1. Pharmacology of Antipsychotics
Dr Andrew P Mallon

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 Pathways Nigrostriatal
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 Pathways Nigrostriatal
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 Pathways Nigrostriatal
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 Pathways Nigrostriatal
Chronic blockade can cause
Potentially irreversible movement disorder
“Tardive Dyskinesia”
Role is undetermined
Douglas L. Geenens, D.O. 2000

11. 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”
Douglas L. Geenens, D.O. 2000

12. Dopamine Pathways Tuberoinfundibular
Blockade produces galactorrhea
Dopamine=PIF
Douglas L. Geenens, D.O. 2000

13. 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
Douglas L. Geenens, D.O. 2000

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

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

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

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

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

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

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

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

22. 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”
Douglas L. Geenens, D.O. 2000

23. Antipsychotics Efficacy
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. Antipsychotics Potency
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. Antipsychotics Potency
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 Blockade Possible Clinical Consequences
Extrapyramidal movement disorders
Endocrine changes
Sexual dysfunction
Douglas L. Geenens, D.O. 2000

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

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

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

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

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

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

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

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

35. Clozaril Clozapine “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. Clozaril Clozapine
One of the most complicated medications in psychopharmacology
Can cause death via agranulocytosis
Cost is typically $10, per year
Douglas L. Geenens, D.O. 2000

37. Extrapyramidal Symptoms Dopamine 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 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
Douglas L. Geenens, D.O. 2000

39. Extrapyramidal Symptoms Dopamine 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 Neurological Effects Tardive Dyskinesia Onset
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.

46. Extrapyramidal Effects
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
Pseudoparkinsonism
Insidious to acute (within 30 days)
May continue through treatment
Oral antiparkinsonian drug. Reduce or change neuroleptic

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