Download Chapter 16 Cholinesterase Inhibitors

Antipsychotic Agents and Their
Use in Schizophrenia
Antipsychotic Agents
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Chemically diverse group of compounds
Used for diverse spectrum of psychotic
disorders
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Schizophrenia, delusional disorders, bipolar
disorders, depressive psychoses, drug-induced
psychoses
Also used to suppress emesis and to treat
Tourette’s syndrome and Huntington’s chorea
Should not be used to treat dementia in the
older adult
Antipsychotic Agents
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First-generation antipsychotics (FGAs) or
conventional antipsychotics
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Block receptors for dopamine in CNS
Cause serious movement disorders
(extrapyramidal symptoms [EPS])
Second-generation antipsychotics (SGAs) or
atypical antipsychotics
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Produce only moderate blockade of dopamine
receptors; stronger blockade for serotonin
Fewer EPS
Antipsychotic Agents
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Top-selling medications in the United States
in 2009
Total sales of $14.6 billion
FGA higher risk of EPS
SGA higher risk of metabolic effects
(diabetes, dyslipidemia)
Clinical Presentation
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Disordered thinking and reduced ability to
comprehend reality
Three types of symptoms
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Positive symptoms and negative symptoms
Cognitive symptoms
Acute episodes
Residual symptoms
Long-term course
Causes
Conventional Antipsychotic Agents I:
Group Properties
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Classification
Mechanism of action
Therapeutic uses
Adverse effects
Physical and psychologic dependence
Drug interactions
Toxicity
Classification
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Classification by potency
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Low potency: chlorpromazine HCl (Thorazine)
Medium potency: loxapine (Loxitane)
High potency: haloperidol (Haldol)
Chemical classification
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Six major chemical categories
Drugs in all groups equivalent with respect to
antipsychotic actions
Mechanism of Action
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Conventional antipsychotic drugs block a
variety of receptors within and outside the
CNS
They block dopamine2 (D2) receptors in the
mesolimbic area of the brain
Therapeutic Uses
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Schizophrenia
Bipolar disorder (manic-depressive illness)
Tourette’s syndrome
Prevention of emesis
Other applications
Adverse Effects
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Extrapyramidal symptoms (EPS)
Acute dystonia
Parkinsonism
Akathisia
Tardive dyskinesia
Adverse Effects
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Other adverse effects
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Neuroleptic malignant syndrome
• Rare but serious reaction
• Risk of death without treatment
• Sweating, rigidity, sudden high fever, autonomic
instability
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Anticholinergic effects
• See Table 31-3.
Orthostatic hypotension
Adverse Effects
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Other adverse effects (cont’d)
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Sedation
Neuroendocrine effects
Seizures
Sexual dysfunction
Dermatologic effects
Agranulocytosis
Severe dysrhythmias
Physical and Psychologic
Dependence
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Development of physical and psychologic
dependence is rare
Abrupt withdrawal of antipsychotics can
precipitate a mild abstinence syndrome
Drug Interactions
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Anticholinergic drugs
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CNS depressants
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Intensify the anticholinergic effect
Can intensify the depressant effect
Levodopa and direct dopamine receptor
agonists
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May counteract the antipsychotic effects of
neuroleptics
Toxicity
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Conventional antipsychotic drugs are very
safe
Death by overdose is extremely rare
Overdose produces hypertension, CNS
depression, and EPS
Treatment
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Intravenous fluids, alpha-adrenergic agonist,
gastric lavage
 Emetics not effective: neuroleptics block the
antiemetic action
Conventional Antipsychotic Agents II:
Individual Agents
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Low-potency agents
Medium-potency agents
High-potency agents
Depot preparations
Low-Potency Agents
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Chlorpromazine (Thorazine)
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Therapeutic uses
Pharmacokinetics
Adverse effects
Drug interactions
Preparations, dosage, and administration
• Oral therapy
• Parenteral therapy
Thioridazine (Mellaril)
Medium-Potency Agents
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Loxapine (Loxitane)
Molindone (Moban)
Perphenazine (Trilafon)
High-Potency Agents
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Haloperidol (Haldol)
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Actions and uses
Pharmacokinetics
Adverse effects
Preparations, dosage, and administration
• Oral therapy
• Intramuscular therapy
Other High-Potency Agents
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Fluphenazine (Prolixin)
Trifluoperazine (Stelazine)
Thiothixene (Navane)
Pimozide (Orap)
Atypical Antipsychotic Agents
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Introduced in the 1990s
Less risk of EPS than FGAs
Increased risk of weight gain, diabetes, and
dyslipidemia
Examples: clozapine and other atypical
antipsychotics
Clozapine
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Mechanism of action
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Therapeutic use
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Blocks dopamine and serotonin
Schizophrenia
Levodopa-induced psychosis
Pharmacokinetics
Clozapine
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Adverse effects and interactions
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Agranulocytosis
Seizures
Diabetes
Weight gain
Myocarditis
Effects in older adult patients with dementia
• About double the mortality rate
Drug interactions
Preparations, dosage, and administration
Other Atypical Antipsychotics
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Risperidone (Risperdal)
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Mechanism of action
• Binds to multiple receptors
Pharmacokinetics
Therapeutic effects
Adverse effects
• Generally infrequent and mild
Preparations, dosage, and administration
• Schizophrenia, oral therapy
• Schizophrenia, intramuscular therapy
• Bipolar disorder
Other Atypical Antipsychotics
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Olanzapine (Zyprexa)
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Mechanism of action
• Blocks 5-HT2 receptors
• Blocks D2 receptors
 Pharmacokinetics
 Therapeutic uses
• Schizophrenia
• Bipolar disorder
 Adverse effects
Other Atypical Antipsychotics
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Olanzapine (Zyprexa) (cont’d)
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Preparations, dosage, and administration
• Schizophrenia dosage

Oral dosage
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Oral formulation
• Bipolar disorder dosage
Other Atypical Antipsychotics
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Quetiapine (Seroquel)
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Actions and uses
Pharmacokinetics
Adverse effects
Drug interactions
Preparations, dosage, and administration
• Schizophrenia dosage
• Bipolar disorder dosage
Other Atypical Antipsychotics
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Ziprasidone (Geodon)
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Mechanism of action
• Blocks multiple receptors: D2, 5-HT2, H1
Pharmacokinetics
Adverse effects
Drug interactions
Preparations, dosage, and administration
• Schizophrenia, intramuscular dosage
• Bipolar disorder (see Table 31-4)
Other Atypical Antipsychotics
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Aripiprazole (Abilify)
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Contrasts with other atypical antipsychotic agents
Mechanism of action
• Blocks multiple receptor types
Pharmacokinetics
Adverse effects
Drug interactions
Preparations, dosage, and administration
• Schizophrenia dosage
• Bipolar disorder dosage
Depot Preparations
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Depot antipsychotics: long-acting, injectable
formulations used for long-term maintenance
therapy of schizophrenia
No evidence that depot preparations pose an
increased risk of side effects
Three depot preparations available
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Haloperidol decanoate (Haldol Decanoate)
 Fluphenazine decanoate (Prolixin Decanoate)
 Risperidone microspheres (Risperdal Consta)
Schizophrenia Drug Therapy
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Three major objectives
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Suppression of acute episodes
Prevention of acute exacerbations
Maintenance of the highest possible level of
functioning
Drug selection
Dosing
Route
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Oral (tablets, capsules, liquids)
Intramuscular
Schizophrenia Drug Therapy
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Most FGAs and SGAs are equally effective,
except for clozapine, which is more effective
than the rest
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FGAs: significant risk of EPS
SGAs: risk of metabolic effects
FGAs: cost 10 times less than SGAs
Schizophrenia Drug Therapy
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Dosing
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Highly individualized
Older adult patients require relatively small doses.
Size and timing likely to be changed over course
of therapy
Routes
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Oral (preferred)
Intramuscular
Schizophrenia Drug Therapy
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Initial therapy
Maintenance therapy
Adjunctive drugs
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Benzodiazepines
Antidepressants
Schizophrenia Drug Therapy
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Promoting adherence
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Ensure that the medication is taken
Encourage family members to oversee medication
for outpatients
Provide patients with instructions
Inform patients and their families that
antipsychotics must be taken on a regular
schedule
Schizophrenia Drug Therapy
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Promoting adherence (cont’d)
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Inform patients about side effects of treatment
Assure patients that antipsychotic drug use does
not lead to addiction
Establish a good therapeutic relationship with
patient
Use an intramuscular depot preparation for longterm therapy
Schizophrenia Nondrug Therapy
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Counseling for patient and family
Behavioral therapy
Vocational training