Pharmacology of Antipsychotics

Douglas L. Geenens, D.O.

University Of Health Sciences College of Osteopathic Medicine

Douglas L. Geenens, D.O. 2000

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

Douglas L. Geenens, D.O. 2000

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

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

Dopamine Pathways
Mesolimbic
Projects from brainstem to limbic areas.

Overactivity produces delusions and hallucinations.

Douglas L. Geenens, D.O. 2000

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

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

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

Dopamine Pathways
Nigrostriatal
Chronic blockade can cause
Potentially irreversible movement disorder
Tardive Dyskinesia

Role is undetermined

Douglas L. Geenens, D.O. 2000

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

Dopamine Pathways
Tuberoinfundibular
Blockade produces galactorrhea

Dopamine=PIF

Douglas L. Geenens, D.O. 2000

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

Douglas L. Geenens, D.O. 2000

Antipsychotics
Phenothiazines (piperidines)
Mesoridazine
Serentil

Thioridazine
Mellaril

Phenothiazines (Aliphatic)
Chlorpromazine
Thorazine
Douglas L. Geenens, D.O. 2000

Antipsychotics
Phenothiazines (piperazines)
Perphenazine
Trilafon

Trifluoperazine
Stelazine

Fluphenazine
Prolixin
Douglas L. Geenens, D.O. 2000

Antipsychotics
Thioxanthenes
Navane

Dibenzazepines
Clozapine
Clozaril

Ioxapine
Loxitane
Douglas L. Geenens, D.O. 2000

Antipsychotics
Butyrophenones
Haloperidol
Haldol

Diphenylbutylpiperidines
Pimozide
Orap

Douglas L. Geenens, D.O. 2000

Douglas L. Geenens, D.O. 2000

Antipsychotics
Indoles
Molindone
Moban

Rauwolfia
Reserpine
Serpasil

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Antipsychotics
Benzisoxazole
Risperidone
Risperdal

Thienobenzodiazepines
Olanzapine
Zyprexa

Douglas L. Geenens, D.O. 2000

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

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

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

Antipsychotics
Potency
Low potency medications cause more:
sedation Anti-ACH Orthostatic hypotension

High potency medications cause more:

EPS

Douglas L. Geenens, D.O. 2000

Dopaminergic D2 Blockade
Possible Clinical Consequences
Extrapyramidal movement disorders Endocrine changes Sexual dysfunction

Douglas L. Geenens, D.O. 2000

Antipsychotics
Relative potencies (mg equivalents)
100 80 60 40 20 0
Douglas L. Geenens, D.O. 2000

chlorpromazine (Thorazine) thioridazine (Mellaril) mesoridazine (Serentil) loxapine (Loxitane) molindone (Moban) thiothixene (Navane) trifluoperazine (Stelazine) haloperidol (Haldol) fluphenazine (Prolixin)

Histamine H1 Blockade
Possible Clinical Consequences
Sedation, drowsiness Weight gain Hypotension

Douglas L. Geenens, D.O. 2000

Antipsychotics
Potency for H-1 blockade
chlorpromazine (Thorazine) thioridazine (Mellaril)
haloperid 0.025

loxapine (Loxitane) molindone (Moban) trifluoperazine (Stelazine) fluphenazine (Prolixin) haloperidol (Haldol)

10

15

20

25

Douglas L. Geenens, D.O. 2000

Alpha-1 receptor blockade

Possible clinical consequences
Postural hypotension Reflex tachycardia Dizziness

Douglas L. Geenens, D.O. 2000

Antipsychotics
Potency for alpha-1 blockade
40 35 30 25 20 15 10 5 0
Douglas L. Geenens, D.O. 2000

chlorpromazine (Thorazine) thioridazine (Mellaril) loxapine (Loxitane) molindone (Moban) trifluoperazine (Stelazine) fluphenazine (Prolixin) haloperidol (Haldol)

Muscarinic receptor blockade

Possible clinical consequences
Blurred vision Dry mouth Sinus tachycardia Constipation Urinary retention Memory dysfunction

Douglas L. Geenens, D.O. 2000

Antipsychotics
Potency for muscarinic blockade
6 5 4 3 2 1 0 Series 1
Douglas L. Geenens, D.O. 2000

chlorpromazine (Thorazine) thioridazine (Mellaril) loxapine (Loxitane) molindone (Moban) trifluoperazine (Stelazine) fluphenazine (Prolixin) haloperidol (Haldol)

Douglas L. Geenens, D.O. 2000

Clozaril
Clozapine
Atypical antipsychotic More effective in persons who fail typical antipsychotic therapy At least nine different receptor affinities

Douglas L. Geenens, D.O. 2000

Clozaril
Clozapine
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

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

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

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

Tardive Dyskinesia
Associated with long-term use of antipsychotics
(chronic dopamine blockade)

Potentially irreversible involuntary movements around the buccal-lingualoral area

Douglas L. Geenens, D.O. 2000

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

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

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

Neurological Side Effects of Neuroleptics

A: Dystonic Reactions B: Akinesia C: Rigidity D: Tremors E: Akathisia F: Tardive Dykinesia
3 6 9 12 15

Douglas L. Geenens, D.O. 2000

Neurological Effects
Neurological Effects Onset Acute or insidious Within 1 30 days Due to decreased dopamine Respond to antiparkinsonian drugs Tardive Dyskinesia

After months or years of treatment, especially if drug dose decreased or discontinued Supersensitivity of postsynaptic dopamine receptors induced by long term neuroleptic blockade 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.

Proposed Mechanism Treatment

Extrapyramidal Effects
Type Onset Risk Group
Young male

Clinical Course
Acute, painful, spasmodic Oculogyria may be recurrent May continue though out treatment May continue through treatment

Treatment

Dystonias

Acute (within 5 days)

I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used

Akathisia

Insidious to acute (within 10 days) Insidious to acute (within 30 days)

12-45% on neuroleptics

I.M. benztropine, I.M. diphenhydramine, sublingual lorazepam If symptoms recur, oral antiparkinsonian agents can be used Oral antiparkinsonian drug. Reduce or change neuroleptic

Pseudoparkinsonism

12-45% on neuroleptics

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

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

Douglas L. Geenens, D.O. 2000