYP1A2 & glucuronyl transferase • Dose related lowering of seizure threshold • Avoid in elderly with Hypertension → risk of CVA
  42. 42. •Weight gain – MC side effect. •↑ in glycosalated Hb, total cholesterol & triglycerides • No agranulocytosis reported •Dose: 2.5-20 mg oral •Resperidone & Olanzapine → useful in calming agitated or aggressive patients with dementia
  43. 43. RISPERIDONE (1994) • Blocks selective D2 + 5-HT2 + α1+ α2 + H1 receptors • Effective for positive & negative symptoms (controversial) • Extrapyramidal side effects low (can occur at high doses) • Uses: Schizophrenia (including adolescent schizophrenia) Schizoaffective disorder Mixed & manic states associated with bipolar disorder Irritability in people with autism
  44. 44. Side effects : sedation, weight gain, ↑ BP, orthostatic hypotension. •↑ prolactin levels •May cause anxiety/agitation & ↑ risk of stroke in elderly •Dose: 2-8 mg oral •Can be given as depot IM (for chronic cases)
  45. 45. QUETIAPINE (1997) • Less potent than risperidone • Given BD due to short half life – 6hrs • Blocks 5HT1A + 5HT2 + D2 + α1 + α2 + H1 receptors in brain • Minimal EPS & ↑ prolactin levels • Metabolised by CYP3A4 • Not useful for negative symptoms • Used in Acute mania/Bipolar disorder (maintenance therapy) • Dose: 50- 400 mg oral
  46. 46. • S/E: sedation, orthostatic hypotension, weight gain, cataract formation, priapism , hyperventilation, hyperglycemia, peripheral oedema. • Anticholinergic side effects (like older drugs & Clozapine) • Urinary incontinence & QTc prolongation can also occur
  47. 47. ZIPRASIDONE • Combined D2 + 5-HT 2A/2C + H1+ α1 blocking property • Also antagonist at 5HT1D & agonist at 5HT1A • In addition has anxiolytic & antidepressant properties(inhibit NA & 5HT reuptake) • T1/2 - 8 hrs, BD dosing • Efficacy rated equivalent to Haloperidol • Uses: Schizophrenia Mania • Dose: 40- 160 mg oral • Parental forms available
  48. 48. • Less weight gain & ↑ blood sugar • Less EPS & hyperprolactinaemia • Nausea & vomiting MC side effects • Dose related QTc prolongation → Cardiac Arrythmias.
  49. 49. PALIPERIDONE • Also known as 9-hydroxyrisperidone • DA antagonist • Given orally or as Depot preparation (IM) • Uses: Mania Maintenance for bipolar disorder (at low dose) Schizophrenia Schizoaffective disorder
  50. 50. • Primary active metabolite of risperidone • MOA - unknown • Antagonist effect at α1 & α2 adrenergic + H1receptors • Also binds with DA & 5HT receptors • Like risperidone, its possible use is in people with Autism and Asperger syndrome • S/E: Restlessness, EPS including involuntary movements, tremors & muscle stiffness • Not approved for treatment of dementia-related psychosis due to ↑ death rate
  51. 51. SERTINDOLE (1995) • Initially there were some poorly supported arguments about improved negative symptom reduction • Low risk for EPS, no sedation & very mild prolactin elevation (major advantages) • S/E: rhinitis, ↓ ejaculatory volume, orthostatic hypotension, tachycardia & weight gain • Concern about sudden cardiac death due to cardiac arrhythmia led to its voluntary removal in 1998
  52. 52. SULPIRIDE •Lesser EPS , sedation & autonomic S/E than haloperidol • S/E: Gynaecomastia (↑ prolactin) • Dose : 400- 800mg oral
  53. 53. 6/30/2014 54 AMISULPRIDE • Congener of sulpiride • High affinity for D2 + D3 & low affinity for 5HT2 receptors • Long & better acting, safer • Less EPS • Less sedation & weight gain • Hyperprolactinemia similar to typical neuroleptics • QTc prolongation seen • t1/2 - 12 hrs •Dose : 200- 400mg oral
  54. 54. Aripiprazole • Partial agonist at D2 & 5HT1A, antagonist at 5HT2 receptors • Longest half life – 3 days !! • Metabolised by CYP3A4 & CYP2D6 •Dose needs to be halved in patients on ketoconazole/quinidine & doubled with carbamazepine • Frequent S/E: nausea, dyspepsia, constipation & light headedness • Weight gain, ↑ BP, prolongation of QTc interval • Uses: Schizophrenia Mania & Bipolar illness Dose : 10-15mg once daily (max: 30mg /day)
  55. 55. Zotepine • Has D2 + D1 + 5HT2 + α1 + H1 receptor blocking property • Also inhibits NA reuptake • Useful for both positive & negative symptoms • Less EPS, least sedation • t1/2 -14 hrs • Use: Schizophrenia • Dose: 25-100 mg oral • S/E: Weakness, headache & postural hypotension • Also hyperprolactinemia, weight gain, cardiac arrythmia, hyperglycemia, lowers seizure threshold, dyslipidemia
  56. 56. ASENAPINE • Given sublingually BD (5-10mg) • S/E: Sedation, oral hypoesthesia, postural hypotension, NMS 6/30/2014 57
  57. 57. HaloperidolHaloperidol ClozapineClozapine RisperidoneRisperidone OlanzapineOlanzapine QuetiapineQuetiapine ZiprasidoneZiprasidone 5HT2A D2 D1 Alpha 1 Musc H1 5HT1A (agonist) Casey 1994Casey 1994 Atypical Antipsychotics In Vivo Binding Affinities
  58. 58. Schizophrenia Schizoaffective disorders Acute control of mania Gilles de la Tourette’s syndrome Autism & Asperger’s syndrome Huntington’s chorea Intractable hiccups Indications for antipsychotics
  59. 59. ANTIPSYCHOTIC DRUG - SCREENING METHODS IN VITRO AND EX VIVO MODELS H Prazosin Competition Binding for alpha 1 adrenoceptors IN VIVO MODELS Catelepsy in Rodents Inhibition of Amphetamine induced Stereotypy in Rats Inhibition of Apomorphine induced sterotypy in Rats Phenycylidine induced Bizzare pattern of Locomotor activity and stereotypy Phenycylidine induced social withdrawal measured in the social interaction test Conditioned avoidance reflex in Rats Neurodevelopmental Models Genetic Models Single unit recording of A9 and A10 Midbrain Dopaminergic Neurons Extrapyramidal side effects Primed Monkey Model 6/30/2014 60
  60. 60. References 1. 6/30/2014 63

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