?????? PHARMACOLOGY OF ANTIPSYCHOTIC DRUGS (NEUROLEPTICS)

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??????PHARMACOLOGY OF ANTIPSYCHOTIC DRUGS
(NEUROLEPTICS)
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SOME DEFINITIONS

• Neuroleptic synonym for antipsychotic drug
  originally indicated drug w/antipsychotic
  efficacy but with neurologic (extrapyramidal
  motor) side effects
• Typical neuroleptic older agents fitting this
  description
• Atypical neuroleptic newer agents antipsychotic
  efficacy with reduced or no neurologic side
  effects

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NEUROLEPTICS ON THE UUHSC DRUG LIST

• TYPICAL NEUROLEPTICS
• PHENOTHIAZINES
• Chlorpromazine (Thorazine )
• Thioridazine (Mellaril )
• Fluphenazine (Prolixin )
• THIOXANTHENE
• Thiothixene (Navane )
• OTHER
• Haloperidol (Haldol )

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NEUROLEPTICS ON THE UUHSC DRUG LIST (Continued)

• ATYPICAL NEUROLEPTICS
• Risperidone (Risperdal most frequently
  prescribed in U.S.)
• Clozapine (Clozaril )
• Olanzapine (Zyprexa )
• Quetiapine (Seroquel )

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KEY CONCEPTS

• All neuroleptics are equally effective in
  treating psychoses, including schizophrenia, but
  differ in their tolerability.
• All neuroleptics block one or more types of
  DOPAMINE receptor, but differ in their other
  neurochemical effects.
• All neuroleptics show a significant delay before
  they become effective.
• All neuroleptics produce significant adverse
  effects.

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GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS

• The older, typical neuroleptics are effective
  antipsychotic agents with neurologic side effects
  involving the extrapyramidal motor system.
• Typical neuroleptics block the dopamine-2
  receptor.

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GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS

• Typical neuroleptics do not produce a general
  depression of the CNS, e.g. respiratory
  depression
• Abuse, addiction, physical dependence do not
  develop to typical neuroleptics.

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GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS

• Typical neuroleptics are generally more effective
  against positive (active) symptoms of
  schizophrenia than the negative (passive)
  symptoms.

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• Positive/active symptoms include thought
  disturbances, delusions, hallucinations
• Negative/passive symptoms include social
  withdrawal, loss of drive, diminished affect,
  paucity of speech. impaired personal hygiene

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THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS

• All appear equally effective choice usually
  based on tolerability of side effects
• Most common are haloperidol (Haldol ),
  chlorpromazine (Thorazine ) and thioridazine
  (Mellaril )
• Latency to beneficial effects 4-6 week delay
  until full response is common
• 70-80 of patients respond, but 30-40 show only
  partial response

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THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS
(Continued)

• Relapse, recurrence of symptoms is common (
  approx. 50 within two years).
• Noncompliance is common.
• Adverse effects are common.

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ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS

• Anticholinergic (antimuscarinic) side effects
• Dry mouth, blurred vision, tachycardia,
  constipation, urinary retention, impotence

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ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS

• Antiadrenergic (Alpha-1) side effects
• Orthostatic hypotension w/ reflex tachycardia
• sedation

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ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS

• Antihistamine effect sedation, weight gain

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KEY CONCEPT DOPAMINE-2 RECEPTOR BLOCKADE IN THE
BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR
SIDE EFFECTS (EPS).

• DYSTONIA
• NEUROLEPTIC MALIGNANT SYNDROME
• PARKINSONISM
• TARDIVE DYSKINESIA
• AKATHISIA

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ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
(Continued)

• Increased prolactin secretion (common with all
  from dopamine blockade)
• Weight gain (common, antihistamine effect?)
• Photosensitivity (v. common w/ phenothiazines)
• Lowered seizure threshold (common with all)
• Leucopenia , agranulocytosis (rare w/
  phenothiazines)
• Retinal pigmentopathy (rare w/ phenothiazines)

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ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
(Continued)

• Chlorpromazine and thioridazine produce marked
  autonomic side effects and sedation EPS tend to
  be weak (thioridazine) or moderate
  (chlorpromazine).
• Haloperidol, thiothixene and fluphenazine produce
  weak autonomic and sedative effects, but EPS are
  marked.

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MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICS

• DOPAMINE-2 receptor blockade in meso-limbic and
  meso-cortical systems for antipsychotic effect.
• DOPAMINE-2 receptor blockade in basal ganglia
  (nigro-striatal system) for EPS
• DOPAMINE-2 receptor supersensitivity in
  nigrostriatal system for tardive dyskinesia

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LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE

• Dopamine neurons reduce activity.
• Postsynaptic D-2 receptor numbers increase
  (compensatory response).
• When D2 blockade is reduced, DA neurons resume
  firing and stimulate increased of receptors gtgt
  hyper-dopamine state gtgt tardive dyskinesia

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MANAGEMENT OF EPS

• Dystonia and parkinsonism anticholinergic
  antiparkinson drugs
• Neuroleptic malignant syndrome muscle relaxants,
  DA agonists, supportive
• Akathisia benzodiazepines, propranolol
• Tardive dyskinesia increase neuroleptic dose
  switch to clozapine

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ADDITIONAL CLINICAL USES OF TYPICAL NEUROLEPTICS

• Adjunctive in Rx of acute manic episode
• Tourettes syndrome (esp. Haldol )
• Rx of drug-induced psychoses
• Phenothiazines are effective anti-emetics,
• Esp. prochlorperazine (Compazine )
• Also, anti-migraine effect

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GENERAL CHARACTERISTICS OF ATYPICAL NEUROLEPTICS

• Effective antipsychotic agents with greatly
  reduced or absent EPS, esp. reduced Parkinsonism
  and tardive dyskinesia
• All atypical neuroleptics block dopamine and
  serotonin receptors other neurochemical effects
  differ
• Are effective against positive and negative
  symptoms of schizophrenia and in patients
  refractory to typical neuroleptics

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PHARMACOLOGY OF CLOZAPINE (CLOZARIL )

• FDA-approved for patients not responding to other
  agents or with severe tardive dyskinesia
• Effective against negative symptoms
• Also effective in bipolar disorder
• Little or no parkinsonism, tardive dyskinesia,
  PRL elevation, neuro-malignant syndrome some
  akathisia

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• Blockade of alpha-1 adrenergic receptors
• Blockade of muscarinic cholinergic receptors
• Blockade of histamine-1 receptors

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PHARMACOLOGY OF CLOZAPINE (Continued )

• Other adverse effects
• Weight gain
• Increased salivation
• Increased risk of seizures
• Risk of agranulocytosis requires continual
  monitoring

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PHARMACOLOGY OF OLANZAPINE (ZYPREXA )

• Olanzapine is clozapine without the
  agranulocytosis.
• Same therapeutic effectiveness
• Same side effect profile

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PHARMACOLOGY OF QUETIAPINE (SEROQUEL )

• Quetiapine is olanzapine without the
  anticholinergic effects.
• Same therapeutic effectiveness
• Same side effect profile

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• Highly effective against positive and negative
  symptoms
• Adverse effects
• EPS incidence is dose-related
• Alpha-1 receptor blockade
• Little or no anticholinergic or antihistamine
  effects
• Weight gain, PRL elevation

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HYPOTHESIZED MECHANISMS OF ACTION OF ATYPICAL
NEUROLEPTICS

• Combination of Dopamine-4 and Serotonin-2
  receptor blockade in cortical and limbic areas
  for the pines
• Combination of Dopamine-2 and Serotonin-2
  receptor blockade (esp. risperidone)

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General Therapeutic Principles for Use of
Neuroleptics in Schizophrenia(NIH Consensus
Statement, 1999)

• Use atypical for
• 1st acute episode w/ or /- symptoms
• Switch to atypical if
• Breakthrough after Rx w/ typical
• Use typical (depot prep) when
• Patient is noncompliant

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General Therapeutic Principles for Use of
Neuroleptics in Schizophrenia

• If response is inadequate to
• Typical switch to Atypical
• Atypical raise dose or switch to another
  Atypical
• Typical and Atypical switch to Clozaril
• For maintenance, lifetime Rx is required.