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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

Pharmacology of Antipsychotics

Douglas L. Geenens, D.O.

University Of Health Sciences College of Osteopathic Medicine

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

Douglas L. Geenens, D.O. 2000

dopamine hypothesis1
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
Dopamine Pathways
  • Mesolimbic
  • Nigrostriatal
  • Mesocortical
  • Tuberoinfundibular

Douglas L. Geenens, D.O. 2000

dopamine pathways mesolimbic
Dopamine Pathways Mesolimbic
  • Projects from brainstem to limbic areas.
  • Overactivity produces delusions and hallucinations.

Douglas L. Geenens, D.O. 2000

dopamine pathways nigrostriatal
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

dopamine pathways nigrostriatal1
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

dopamine pathways nigrostriatal2
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

dopamine pathways nigrostriatal3
Dopamine PathwaysNigrostriatal
  • Chronic blockade can cause
    • Potentially irreversible movement disorder
      • “Tardive Dyskinesia”
  • Role is undetermined

Douglas L. Geenens, D.O. 2000

dopamine pathways mesocortical
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

dopamine pathways tuberoinfundibular
Dopamine PathwaysTuberoinfundibular
  • Blockade produces galactorrhea
  • Dopamine=PIF

Douglas L. Geenens, D.O. 2000

dopamine pathways summary
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

antipsychotics
Antipsychotics
  • Phenothiazines (piperidines)
    • Mesoridazine
      • Serentil
    • Thioridazine
      • Mellaril
  • Phenothiazines (Aliphatic)
    • Chlorpromazine
      • Thorazine

Douglas L. Geenens, D.O. 2000

antipsychotics phenothiazines piperazines
AntipsychoticsPhenothiazines (piperazines)
  • Perphenazine
    • Trilafon
  • Trifluoperazine
    • Stelazine
  • Fluphenazine
    • Prolixin

Douglas L. Geenens, D.O. 2000

antipsychotics1
Antipsychotics
  • Thioxanthenes
    • Navane
  • Dibenzazepines
    • Clozapine
      • Clozaril
    • Ioxapine
      • Loxitane

Douglas L. Geenens, D.O. 2000

antipsychotics2
Antipsychotics
  • Butyrophenones
    • Haloperidol
      • Haldol
  • Diphenylbutylpiperidines
    • Pimozide
      • Orap

Douglas L. Geenens, D.O. 2000

antipsychotics3
Antipsychotics
  • Indoles
    • Molindone
      • Moban
  • Rauwolfia
    • Reserpine
      • Serpasil

Douglas L. Geenens, D.O. 2000

antipsychotics4
Antipsychotics
  • Benzisoxazole
    • Risperidone
      • Risperdal
  • Thienobenzodiazepines
    • Olanzapine
      • Zyprexa

Douglas L. Geenens, D.O. 2000

antipsychotics efficacy
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

antipsychotics efficacy1
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

antipsychotics potency
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

antipsychotics potency1
AntipsychoticsPotency
  • 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
Dopaminergic D2 BlockadePossible Clinical Consequences
  • Extrapyramidal movement disorders
  • Endocrine changes
  • Sexual dysfunction

Douglas L. Geenens, D.O. 2000

histamine h1 blockade possible clinical consequences
Histamine H1 BlockadePossible Clinical Consequences
  • Sedation, drowsiness
  • Weight gain
  • Hypotension

Douglas L. Geenens, D.O. 2000

antipsychotics potency for h 1 blockade
AntipsychoticsPotency for H-1 blockade

Douglas L. Geenens, D.O. 2000

alpha 1 receptor blockade possible clinical consequences
Alpha-1 receptor blockadePossible clinical consequences
  • Postural hypotension
  • Reflex tachycardia
  • Dizziness

Douglas L. Geenens, D.O. 2000

antipsychotics potency for alpha 1 blockade
AntipsychoticsPotency for alpha-1 blockade

Douglas L. Geenens, D.O. 2000

muscarinic receptor blockade possible clinical consequences
Blurred vision

Dry mouth

Sinus tachycardia

Constipation

Urinary retention

Memory dysfunction

Muscarinic receptor blockadePossible clinical consequences

Douglas L. Geenens, D.O. 2000

clozaril clozapine
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

clozaril clozapine1
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

extrapyramidal symptoms dopamine vs acetylcholine
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

extrapyramidal symptoms dopamine vs acetylcholine1
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

extrapyramidal symptoms dopamine vs acetylcholine2
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

tardive dyskinesia
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

tardive dyskinesia1
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
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 effects1
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
Neurological Side Effects of Neuroleptics

Douglas L. Geenens, D.O. 2000

neurological effects

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
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

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
neuroleptic malignant syndrome
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 syndrome1
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