Psychotherapeutic Drugs

Chapter 10 Psychotherapeutic Drugs

I. Antipsychotic Drugs, Sometimes Referred to as Neuroleptic Drugs (Box 10-1)

1. Neuroleptics are useful in the treatment of schizophrenia.

Neuroleptics useful in treatment of schizophrenia

2. These drugs reduce positive symptoms (e.g., paranoia, hallucinations, delusions) more than negative symptoms (e.g., emotional blunting, poor socialization, cognitive deficit) in patients with schizophrenia.

3. The newer “atypical” antipsychotics are more effective, especially against negative symptoms, and less toxic than the older but less expensive conventional antipsychotics.

“Atypical” antipsychotics better for negative symptoms, especially clozapine.

4. Late in 2003, the U.S. Food and Drug Administration (FDA) requested all manufacturers to include product label warnings about the potential for an increased risk of hyperglycemia and diabetes with the use of “atypical” antipsychotics.

“Atypical” antipsychotics may increase risk of metabolic syndrome including diabetes mellitus.

5. April 2005, FDA issued a boxed warning that “atypical” antipsychotics increased risk of death in patients treated with certain “atypical” antipsychotics for dementia-related behavioral disorders.

Antipsychotics may increase risk of death in patients with dementia-related behavioral disorders.

6. June 2008, this boxed warning was extended to conventional antipsychotics (e.g., haloperidol, fluphenazine) as well.

B. Pharmacokinetics

1. Immediate onset after intramuscular or intravenous injection

2. Slow and variable absorption after oral administration

3. Most antipsychotics are metabolized to active and inactive metabolites.

4. Haloperidol (every 4 weeks) and fluphenazine (every 2 weeks) decanoate salts are available as depot preparations for noncompliant patients.

5. Risperidone is also available as an intramuscular preparation that can be given every 2 weeks.

Intramuscular “depot” preparations good for noncompliant patients.

C. Mechanism of action (Table 10-1)

1. All antipsychotics alter dopamine pathways; the antipsychotic activity correlates best with changes in mesolimbic and mesocortical pathways where adverse effects are often due to changes in nigrostriatal and tuberoinfundibular pathways (Table 10-2 and Fig. 10-1)

TABLE 10-1 Mechanisms and Effects of Neuroleptic Agents

Mechanism	Action
Blockade of dopamine D₁ and D₂ receptors	Antipsychotic, extrapyramidal, and endocrine effects
Blockade of α-adrenergic receptors	Hypotension, failure to ejaculate
Blockade of histamine H₁ receptors	Sedation
Blockade of muscarinic receptors	Anticholinergic effects (e.g., dry mouth, urinary retention)
Blockade of serotonin receptors	Antipsychotic effects

TABLE 10-2 Central Dopamine Pathways

10-1 Dopaminergic (DA) pathways in the brain responsible for the beneficial and adverse effects of many antipsychotic drugs.

(From Kester M, et al.: Elsevier’s Integrated Pharmacology. Philadelphia, Mosby, 2007, Figure 13-6.)

Antipsychotic effects of neuroleptic agents are related to blockade of dopamine receptors.

2. Blockade of dopamine D₂ receptor correlates best with antipsychotic activity.

3. Blockade of dopamine D₃ and D₄ receptors may also contribute to therapeutic effects.

4. Blockade of serotonin receptors may contribute to benefits against negative symptoms.

5. Blockade of other receptors also occurs (see Table 10-1).

1. Schizophrenic reactions, mania, psychosis

• The actions of the neuroleptic agents in the mesolimbic and mesocortical pathways are most important for their antipsychotic effects.

2. Nausea (antiemetic)

a. Prochlorperazine

b. Benzquinamide

3. Intractable hiccoughs

• Chlorpromazine

4. Antipruritic

• Promethazine

E. Adverse effects

• Neuroleptics cause unpleasant effects, thus have no abuse potential.

1. Behavioral effects, such as pseudodepression

2. Phenothiazines and related compounds produce many adverse effects by antagonizing:

a. Alpha adrenergic receptors

b. Muscarinic cholinergic receptors

c. Histamine receptors

Many adverse effects of phenothiazines associated with blocking alpha, muscarinic or histaminergic receptors.

3. Neurologic effects

a. Extrapyramidal effects and iatrogenic Parkinsonism

Antipsychotics with strongest D₂ blocking actions have highest incidence of extrapyramidal adverse effects.

b. Dystonic reactions and akathisia

• The best treatment is diphenhydramine or benztropine (antimuscarinic action).

(1) Acute dystonic reactions (1−5 days)

• Involvement of neck and head muscles

(2) Akathisia (5−60 days)

• Restlessness and agitation seen as continuous movement

(3) Parkinsonian syndrome (5−30 days)

Acute dystonia, akathisia, and Parkinsonian extrapyramidal adverse effects of antipsychotics can be treated with anticholinergics.

(a) Extrapyramidal effects

(d) Shuffling gait

(e) Postural abnormalities

(4) Neuroleptic malignant syndrome (weeks)

(d) Unstable blood pressure (autonomic instability)

• May be fatal

• Treatment involves stopping the neuroleptic drug and using dantrolene and/or bromocriptine.

Neuroleptic malignant syndrome is treated with dantrolene and/or bromocriptine.

(5) Perioral tremor (months or years)

(a) Rabbit syndrome (involuntary movement of the lips)

(b) Treatment involves the use of anticholinergic agents.

(6) Tardive dyskinesia (months or years) producing stereotypical involuntary movements

(a) Frequently irreversible

(b) Results from effects on dopamine D₂ receptors

(c) Treatment involves clozapine or diazepam

Tardive dyskinesia is associated with prolonged use of traditional neuroleptics; especially those with strong dopamine receptor antagonism

c. Decrease in seizure threshold

(1) Use caution when giving neuroleptics to individuals with epilepsy.

(2) Avoid giving these drugs to patients who are undergoing withdrawal from central nervous system (CNS) depressants.

d. Weight gain is high with many

Extensive weight gain with olanzapine and quetiapine.

e. QT_c prolongation

(1) Ziprasidone

(2) Thioridazine

(3) Haloperidol

f. Elevated serum prolactin

Use of neuroleptics leads to hyperprolactinemia, which results in amenorrhea-galactorrhea syndrome and infertility in women and loss of libido, impotence, and infertility in men.

F. Specific drugs (Table 10-3)

1. Aliphatic phenothiazines (e.g., chlorpromazine)

• Least potent phenothiazine

2. Piperidine phenothiazines (e.g., thioridazine)

a. Generally low incidence of acute extrapyramidal effects

b. Requires regular eye examinations because of retinitis pigmentosa

TABLE 10-3 Effects of Antipsychotic Drugs

Thioridazine noted for causing retinitis pigmentosa (irreversible).

3. Piperazine phenothiazines (e.g., fluphenazine)

• Generally high incidence of acute extrapyramidal effects

4. Butyrophenones

(1) Haloperidol

b. Additional uses for haloperidol

(1) Tourette’s syndrome

(2) Acute psychosis

(3) Alcoholic hallucinosis

c. Extremely high incidence of acute extrapyramidal effects

5. Azepines (“atypical” agents)

(1) Mechanism of action

(a) Blocks serotonin and dopamine (especially, D₁ and D₄) receptors, with a greater effect on the serotonin receptors (5-hydroxytryptamine [5-HT_2A])

(b) Has less effect on dopamine D₂ receptors than conventional antipsychotics

(c) Has a greater effect on negative symptoms of schizophrenia than the older conventional antipsychotics

(2) Adverse effects

(a) Low incidence of extrapyramidal effects

(b) High incidence of agranulocytosis (1−2%), which necessitates regular (weekly) complete blood counts (CBCs)

Clozapine is associated with agranulocytosis.

(c) Very sedating

Clozapine is very sedating.

• Newer clozapine-like agent with no notable incidence of agranulocytosis

Olanzapine is worst for producing weight gain.

• Newer “atypical” antipsychotic agent structurally similar to clozapine, a dibenzodiazepine structure

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Tags: Rapid Review Pharmacology

Apr 8, 2017 | Posted by admin in PHARMACY | Comments Off

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