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Pharmacology of Antipsychotics

Pharmacology of Antipsychotics. Douglas L. Geenens, D.O. University Of Health Sciences College of Osteopathic Medicine. Dopamine Hypothesis. Drugs that increase dopamine will enhance or produce positive psychotic symptoms E.G. Cocaine, amphetamine. Dopamine Hypothesis.

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Pharmacology of Antipsychotics

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  1. Pharmacology of Antipsychotics Douglas L. Geenens, D.O. University Of Health Sciences College of Osteopathic Medicine

  2. Douglas L. Geenens, D.O. 2000

  3. Dopamine Hypothesis • Drugs that increase dopamine will enhance or produce positive psychotic symptoms • E.G. Cocaine, amphetamine Douglas L. Geenens, D.O. 2000

  4. Dopamine Hypothesis • All known antipsychotics drugs capable of treating positive psychotic symptoms block the dopamine receptors • Esp..D-2 receptors Douglas L. Geenens, D.O. 2000

  5. Dopamine Pathways • Mesolimbic • Nigrostriatal • Mesocortical • Tuberoinfundibular Douglas L. Geenens, D.O. 2000

  6. Dopamine Pathways Mesolimbic • Projects from brainstem to limbic areas. • Overactivity produces delusions and hallucinations. Douglas L. Geenens, D.O. 2000

  7. Dopamine PathwaysNigrostriatal • Projects from the substania nigra to the basal ganglia • A part of the extrapyramidal system • Thus side effects are called “extrapyramidal” Douglas L. Geenens, D.O. 2000

  8. Dopamine PathwaysNigrostriatal • Controls movements • The term “neuroleptics” refers to: • Antipsychotics ability to “quiet the neurological system” • To their neurological side effects Douglas L. Geenens, D.O. 2000

  9. Dopamine PathwaysNigrostriatal • Types of movement disorders caused by this pathway include: • Akathisia • Dystonia • Tremor, rigidity, bradykinesia • Drug-induced Parkinsonism Douglas L. Geenens, D.O. 2000

  10. Dopamine PathwaysNigrostriatal • Chronic blockade can cause • Potentially irreversible movement disorder • “Tardive Dyskinesia” • Role is undetermined Douglas L. Geenens, D.O. 2000

  11. Dopamine PathwaysMesocortical • May be associated with both positive and negative symptoms • Blockade may help reduce negative symptoms of schizophrenia • May be involved in the cognitive side effects of antipsychotics “mind dulling” Douglas L. Geenens, D.O. 2000

  12. Dopamine PathwaysTuberoinfundibular • Blockade produces galactorrhea • Dopamine=PIF Douglas L. Geenens, D.O. 2000

  13. Dopamine PathwaysSummary • Four dopamine pathways • Appears that blocking dopamine receptors in only one of them is useful • Blocking dopamine receptors in the other three may be harmful Douglas L. Geenens, D.O. 2000

  14. Douglas L. Geenens, D.O. 2000

  15. Antipsychotics • Phenothiazines (piperidines) • Mesoridazine • Serentil • Thioridazine • Mellaril • Phenothiazines (Aliphatic) • Chlorpromazine • Thorazine Douglas L. Geenens, D.O. 2000

  16. AntipsychoticsPhenothiazines (piperazines) • Perphenazine • Trilafon • Trifluoperazine • Stelazine • Fluphenazine • Prolixin Douglas L. Geenens, D.O. 2000

  17. Antipsychotics • Thioxanthenes • Navane • Dibenzazepines • Clozapine • Clozaril • Ioxapine • Loxitane Douglas L. Geenens, D.O. 2000

  18. Antipsychotics • Butyrophenones • Haloperidol • Haldol • Diphenylbutylpiperidines • Pimozide • Orap Douglas L. Geenens, D.O. 2000

  19. Douglas L. Geenens, D.O. 2000

  20. Antipsychotics • Indoles • Molindone • Moban • Rauwolfia • Reserpine • Serpasil Douglas L. Geenens, D.O. 2000

  21. Antipsychotics • Benzisoxazole • Risperidone • Risperdal • Thienobenzodiazepines • Olanzapine • Zyprexa Douglas L. Geenens, D.O. 2000

  22. AntipsychoticsEfficacy • All antipsychotics are considered equally effective • Rationale for determining which medication to use is based on side effect profile • Primary mechanism of action is • Postsynaptic blockade of the D-2 receptor • “D-2, me too” Douglas L. Geenens, D.O. 2000

  23. AntipsychoticsEfficacy • Newer agents • e.g. Clozaril • Have significant activity at the D-1 receptor; • Risperdal and Zyprexa have significant 5-HT2 activity Douglas L. Geenens, D.O. 2000

  24. AntipsychoticsPotency • Potency is an important variable in terms of pharmacodynamic properties of these medicines. • Potency determines the predictable side effects of the antipsychotics. Douglas L. Geenens, D.O. 2000

  25. AntipsychoticsPotency • Low potency medications cause more: • sedation • Anti-ACH • Orthostatic hypotension • High potency medications cause more: • EPS Douglas L. Geenens, D.O. 2000

  26. Dopaminergic D2 BlockadePossible Clinical Consequences • Extrapyramidal movement disorders • Endocrine changes • Sexual dysfunction Douglas L. Geenens, D.O. 2000

  27. AntipsychoticsRelative potencies (mg equivalents) Douglas L. Geenens, D.O. 2000

  28. Histamine H1 BlockadePossible Clinical Consequences • Sedation, drowsiness • Weight gain • Hypotension Douglas L. Geenens, D.O. 2000

  29. AntipsychoticsPotency for H-1 blockade Douglas L. Geenens, D.O. 2000

  30. Alpha-1 receptor blockadePossible clinical consequences • Postural hypotension • Reflex tachycardia • Dizziness Douglas L. Geenens, D.O. 2000

  31. AntipsychoticsPotency for alpha-1 blockade Douglas L. Geenens, D.O. 2000

  32. Blurred vision Dry mouth Sinus tachycardia Constipation Urinary retention Memory dysfunction Muscarinic receptor blockadePossible clinical consequences Douglas L. Geenens, D.O. 2000

  33. AntipsychoticsPotency for muscarinic blockade Douglas L. Geenens, D.O. 2000

  34. Douglas L. Geenens, D.O. 2000

  35. ClozarilClozapine • “Atypical” antipsychotic • More effective in person’s who fail typical antipsychotic therapy • At least nine different receptor affinities Douglas L. Geenens, D.O. 2000

  36. ClozarilClozapine • One of the most complicated medications in psychopharmacology • Can cause death via agranulocytosis • Cost is typically $10,000.00 per year Douglas L. Geenens, D.O. 2000

  37. Extrapyramidal SymptomsDopamine Vs Acetylcholine • Dopamine and Acetylcholine have a reciprocal relationship in the Nigrostriatal pathway. • A delicate balance allows for normal movement. Douglas L. Geenens, D.O. 2000

  38. Extrapyramidal SymptomsDopamine Vs Acetylcholine • Dopamine blockade: • A relative increase in cholinergic activity • causing EPS • Those antipsychotics that have significant anti-ACH activity are therefore less likely to cause EPS Douglas L. Geenens, D.O. 2000

  39. Extrapyramidal SymptomsDopamine Vs Acetylcholine • When high potency antipsychotics are chosen, we often prescribe anti-ACH medication like • Cogentin, diphenhydramine, or Artane Douglas L. Geenens, D.O. 2000

  40. Tardive Dyskinesia • Associated with long-term use of antipsychotics • (chronic dopamine blockade) • Potentially irreversible involuntary movements around the buccal-lingual-oral area Douglas L. Geenens, D.O. 2000

  41. Tardive Dyskinesia • Attempt of decrease dose • will initially exacerbate the movements • Increasing the dose will initially decrease the movements Douglas L. Geenens, D.O. 2000

  42. Neurological Side Effects: • Dystonic Reactions: • Uncoordinated spastic movements of muscle groups • Trunk, tongue, face • Akinesia: • Decreased muscular movements • Rigidity: • Coarse muscular movement • Loss of facial expression Douglas L. Geenens, D.O. 2000

  43. Neurological Side Effects: • Tremors: • Fine movement (shaking) of the extremities • Akathisia: • Restlessness • Pacing • May result in insomnia • Tardive Dyskinesia: • Buccolinguo-masticalory syndrome • Choreoathetoid movements Douglas L. Geenens, D.O. 2000

  44. Neurological Side Effects of Neuroleptics Douglas L. Geenens, D.O. 2000

  45. Neurological Effects Tardive Dyskinesia Onset Acute or insidious Within 1 – 30 days After months or years of treatment, especially if drug dose decreased or discontinued Proposed Mechanism Due to decreased dopamine Supersensitivity of postsynaptic dopamine receptors induced by long term neuroleptic blockade Treatment Respond to antiparkinsonian drugs Generally worsen Tardive Dyskinesia Other treatments unsatisfactory; some aimed at balancing Dopaminergic and cholinergic systems. Can mask symptoms by further suppressing dopamine with neuroleptics. Pimozide or loxapine may least aggravate Tardive Dyskinesia. Neurological Effects

  46. Type Onset Risk Group Clinical Course Treatment Dystonias Acute (within 5 days) Young male Acute, painful, spasmodic Oculogyria may be recurrent I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used Akathisia Insidious to acute (within 10 days) 12-45% on neuroleptics May continue though out treatment I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used Pseudoparkinsonism Insidious to acute (within 30 days) 12-45% on neuroleptics May continue through treatment Oral antiparkinsonian drug. Reduce or change neuroleptic Extrapyramidal Effects

  47. Neuroleptic Malignant Syndrome • An idiosyncratic, life-threatening illness associated with antipsychotic therapy • Clinical manifestations include • hyperpyrexia • autonomic instability, • “board-like” rigidity Douglas L. Geenens, D.O. 2000

  48. Neuroleptic Malignant Syndrome • Resembles malignant hyperthermia associated with anesthesia • Treatment involves • Immediate discontinuation of antipsychotic • Hydration • Maintain vital functions • Prescribe bromocriptine and dantrolene Douglas L. Geenens, D.O. 2000

  49. Douglas L. Geenens, D.O. 2000

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