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Pharmacology of Antipsychotics

• Douglas L. Geenens, D.O.
• University Of Health Sciences College of
  Osteopathic Medicine

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Dopamine Hypothesis

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

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Dopamine Hypothesis

• All known antipsychotics drugs capable of
  treating positive psychotic symptoms block the
  dopamine receptors
• Esp..D-2 receptors

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Dopamine Pathways

• Mesolimbic
• Nigrostriatal
• Mesocortical
• Tuberoinfundibular

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Dopamine Pathways Mesolimbic

• Projects from brainstem to limbic areas.
• Overactivity produces delusions and
  hallucinations.

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Dopamine PathwaysNigrostriatal

• Projects from the substania nigra to the basal
  ganglia
• A part of the extrapyramidal system
• Thus side effects are called extrapyramidal

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Dopamine PathwaysNigrostriatal

• Controls movements
• The term neuroleptics refers to
• Antipsychotics ability to quiet the neurological
  system
• To their neurological side effects

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Dopamine PathwaysNigrostriatal

• Types of movement disorders caused by this
  pathway include
• Akathisia
• Dystonia
• Tremor, rigidity, bradykinesia
• Drug-induced Parkinsonism

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Dopamine PathwaysNigrostriatal

• Chronic blockade can cause
• Potentially irreversible movement disorder
• Tardive Dyskinesia
• Role is undetermined

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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

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Dopamine PathwaysTuberoinfundibular

• Blockade produces galactorrhea
• DopaminePIF

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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

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Antipsychotics

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

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AntipsychoticsPhenothiazines (piperazines)

• Perphenazine
• Trilafon
• Trifluoperazine
• Stelazine
• Fluphenazine
• Prolixin

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Antipsychotics

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

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Antipsychotics

• Butyrophenones
• Haloperidol
• Haldol
• Diphenylbutylpiperidines
• Pimozide
• Orap

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Antipsychotics

• Indoles
• Molindone
• Moban
• Rauwolfia
• Reserpine
• Serpasil

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Antipsychotics

• Benzisoxazole
• Risperidone
• Risperdal
• Thienobenzodiazepines
• Olanzapine
• Zyprexa

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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

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AntipsychoticsEfficacy

• Newer agents
• e.g. Clozaril
• Have significant activity at the D-1 receptor
• Risperdal and Zyprexa have significant 5-HT2
  activity

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AntipsychoticsPotency

• Potency is an important variable in terms of
  pharmacodynamic properties of these medicines.
• Potency determines the predictable side effects
  of the antipsychotics.

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AntipsychoticsPotency

• Low potency medications cause more
• sedation
• Anti-ACH
• Orthostatic hypotension
• High potency medications cause more
• EPS

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Dopaminergic D2 BlockadePossible Clinical
Consequences

• Extrapyramidal movement disorders
• Endocrine changes
• Sexual dysfunction

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AntipsychoticsRelative potencies (mg equivalents)
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Histamine H1 BlockadePossible Clinical
Consequences

• Sedation, drowsiness
• Weight gain
• Hypotension

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AntipsychoticsPotency for H-1 blockade
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Alpha-1 receptor blockadePossible clinical
consequences

• Postural hypotension
• Reflex tachycardia
• Dizziness

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AntipsychoticsPotency for alpha-1 blockade
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Muscarinic receptor blockadePossible clinical
consequences

• Blurred vision
• Dry mouth
• Sinus tachycardia

• Constipation
• Urinary retention
• Memory dysfunction

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AntipsychoticsPotency for muscarinic blockade
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ClozarilClozapine

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

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ClozarilClozapine

• One of the most complicated medications in
  psychopharmacology
• Can cause death via agranulocytosis
• Cost is typically 10,000.00 per year

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Extrapyramidal SymptomsDopamine Vs Acetylcholine

• Dopamine and Acetylcholine have a reciprocal
  relationship in the Nigrostriatal pathway.
• A delicate balance allows for normal movement.

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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

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Extrapyramidal SymptomsDopamine Vs Acetylcholine

• When high potency antipsychotics are chosen, we
  often prescribe anti-ACH medication like
• Cogentin, diphenhydramine, or Artane

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Tardive Dyskinesia

• Associated with long-term use of antipsychotics
• (chronic dopamine blockade)
• Potentially irreversible involuntary movements
  around the buccal-lingual-oral area

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Tardive Dyskinesia

• Attempt of decrease dose
• will initially exacerbate the movements
• Increasing the dose will initially decrease the
  movements

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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

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Neurological Side Effects

• Tremors
• Fine movement (shaking) of the extremities
• Akathisia
• Restlessness
• Pacing
• May result in insomnia
• Tardive Dyskinesia
• Buccolinguo-masticalory syndrome
• Choreoathetoid movements

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Neurological Side Effects of Neuroleptics
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Neurological Effects
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Extrapyramidal Effects
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Neuroleptic Malignant Syndrome

• An idiosyncratic, life-threatening illness
  associated with antipsychotic therapy
• Clinical manifestations include
• hyperpyrexia
• autonomic instability,
• board-like rigidity

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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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