Extrapyramidal Syndrome

Pseudoparkinsonism, which resembles symptoms of Parkinson’s disease, is a major side effect of typical antipsychotic drugs. Symptoms of pseudoparkinsonism, or EPS, include stooped posture, masklike facies, rigidity, tremors at rest, shuffling gait, pill-rolling motion of the hand, and bradykinesia. When patients take high-potency typical antipsychotic drugs, these symptoms are more pronounced. Patients who take low-strength antipsychotics such as chlorpromazine (Thorazine) are not as likely to have symptoms of pseudoparkinsonism as those who take fluphenazine (Prolixin).

During early treatment with typical antipsychotic agents for schizophrenia and other psychotic disorders, two adverse extrapyramidal reactions that may occur are acute dystonia and akathisia. Tardive dyskinesia is a later phase of extrapyramidal reaction to antipsychotics. Use of anticholinergic drugs helps decrease pseudoparkinsonism symptoms, acute dystonia, and akathisia, but has little effect on alleviating tardive dyskinesia.

The symptoms of acute dystonia usually occur in 5% of patients within days of taking typical antipsychotics. Characteristics of the reaction include muscle spasms of the face, tongue, neck, and back; facial grimacing; abnormal or involuntary upward eye movement; and laryngeal spasms that can impair respiration. This condition is treated with anticholinergic/antiparkinsonism drugs such as benztropine (Cogentin). The benzodiazepine lorazepam (Ativan) may also be prescribed.

Akathisia occurs in approximately 20% of patients who take a typical antipsychotic drug. With this reaction, the patient has trouble standing still, is restless, paces the floor, and is in constant motion (e.g., rocks back and forth). Akathisia is best treated with a benzodiazepine (e.g., lorazepam) or a beta blocker (e.g., propranolol).

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal condition associated with antipsychotic drugs. Predisposing factors include excess agitation, exhaustion, and dehydration. NMS symptoms involve muscle rigidity, sudden high fever, altered mental status, blood pressure fluctuations, tachycardia, dysrhythmias, seizures, rhabdomyolysis, acute renal failure, respiratory failure, and coma. Treatment of NMS involves immediate withdrawal of antipsychotics, adequate hydration, hypothermic blankets, and administration of antipyretics, benzodiazepines, and muscle relaxants such as dantrolene (Dantrium).

Pharmacokinetics

Oral absorption of fluphenazine is rapid and not affected by food. This drug is strongly protein-bound and has a long half-life; therefore, the drug may accumulate. Fluphenazine is metabolized by the liver, crosses the blood-brain barrier and placenta, and is excreted as metabolites primarily in the urine. With hepatic dysfunction, the phenothiazine dose may need to be decreased. Lack of drug metabolism in the liver will cause an elevation in serum drug level.

Pharmacodynamics

Fluphenazine is prescribed primarily for psychotic disorders. This drug has anticholinergic properties and should be cautiously administered to patients with glaucoma, especially narrow-angle glaucoma. Because hypotension is a side effect of these phenothiazines, any antihypertensives simultaneously administered can cause an additive hypotensive effect. Narcotics and sedative-hypnotics administered simultaneously with these phenothiazines can cause an additive CNS depression. Antacids decrease the absorption rate of both drugs and all phenothiazines, so they should be given 1 hour before or 2 hours after an oral phenothiazine.

The onset of action for fluphenazine hydrochloride is 1 hour, with a duration rate of 6 to 8 hours. Fluphenazine decanoate has delayed absorption, with an onset of action of 24 to 72 hours and a duration of 1 to 6 weeks.

Pharmacokinetics

Haloperidol is absorbed well through the gastrointestinal (GI) mucosa. It has a long half-life and is highly protein-bound, so the drug may accumulate. Haloperidol is metabolized in the liver and excreted in urine and feces.

Pharmacodynamics

Haloperidol alters the effects of dopamine by blocking dopamine receptors; thus sedation and EPS may occur. The drug is used to control psychoses and decrease agitation in adults and children. Dosages need to be decreased in older adults because of decreased liver function and potential side effects. It may be prescribed for children with hyperactive behavior. Haloperidol has anticholinergic activity, so care should be taken when administering it to patients with a history of glaucoma.

Haloperidol has a similar onset of action, peak time of concentration, and duration of action as phenothiazines. It has strong EPS effects. Skin protection is necessary for prolonged use because of the possible side effect of photosensitivity.

From the dibenzoxazepine group, loxapine (Loxitane) is a moderately potent agent. It has moderate sedative and orthostatic hypotensive effects and a strong EPS effect.

The typical antipsychotic molindone hydrochloric acid (Moban) from the dihydroindolone group is a moderately potent agent. It has low sedative and orthostatic hypotensive effects and a strong EPS effect.

In the nonphenothiazine group known as thioxanthenes is thiothixene (Navane), a highly potent typical antipsychotic drug. It has side effects similar to those of molindone with low sedative and orthostatic hypotensive effects and a strong EPS effect.

Side Effects and Adverse Reactions

Several side effects are associated with antipsychotics. The most common side effect for all antipsychotics is drowsiness. Many of the antipsychotics have some anticholinergic effects: dry mouth, increased heart rate, urinary retention, and constipation. Blood pressure decreases with the use of antipsychotics; aliphatics and piperidines cause a greater decrease in blood pressure than the others.

EPS can begin within 5 to 30 days after initiation of antipsychotic therapy and are most prevalent with the phenothiazines, butyrophenones, and thioxanthenes. These symptoms include pseudoparkinsonism, akathisia, dystonia (prolonged muscle contractions with twisting, repetitive movements), and tardive dyskinesia. Tardive dyskinesia may develop in 20% of patients taking antipsychotics for long-term therapy. Antiparkinsonian anticholinergic drugs may be given to control EPS, but they are not always effective in treating tardive dyskinesia.

High dosing or long-term use of some antipsychotics can cause blood dyscrasias (blood cell disorders) such as agranulocytosis. White blood cell (WBC) count should be closely monitored and reported to the health care provider if there is an extreme decrease in leukocytes.

Dermatologic side effects seen early in drug therapy are pruritus and marked photosensitivity. Patients are urged to use sunscreen, hats, and protective clothing and to stay out of the sun.

Drug Interactions

Because phenothiazine lowers the seizure threshold, dosage adjustment of an anticonvulsant may be necessary. If either aliphatic phenothiazine or the thioxanthene group is administered, a higher dose of anticonvulsant might be necessary to prevent seizures.

Antipsychotics interact with alcohol, hypnotics, sedatives, narcotics, and benzodiazepines to potentiate the sedative effects of antipsychotics. Atropine counteracts EPS and potentiates antipsychotic effects. Use of antihypertensives can cause an additive hypotensive effect.

Antipsychotics should not be given with other antipsychotic or antidepressant drugs except to control psychotic behavior for selected individuals who are refractory to drug therapy. Under ordinary circumstances, if one antipsychotic drug is ineffective, a different one is prescribed. Individuals should not take alcohol or other CNS depressants (e.g., narcotic analgesics, barbiturates) with antipsychotics, because additive depression is likely to occur.