chapter 31

Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

Chapter 31

Antipsychotic Agents and Their Use in Schizophrenia

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

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


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


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)


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


Conventional Antipsychotic Agents I: Group Properties

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


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


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


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


Adverse Effects Extrapyramidal symptoms (EPS) Acute dystonia Parkinsonism Akathisia Tardive dyskinesia


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


Adverse Effects Other adverse effects (cont’d)

Sedation Neuroendocrine effects Seizures Sexual dysfunction Dermatologic effects Agranulocytosis Severe dysrhythmias


Physical and Psychologic Dependence

Development of physical and psychologic dependence is rare

Abrupt withdrawal of antipsychotics can precipitate a mild abstinence syndrome


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


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


Conventional Antipsychotic Agents II: Individual Agents

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


Low-Potency Agents Chlorpromazine (Thorazine)

Therapeutic uses Pharmacokinetics Adverse effects Drug interactions Preparations, dosage, and administration

• Oral therapy• Parenteral therapy

Thioridazine (Mellaril)


Medium-Potency Agents Loxapine (Loxitane) Molindone (Moban) Perphenazine (Trilafon)


High-Potency Agents Haloperidol (Haldol)

Actions and uses Pharmacokinetics Adverse effects Preparations, dosage, and administration

• Oral therapy • Intramuscular therapy


Other High-Potency Agents Fluphenazine (Prolixin) Trifluoperazine (Stelazine) Thiothixene (Navane) Pimozide (Orap)


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


Clozapine Mechanism of action

Blocks dopamine and serotonin Therapeutic use

Schizophrenia Levodopa-induced psychosis

Pharmacokinetics


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


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


Other Atypical Antipsychotics

Olanzapine (Zyprexa) Mechanism of action

• Blocks 5-HT2 receptors• Blocks D2 receptors

Pharmacokinetics Therapeutic uses

• Schizophrenia• Bipolar disorder

Adverse effects



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

• Schizophrenia dosage Oral dosage

• Bipolar disorder dosage Oral formulation



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

• Schizophrenia dosage• Bipolar disorder dosage



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)



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


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)


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


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


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


Schizophrenia Drug Therapy Initial therapy Maintenance therapy Adjunctive drugs

Benzodiazepines Antidepressants


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


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


Schizophrenia Nondrug Therapy Counseling for patient and family Behavioral therapy Vocational training

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antipsychotic actions

antipsychotic agentstop

variety of receptors

potencylow potency

bipolar disorders

delusional disorders

loxapine loxitanehigh