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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
3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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)
5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Conventional Antipsychotic Agents I: Group Properties
Classification Mechanism of action Therapeutic uses Adverse effects Physical and psychologic dependence Drug interactions Toxicity
7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Therapeutic Uses
Schizophrenia Bipolar disorder (manic-depressive illness) Tourette’s syndrome Prevention of emesis Other applications
10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Adverse Effects
Extrapyramidal symptoms (EPS) Acute dystonia Parkinsonism Akathisia Tardive dyskinesia
11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Adverse Effects
Other adverse effects (cont’d) Sedation Neuroendocrine effects Seizures Sexual dysfunction Dermatologic effects Agranulocytosis Severe dysrhythmias
13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Physical and Psychologic Dependence
Development of physical and psychologic dependence is rare
Abrupt withdrawal of antipsychotics can precipitate a mild abstinence syndrome
14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Conventional Antipsychotic Agents II: Individual Agents
Low-potency agents Medium-potency agents High-potency agents Depot preparations
17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Low-Potency Agents
Chlorpromazine (Thorazine) Therapeutic uses Pharmacokinetics Adverse effects Drug interactions Preparations, dosage, and administration
• Oral therapy• Parenteral therapy
Thioridazine (Mellaril)
18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Medium-Potency Agents
Loxapine (Loxitane) Molindone (Moban) Perphenazine (Trilafon)
19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
High-Potency Agents
Haloperidol (Haldol) Actions and uses Pharmacokinetics Adverse effects Preparations, dosage, and administration
• Oral therapy • Intramuscular therapy
20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Other High-Potency Agents
Fluphenazine (Prolixin) Trifluoperazine (Stelazine) Thiothixene (Navane) Pimozide (Orap)
21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Clozapine
Mechanism of action Blocks dopamine and serotonin
Therapeutic use Schizophrenia Levodopa-induced psychosis
Pharmacokinetics
23Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
24Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
25Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Other Atypical Antipsychotics
Olanzapine (Zyprexa) Mechanism of action
• Blocks 5-HT2 receptors• Blocks D2 receptors
Pharmacokinetics Therapeutic uses
• Schizophrenia• Bipolar disorder
Adverse effects
26Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Other Atypical Antipsychotics
Olanzapine (Zyprexa) (cont’d) Preparations, dosage, and administration
• Schizophrenia dosage Oral dosage
• Bipolar disorder dosage Oral formulation
27Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Other Atypical Antipsychotics
Quetiapine (Seroquel) Actions and uses Pharmacokinetics Adverse effects Drug interactions Preparations, dosage, and administration
• Schizophrenia dosage• Bipolar disorder dosage
28Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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)
29Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
30Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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)
31Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
32Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
33Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
34Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Schizophrenia Drug Therapy
Initial therapy Maintenance therapy Adjunctive drugs
Benzodiazepines Antidepressants
35Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
36Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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
37Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
Schizophrenia Nondrug Therapy
Counseling for patient and family Behavioral therapy Vocational training