1. Pharmacology of Antipsychotics Douglas L. Geenens, D.O. University Of Health Sciences College of Osteopathic Medicine Downloaded from www.pharmacy123.blogfa.com

3. Dopamine Hypothesis Drugs that increase dopamine will enhance or produce positive psychotic symptoms –E.G. Cocaine, amphetamine

4. Downloaded from www.pharmacy123.blogfa.com All known antipsychotics drugs capable of treating positive psychotic symptoms block the dopamine receptors –Esp..D-2 receptors Dopamine Hypothesis

5. Downloaded from www.pharmacy123.blogfa.com Dopamine Pathways Mesolimbic Nigrostriatal Mesocortical Tuberoinfundibular

6. Downloaded from www.pharmacy123.blogfa.com Dopamine Pathways Mesolimbic Projects from brainstem to limbic areas. Overactivity produces delusions and hallucinations.

7. Downloaded from www.pharmacy123.blogfa.com Dopamine Pathways Nigrostriatal Projects from the substania nigra to the basal ganglia –A part of the extrapyramidal system –Thus side effects are called “extrapyramidal”

8. Downloaded from www.pharmacy123.blogfa.com Dopamine Pathways Nigrostriatal Controls movements The term “neuroleptics” refers to: –Antipsychotics ability to “quiet the neurological system” – To their neurological side effects

9. Downloaded from www.pharmacy123.blogfa.com Dopamine Pathways Nigrostriatal Types of movement disorders caused by this pathway include: –Akathisia –Dystonia –Tremor, rigidity, bradykinesia Drug-induced Parkinsonism

10. Downloaded from www.pharmacy123.blogfa.com Dopamine Pathways Nigrostriatal Chronic blockade can cause –Potentially irreversible movement disorder “ Tardive Dyskinesia” Role is undetermined

11. Downloaded from www.pharmacy123.blogfa.com Dopamine Pathways Mesocortical 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”

12. Downloaded from www.pharmacy123.blogfa.com Dopamine Pathways Tuberoinfundibular Blockade produces galactorrhea Dopamine=PIF

13. Downloaded from www.pharmacy123.blogfa.com Dopamine Pathways Summary 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

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15. Antipsychotics Phenothiazines (piperidines) –Mesoridazine Serentil –Thioridazine Mellaril Phenothiazines (Aliphatic) –Chlorpromazine Thorazine

16. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Phenothiazines (piperazines) Perphenazine –Trilafon Trifluoperazine –Stelazine Fluphenazine –Prolixin

17. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Thioxanthenes –Navane Dibenzazepines –Clozapine Clozaril –Ioxapine Loxitane

18. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Butyrophenones –Haloperidol Haldol Diphenylbutylpiperidines –Pimozide Orap

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20. Antipsychotics Indoles –Molindone Moban Rauwolfia –Reserpine Serpasil

21. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Benzisoxazole –Risperidone Risperdal Thienobenzodiazepines –Olanzapine Zyprexa

22. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Efficacy 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”

23. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Efficacy Newer agents –e.g. Clozaril –Have significant activity at the D-1 receptor; –Risperdal and Zyprexa have significant 5- HT2 activity

24. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Potency Potency is an important variable in terms of pharmacodynamic properties of these medicines. Potency determines the predictable side effects of the antipsychotics.

25. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Potency Low potency medications cause more: –sedation –Anti-ACH –Orthostatic hypotension High potency medications cause more: –EPS

26. Downloaded from www.pharmacy123.blogfa.com Dopaminergic D2 Blockade Possible Clinical Consequences Extrapyramidal movement disorders Endocrine changes Sexual dysfunction

27. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Relative potencies (mg equivalents)

28. Downloaded from www.pharmacy123.blogfa.com Histamine H1 Blockade Possible Clinical Consequences Sedation, drowsiness Weight gain Hypotension

29. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Potency for H-1 blockade

30. Downloaded from www.pharmacy123.blogfa.com Alpha-1 receptor blockade Possible clinical consequences Postural hypotension Reflex tachycardia Dizziness

31. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Potency for alpha-1 blockade

32. Downloaded from www.pharmacy123.blogfa.com Muscarinic receptor blockade Possible clinical consequences Blurred vision Dry mouth Sinus tachycardia Constipation Urinary retention Memory dysfunction

33. Downloaded from www.pharmacy123.blogfa.com Antipsychotics Potency for muscarinic blockade

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35. Clozaril Clozapine “Atypical” antipsychotic More effective in person’s who fail typical antipsychotic therapy At least nine different receptor affinities

36. Downloaded from www.pharmacy123.blogfa.com Clozaril Clozapine One of the most complicated medications in psychopharmacology Can cause death via agranulocytosis Cost is typically $10,000.00 per year

37. Downloaded from www.pharmacy123.blogfa.com Extrapyramidal Symptoms Dopamine Vs Acetylcholine Dopamine and Acetylcholine have a reciprocal relationship in the Nigrostriatal pathway. A delicate balance allows for normal movement.

38. Downloaded from www.pharmacy123.blogfa.com Extrapyramidal Symptoms Dopamine 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

39. Downloaded from www.pharmacy123.blogfa.com Extrapyramidal Symptoms Dopamine Vs Acetylcholine When high potency antipsychotics are chosen, we often prescribe anti-ACH medication like –Cogentin, diphenhydramine, or Artane

40. Downloaded from www.pharmacy123.blogfa.com Tardive Dyskinesia Associated with long-term use of antipsychotics –(chronic dopamine blockade) Potentially irreversible involuntary movements around the buccal-lingual- oral area

41. Downloaded from www.pharmacy123.blogfa.com Tardive Dyskinesia Attempt of decrease dose –will initially exacerbate the movements Increasing the dose will initially decrease the movements

42. Downloaded from www.pharmacy123.blogfa.com 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

43. Downloaded from www.pharmacy123.blogfa.com Neurological Side Effects: Tremors: –Fine movement (shaking) of the extremities Akathisia: –Restlessness –Pacing May result in insomnia Tardive Dyskinesia: –Buccolinguo-masticalory syndrome –Choreoathetoid movements

44. Downloaded from www.pharmacy123.blogfa.com Neurological Side Effects of Neuroleptics

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. Downloaded from www.pharmacy123.blogfa.com

46. Extrapyramidal Effects TypeOnsetRisk Group Clinical Course Treatment DystoniasAcute (within 5 days) Young maleAcute, painful, spasmodic Oculogyria may be recurrent I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used AkathisiaInsidious 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 PseudoparkinsonismInsidious to acute (within 30 days) 12-45% on neuroleptics May continue through treatment Oral antiparkinsonian drug. Reduce or change neuroleptic Downloaded from www.pharmacy123.blogfa.com

47. Neuroleptic Malignant Syndrome An idiosyncratic, life-threatening illness associated with antipsychotic therapy Clinical manifestations include –hyperpyrexia –autonomic instability, –“board-like” rigidity

48. Downloaded from www.pharmacy123.blogfa.com Neuroleptic Malignant Syndrome Resembles malignant hyperthermia associated with anesthesia Treatment involves –Immediate discontinuation of antipsychotic –Hydration –Maintain vital functions –Prescribe bromocriptine and dantrolene

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