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Thiothixene
Typical (Conventional) Chlorprothixene
Thioxanthines Clopenthixol
Antipsychotics Flupenthixol
Haloperidol
Butyrophenones Droperidol
Clozapine
Loxapine
Olanzapine
Quetiapine
Atypical Miscellaneous Risperidone
Antipsychotics Structures Ziprasidone
Aripiprazole
Pimozide
Sertindole
Therapeutic Indications
Psychosis/
Schizophrenia
Agitation/Disruptive Behavior
(e.g. anxiety associated with
chronic pain)
Pruritis (itch)
Receptor Mechanisms of
Action of Antipsychotic Drugs
Dopamine Hypothesis of
Schizophrenia!
Antipsychotic Drugs Affect Multiple Receptors
Dopamine Receptor Take-home Points:
Antipscychotic
Block Antipsychotic drugs affect multiple
receptor subtypes responsible for
Effects
Serotonergic (5HT2A) therapeutic effects and for a broad
Receptor array of unwanted effects.
Block D2 receptor binding predictive of
efficacy for typical antipsychotics.
D1 receptor binding is least predictive
of clinical efficacy for typical
antipsychotics.
Antipsychotic 5HT2A receptor block underlies clinical
efficacy of atypical antipsychotics
Drugs (e.g. risperidone, aripiprazole).
Muscarinic
Adverse
Effects
Receptor Block
Alpha-adrenoceptor
Block
Histamine (H1)
Receptor Block
Dopamine D2 and Serotonin 5HT2A
Receptor Antagonism Primarily
Responsible for Antipsychotic
Mechanism of Action
Dopamine Pathways and Antipsychotics
(See next page for summary)
MESOLIMBIC
NIGROSTRIATAL
MESOCORTICAL
Serotonergic (5HT2A)
Receptor Antipsychotic effects (Atypicals)
Block
Drug
Muscarinic Dry mouth, blurred vision, loss of
Receptor Block accommodation, constipation, difficulty
urinating, toxic-confusional state
Histamine (H1)
Sedation
Receptor Block
Additional Therapeutic Indications
Autism Spectrum
Disorder
Tourette Disorder
Antipsychotic
Drugs
Pruritis (itch)
Emesis/nausea
Antiemetic Effects
D2
Typical Antipsychotic
D2 Drugs
Motion Sickness
Chemotherapy/Radiation Therapy
Antiemetic effects
Typical antipsychotics are effective anti-emetics.
Atypical antipsychotics not effective anti-emetics.
Abnormal postures,
twitching, and
*Involuntary, repetitive movements that
repetitive movements
are belated in onset.
caused by sustained
*Slow onset (develops 6 months to years
muscle contractions.
following initiation of therapy).
Syndrome characterized *Limited pharmacological treatments
by inability to sit still or *May be caused by dopamine receptor
remain motionless. sensitization (i.e. long-term dopamine
receptor block may cause body to
Bradykinesia, produce more dopamine receptors)
tremor, and rigidity increasing antipsychotic doses
temporarily relieves symptoms.
Neuroendocrine Adverse Effects
(Hyperprolactinemia)
Hypothalamus
D2 receptor antagonism by typical antipsychotics
(Dopamine) can cause excessive release of prolactin from the
anterior pituitary and produce hyperprolactinemia.
Typical Normal (absence of drug): prolactin (hormone
Antipsychotic that stimulates mammary gland development and
_
Drug milk production) secretion from anterior pituitary
D2 is tonically inhibited by dopaminergic activation of
D2 receptors.
Antipsychotic Drug: inhibits D2 receptors,
Anterior Pituitary leading to increased prolactin secretion.
(Prolactin)
Hyperprolactinemia: high blood prolactin
concentration. Symptoms are:
Galactorrhoea (unexplained milk secretion)
Infertility
Prolactin Irregular menstrual cycles and amenorrhea
(Blood) (absence of menstrual bleeding)
Gynecomastia (breast enlargement in males)
Neuroleptic Malignant Syndrome
(Adverse Effect)
Definition:
Rare side effect of antipsychotic therapy that can be lethal.
Mechanism:
Due to rapid blockade of postsynaptic dopamine D2 receptors
located in thermoregulatory center of hypothalamus.
Symptoms:
Hyperthermia, muscle rigidity, tachycardia, tachypnea
Diagnostics:
Creatine kinase isozymes elevated reflecting muscle damage.
Clinical intervention:
Discontinuation of antipsychotic therapy followed by
administration of dopamine agonists (bromocriptine) or a
muscle relaxant (dantrolene).
Adverse Effects at
Non-dopaminergic Targets
Antipsychotic
Drug
_ _ _
30
Conventionals (Typicals)
25 Atypicals
20
Diagnosed
with diabetes 15
(%)
10
0
All Ages <40 y 40-49 y 50-59 y 60-69 y >70 y
Sernyak MJ et al. Am J Psychiatry. 2002;159:561-566.
Side Effects of Atypical Antipsychotics
Miscellaneous toxicities
Thioridazine retinal deposits cause visual
impairments, high doses leads to fatal ventricular
arrhythmias.
Sertindole prolonged QT segment leading to
arrhythmias.
Clozapine 1-2% incidence of agranulocytosis
that lowers white blood cell count.
Summary
ATYPICALS
TYPICALS
EXTRAPYRAMIDAL
SIDE EFFECTS
POSITIVE
SYMPTOMS