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Chapter 31

Antipsychotic Agents and Their Use in Schizophrenia

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Antipsychotic Agents

Chemically diverse group of compounds Used for diverse spectrum of psychotic

disorders 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

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Antipsychotic Agents

First-generation antipsychotics (FGAs) or conventional antipsychotics Block receptors for dopamine in CNS Cause serious movement disorders

(extrapyramidal symptoms [EPS]) Second-generation antipsychotics (SGAs) or

atypical antipsychotics Produce only moderate blockade of dopamine

receptors; stronger blockade for serotonin Fewer EPS

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Antipsychotic Agents

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)

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Clinical Presentation

Disordered thinking and reduced ability to comprehend reality

Three types of symptoms Positive symptoms and negative symptoms Cognitive symptoms

Acute episodes Residual symptoms Long-term course Causes

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Conventional Antipsychotic Agents I: Group Properties

Classification Mechanism of action Therapeutic uses Adverse effects Physical and psychologic dependence Drug interactions Toxicity

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Classification

Classification by potency Low potency: chlorpromazine HCl (Thorazine) Medium potency: loxapine (Loxitane) High potency: haloperidol (Haldol)

Chemical classification Six major chemical categories Drugs in all groups equivalent with respect to

antipsychotic actions

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Mechanism of Action

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

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Therapeutic Uses

Schizophrenia Bipolar disorder (manic-depressive illness) Tourette’s syndrome Prevention of emesis Other applications

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Adverse Effects

Extrapyramidal symptoms (EPS) Acute dystonia Parkinsonism Akathisia Tardive dyskinesia

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Adverse Effects

Other adverse effects Neuroleptic malignant syndrome

• Rare but serious reaction• Risk of death without treatment• Sweating, rigidity, sudden high fever, autonomic

instability Anticholinergic effects

• See Table 31-3. Orthostatic hypotension

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Adverse Effects

Other adverse effects (cont’d) Sedation Neuroendocrine effects Seizures Sexual dysfunction Dermatologic effects Agranulocytosis Severe dysrhythmias

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Physical and Psychologic Dependence

Development of physical and psychologic dependence is rare

Abrupt withdrawal of antipsychotics can precipitate a mild abstinence syndrome

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Drug Interactions

Anticholinergic drugs Intensify the anticholinergic effect

CNS depressants Can intensify the depressant effect

Levodopa and direct dopamine receptor agonists May counteract the antipsychotic effects of

neuroleptics

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Toxicity

Conventional antipsychotic drugs are very safe

Death by overdose is extremely rare Overdose produces hypertension, CNS

depression, and EPS Treatment

Intravenous fluids, alpha-adrenergic agonist, gastric lavage

Emetics not effective: neuroleptics block the antiemetic action

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Conventional Antipsychotic Agents II: Individual Agents

Low-potency agents Medium-potency agents High-potency agents Depot preparations

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Low-Potency Agents

Chlorpromazine (Thorazine) Therapeutic uses Pharmacokinetics Adverse effects Drug interactions Preparations, dosage, and administration

• Oral therapy• Parenteral therapy

Thioridazine (Mellaril)

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Medium-Potency Agents

Loxapine (Loxitane) Molindone (Moban) Perphenazine (Trilafon)

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High-Potency Agents

Haloperidol (Haldol) Actions and uses Pharmacokinetics Adverse effects Preparations, dosage, and administration

• Oral therapy • Intramuscular therapy

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Other High-Potency Agents

Fluphenazine (Prolixin) Trifluoperazine (Stelazine) Thiothixene (Navane) Pimozide (Orap)

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Atypical Antipsychotic Agents

Introduced in the 1990s Less risk of EPS than FGAs Increased risk of weight gain, diabetes, and

dyslipidemia Examples: clozapine and other atypical

antipsychotics

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Clozapine

Mechanism of action Blocks dopamine and serotonin

Therapeutic use Schizophrenia Levodopa-induced psychosis

Pharmacokinetics

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Clozapine

Adverse effects and interactions Agranulocytosis Seizures Diabetes Weight gain Myocarditis Effects in older adult patients with dementia

• About double the mortality rate Drug interactions

Preparations, dosage, and administration

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Other Atypical Antipsychotics

Risperidone (Risperdal) 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

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Other Atypical Antipsychotics

Olanzapine (Zyprexa) Mechanism of action

• Blocks 5-HT2 receptors• Blocks D2 receptors

Pharmacokinetics Therapeutic uses

• Schizophrenia• Bipolar disorder

Adverse effects

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Other Atypical Antipsychotics

Olanzapine (Zyprexa) (cont’d) Preparations, dosage, and administration

• Schizophrenia dosage Oral dosage

• Bipolar disorder dosage Oral formulation

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Other Atypical Antipsychotics

Quetiapine (Seroquel) Actions and uses Pharmacokinetics Adverse effects Drug interactions Preparations, dosage, and administration

• Schizophrenia dosage• Bipolar disorder dosage

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Other Atypical Antipsychotics

Ziprasidone (Geodon) 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)

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Other Atypical Antipsychotics

Aripiprazole (Abilify) 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

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Depot Preparations

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 Haloperidol decanoate (Haldol Decanoate) Fluphenazine decanoate (Prolixin Decanoate) Risperidone microspheres (Risperdal Consta)

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Schizophrenia Drug Therapy

Three major objectives Suppression of acute episodes Prevention of acute exacerbations Maintenance of the highest possible level of

functioning Drug selection Dosing Route

Oral (tablets, capsules, liquids) Intramuscular

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Schizophrenia Drug Therapy

Most FGAs and SGAs are equally effective, except for clozapine, which is more effective than the rest FGAs: significant risk of EPS SGAs: risk of metabolic effects FGAs: cost 10 times less than SGAs

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Schizophrenia Drug Therapy

Dosing Highly individualized Older adult patients require relatively small doses. Size and timing likely to be changed over course

of therapy Routes

Oral (preferred) Intramuscular

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Schizophrenia Drug Therapy

Initial therapy Maintenance therapy Adjunctive drugs

Benzodiazepines Antidepressants

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Schizophrenia Drug Therapy

Promoting adherence 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

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Schizophrenia Drug Therapy

Promoting adherence (cont’d) 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 long-

term therapy

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Schizophrenia Nondrug Therapy

Counseling for patient and family Behavioral therapy Vocational training