Antipsychotic Agents

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Anti-psychotic Agents

• Neuroleptic Anti-psychotic tranquilizer
• Are different from sedative-hypnotic or
  anti-anxiety agents
• Symptoms and nature of psychosis/schizophrenia
  may vary
• Dopamine hypothesis of schizophrenia -
  overactivity of dopaminergic pathways in
  mesolimbic-frontal brain region
• 5 receptor types (D1-5) most anti-psychotic
  agents block D2
• Drugs that increase dopaminergic activity ?
  psychotic episodes
• Agents amphetamines, levodopa or dopamine
  agonists
• Not all patients respond to these drugs! May also
  have problems at other receptor subtypes or at
  the serotonin or a-adrenoreceptors
• Clinical indications psychiatric disorders,
  medical, surgical and obstetrical uses
• Hepatic metabolism with long half-lives - once a
  day dosing
• Extensive binding to plasma proteins - watch for
  drug-drug displacement interactions
• Extrapyramidal effects a concern See Handout!

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Phenothiazines - aliphatics
Indications psychotic disorders including
children, anti-emetic High sedative effects, 4X
potency of chlorpromazine Dosage 60-150
mg/dayIM injection only
Indications psychotic disorders including
children Moderate sedative effects 1/2 potency
of chlorpromazine Dosage 40-1200 mg/day but
improvement at doses gt 1000 mg/day
unlikely Tablets and injection
Indications psychotic disorders, pediatric
behavioral problems, surgery, adjunct in tetanus,
prophyria, anti-emetic, PCP psychosis, migraine
headaches (IV or IM) High sedative effects, Low
potency agent Dosage 300-800 mg/day Thorazine
shuffle and numerous other side effects
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Structure function
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Phenothiazines - piperidines
Indications Schizophrenia, behavioral problems
in mental deficiency and chronic brain syndrome,
acute and chronic alcoholism in hepatic
dysfunction, psychoneurotic manifestations High
sedative effects, Highly potent agent 2X as
potent than chlorpromazine Tablets, concentrate
and injection Dosage 30-400 mg/day Indications
psychotic disorders, psychoneurotic
manifestations, pediatric behavioral
disorders High sedative effects, Equipotent to
chlorpromazine with milder EE, cardiotoxic
agent Tablets, concentrate and suspension 150-800
mg/day
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Phenothiazines - piperazines
Think More potent, more selective!
Indications psychotic disorders Low sedative
effects, Highly potent agent 50X more potent
than chlorpromazine Tablets, elixir, concentrate
and injection Two prodrug esters for use as depot
agents Ethonate duration 1-3 weeks and Deconate
duration gt4 weeks Dosage 0.5-40 mg/day orally,
increased tardive dyskinesia side
effects Indications psychotic disorders,
anti-emetic (IV only) Moderate sedative effects,
10X more potent than chlorpromazine Concentrate
and injection dose forms 12-64 mg/day Administer
1/3 to ½ of the typical adult dose to elderly
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Phenothiazines - piperazines
Think More potent, more selective!
Indications psychotic disorders and
non-psychotic anxiety (short term only) Low
sedative effects, Highly potent agent 20X more
potent than chlorpromazine Tablets, concentrate
and injection Dosage 2-40 mg/day Indications
psychotic disorders, anxiety, acute headache in
the ER, commonly used anti-emetic Moderate
sedative effects, 7.5 times more potent than
chlorpromazine Tablets, SR capsules, syrup,
injection (depot) IM only suppositories 15-150
mg/day
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Dibenzepines
Indications Schizophrenia, bipolar mania,
dementia related to Alzheimers disease Tablets
and orally disintegrating tablets Dosing in
debilitated patients 5 mg to start with max
dose of 20 mg/day Heavily sedating with less
weight gain
Indications Psychotic disorders Tablets
Dosing 50-800 mg/day Multiple neurotransmitter
receptor antagonist 5-HT2, Dopamine, Histamine
H1, a1 and a2 NO anticholinergic side
effects!!no binding to muscarinic receptors
Moderately sedating, less weight gain
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Dibenzepines
Indications Psychotic disorders Capsules,
concentrate, injection dosages gt 250 mg/day are
not recommended, normal doses 20-250 mg 7.5X as
potent as chlorpromazine Injection must be given
IM only for severely agitated patients Mildly
sedating, less weight gain as a side
effect Indications Psychotic disorders not
responding to other agents Tablets dosage
300-900 mg/day Significant (1-2) risk of
agranulocytosis - monitor white cell and
granulocyte counts DO NOT dispense more than a 1
week supply-available only through the Clozaril
patient management system 2X as potent as
chlorpromazine, heavily sedating, less weight
gain as a side effect
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Other agents
Indications Psychotic disorders Low sedative
effects, Highly potent agent 25X as potent than
chlorpromazine Not recommended for children lt12
years old Capsules, concentrate Dosage 8 to 30
mg/day, exceeding 60 mg/day rarely increases
response Indications Psychotic disorders,
Tourettes syndrome, Childhood behavior problems,
hyperactivity, PCP overdosage Tablets,
concentrate and injection (includes a decanate
prodrug for depot use in chronic
schizophrenia) Dosage Should be individualized
- 1 to 15 mg/day, severe extrapyramidal effects,
less sedation (5-HT2) Fewer autonomic effects -
hypotension 50X as potent as chlorpromazine
Thioxanthenes
Butyrophenones
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Other agents
Diphenylbutylpiperadines
Dihydroindolones
Indications Psychotic disorders Tablets and
concentrate Tablets contain calcium sulfatemay
interfere with absorption of other drugs
Tetracyclines (TCN) or phenytoin 10X as potent as
chlorpromazine Dosage 50-75 mg/day to start with
up to 225 mg/day
Indications Tourettes syndrome - suppression
of motor and phonic tics Monitor ECG 2 mg
tabletsno more than 10 mg/day NOT a first line
drug
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Other agents
Benzisoxazoles
Indications Psychotic disorders, bipolar
disorders, dementia-related symptoms Tablets and
oral solution Initial dose in debilitated or
elderly patients is 0.5 mg BID---total dose 4-16
mg/day Mildly sedating, NO anticholinergic side
effects, weight gain
Other Unrelated to phenothiazines/butyrophenone
s
Indications Schizophrenia 20, 40, 60 80 mg
capsules Initial dose 20 mg bid taken with
food gt80 mg not recommended due to dose dependent
QT elongation Extensive hepatic metabolism via
CYP3A4 and 1A2, no inhibition effect on CYP
enzymes
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Drug Effectiveness
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Choosing the right agent
EE Extrapyramidal effects
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Lithium Salts
Warning Lithium concentrations of the serum
must be monitored Eskalith Lithium carbonate
capsules, tablets (normal, slow-release and
controlled release) Syrup Lithium
citrate Indications Mania episodes in
manic-depressive illness (bipolar disorder), and
several unlabeled usesincrease neutrophil counts
in chemotherapy patients, cluster headaches, etc
MOA Alters sodium transport and affects
intraneuronal catecholamine metabolism including
synthesis, reuptake, release and storage of
sympathomimetic biogenic amines High-risk Renal
or CV disease, diuretic use, dehydration -
monitor lithium levels daily after initiating
therapy Many drug interactions, take with food or
milk to prevent GI upset, stay hydrated!
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Misc. Psychotherapeutic Agents
Benzodiazepine TCA - 3º
Piperazine antipsychotic TCA - 3º