Chlorpromazine

Chlorpromazine is readily absorbed from the gastrointestinal tract; however, its bioavailability is variable due to considerable first-pass metabolism by the liver. Liquid concentrates may have greater bioavailability than tablets. Food does not appear to affect bioavailability consistently. I.M. administration bypasses much of the first-pass effect and higher plasma concentrations are achieved. The onset of action after i.m. administration is usually 15 to 30 minutes and after oral administration 30 to 60 minutes. Rectally administered chlorpromazine has a longer onset of action compared to the oral route.

Chlorpromazine is highly bound to plasma proteins (> 90%), principally albumin. It is not dialyzable. It is distributed widely throughout the body; it crosses the blood brain barrier and the placenta and is distributed into breast milk. Volume of distribution is approximately 20 L/kg.

Chlorpromazine is metabolized extensively by the cytochrome P450 isoenzymes CYP2D6 and CYP3A4, and at least 12 different metabolites are known. Less than 1% is excreted unchanged. Most metabolites are excreted in the urine as unconjugated or conjugated forms. The half-life of chlorpromazine is variable at approximately 30 hours.

Use reduced dosages. Elderly patients are more sensitive to the therapeutic and adverse effects of phenothiazines particularly postural hypotension, cognitive impairment, extrapyramidal effects and anticholinergic effects such as constipation, urinary retention and blurred vision.

As a substrate of the cytochrome P450 isoenzymes CYP2D6 and CYP3A4, chlorpromazine can interact with inducers, inhibitors or other substrates of these isoenzymes. For more information, see Cytochrome P450 Drug Interactions in the Clin-Info section.

Anticholinergics: Anticholinergic drugs such as antihistamines, antiparkinsonian drugs, atropine, MAO inhibitors and tricyclic antidepressants may have additive anticholinergic effects when administered with chlorpromazine. Concomitant use of these drugs may increase the predisposition of patients treated with phenothiazines to heat stroke and paralytic ileus.

Anticonvulsants: Chlorpromazine may lower the seizure threshold. It may also decrease phenytoin metabolism. Anticonvulsant therapy should be monitored closely and may require dosage adjustment.

Antidepressants, Tricyclic: Concomitant use of chlorpromazine and tricyclic antidepressants may result in increased plasma concentrations of both drugs. The risk of neuroleptic malignant syndrome may also be increased.

Antihypertensives: Concomitant use of chlorpromazine and antihypertensives may result in additive hypotensive effects and an increased risk of orthostatic hypotension or syncope.

Antipsychotic Agents: Use of chlorpromazine with other antipsychotics, particularly other first-generation antipsychotics, may increase the risk of extrapyramidal side effects.

Antithyroid agents: Concomitant use of chlorpromazine and antithyroid agents such as methimazole and propylthiouracil may increase the risk of agranulocytosis.

Bromocriptine: Chlorpromazine may antagonize the prolactin-lowering activity of bromocriptine.

Cigarette Smoking: Hepatic metabolism may be induced by smoking, leading to decreased plasma concentrations of chlorpromazine. Conversely, levels may increase if smoking is discontinued during therapy.

CNS depressants: Chlorpromazine may enhance the CNS depressant effects of drugs including alcohol, anticonvulsants, antihistamines, barbiturates, benzodiazepines, MAO inhibitors, opioid analgesics and tricyclic antidepressants. Monitor to avoid excessive sedation or respiratory depression.

CYP2D6/3A4 Inducers: May decrease the effectiveness of chlorpromazine (e.g., carbamazepine, phenobarbital, phenytoin).

CYP2D6/3A4 Inhibitors: May increase the levels, therapeutic effects and toxicity of chlorpromazine (e.g., amiodarone, celecoxib, chloroquine, cimetidine, clarithromycin, erythromycin, fluoxetine, imatinab, itraconazole, ketoconazole, methadone, metronidazole, paroxetine, quinidine, ritonavir).

Levodopa: Chlorpromazine may inhibit the antiparkinsonian effects of levodopa as a result of its dopamine blocking effects in the CNS.

Lithium: Patients receiving lithium and chlorpromazine for treatment of acute mania should be monitored closely for signs of adverse neurologic effects, especially if serum concentrations of lithium are in the upper range. Rare cases of severe neurotoxicity have been reported.

Metoclopramide: Concomitant use of chlorpromazine and metoclopramide may increase the risk of extrapyramidal reactions.

Patients should be warned that chlorpromazine may impair their ability to safely perform activities requiring full mental alertness, such as driving or operating machinery.

Phenothiazines are distributed into breast milk in small amounts. Use with caution during lactation because of possible sedative and anticholinergic side effects on the infant.

Children with acute illnesses such as viral infections, CNS infections or dehydration may be more susceptible to dystonic reactions to phenothiazines.

Most studies have found chlorpromazine to be nonteratogenic and otherwise relatively safe for use during pregnancy, when it is necessary for the treatment of psychotic disorders. Chlorpromazine use near term should be avoided because of the danger of maternal hypotension and possible adverse effects in the neonate.

urinary retention, priapism, inhibition of ejaculation.

nausea, vomiting, increase or decrease in appetite, gastric irritation, constipation, paralytic ileus, rarely diarrhea.

extrapyramidal reactions, including pseudoparkinsonism (with motor retardation, rigidity, mask-like facies, pill rolling and other tremors, drooling, shuffling gait, etc.); dystonic reactions (including periroral spasms, trismus, tics, torticollis, oculogyric crises, protrusion of the tongue, difficulty swallowing, carpopedal spasm, opisthotonos of the back muscles); and akathisia. In addition, slowing of the EEG rhythm, disturbed body temperature and lowering of the convulsive threshold have occurred. Dizziness has been reported.

Tardive Dyskinesia: Tardive dyskinesia may appear in some patients on long-term antipsychotic therapy or may appear after drug therapy has been discontinued. The risk appears to be greater in elderly patients on high-dose therapy, especially females. The symptoms are persistent and in some patients appear to be irreversible. The syndrome is characterized by rhythmical involuntary movements of the tongue, face, mouth or jaw (e.g., protrusion of the tongue, puffing of the cheeks, puckering of the mouth and chewing movements). Sometimes these may be accompanied by involuntary movements of the extremities.

All antipsychotic agents should be discontinued if these symptoms appear. Should it be necessary to reinstitute treatment, increase the dosage of the agent, or switch to a different antipsychotic agent, the syndrome may be masked. In general, the lowest effective dose of phenothiazine should be used for the shortest duration of therapy that produces an adequate clinical response. The need for continued therapy should be reassessed periodically. Fine vermicular movements of the tongue may be an early sign of the syndrome. If the medication is stopped at that time, the syndrome may not develop.

Neuroleptic Malignant Syndrome: As with other antipsychotic drugs, a symptom complex sometimes referred to as neuroleptic malignant syndrome (NMS) has been reported. Cardinal features of NMS are hyperpyrexia, muscle rigidity, altered mental status (including catatonic signs) and evidence of autonomic instability (irregular pulse or unstable blood pressure). Additional signs may include elevated CPK, myoglobinuria (rhabdomyolysis), acute renal failure and leukocytosis. The syndrome seems to occur more frequently in young males. Other predisposing factors may include dehydration, organic brain disease, use of depot injections of phenothiazines, rapid dose titration, and concomitant use of lithium. NMS is rare but potentially fatal and therefore requires intensive symptomatic and supportive treatment and immediate discontinuation of antipsychotic therapy.

Dermatologic: itching, rash, hypertrophic papillae of the tongue, angioneurotic edema, erythema, allergic purpura, exfoliative dermatitis, photosensitivity, skin-eye syndrome (see Ophthalmologic). Contact dermatitis has occurred in personnel handling solutions or injections of chlorpromazine.

Endocrine: increased prolactin secretion; gynecomastia, galactorrhea, mastalgia, altered libido, menstrual irregularities, weight gain, alterations in glucose tolerance and false positive pregnancy tests have occurred.

agranulocytosis, leukopenia, granulocytopenia, eosinophilia, thrombocytopenia, anemia, aplastic anemia, pancytopenia. Agranulocytosis occurs in fewer than 1 in 10 000 patients receiving chlorpromazine.

Hepatic: cholestatic jaundice; symptoms generally subside following discontinuance of the drug but cholestasis may be prolonged.

Ophthalmologic: A skin-eye syndrome has been recognized as an adverse effect following long-term treatment with phenothiazines. This reaction is marked by progressive pigmentation of areas of skin or conjunctiva and/or discoloration of the exposed sclera and cornea. Opacities of the anterior lens and cornea described as irregular or stellate in shape have also been reported. Patients expected to receive higher doses of phenothiazines for prolonged periods should have complete eye examinations at baseline and every 6 to 12 months.

General Systemic Events: Sudden death has occasionally been reported in patients who have received phenothiazines. In some cases, the death was apparently due to cardiac arrest; in others, the cause appeared to be asphyxia due to failure of the cough reflex. In some patients, the cause could not be determined nor could it be established that the death was due to the phenothiazine.

hypotension, tachycardia, ECG changes (see Precautions).

Symptoms of chlorpromazine overdosage are an extension of its pharmacologic action. The primary symptoms observed are severe extrapyramidal reactions, hypotension and sedation. Mild or early intoxication may cause restlessness, confusion and excitement. CNS sedation may progress to coma. Disturbed temperature regulation can occur; both hypothermia and hyperthermia have been reported. Neuroleptic malignant syndrome can occur in overdose or with therapeutic doses (see Adverse Effects). Other symptoms may include: tachycardia, cardiac arrhythmias, seizures, miosis, and respiratory and/or vasomotor collapse.

Patients who have ingested chlorpromazine in overdose occasionally require respiratory and hemodynamic support. This may include intubation, ventilation, boluses of isotonic i.v. fluids, and inotropic support. Patients who seize should be treated with benzodiazepines. Ventricular arrhythmias are uncommon, and should be treated with boluses of sodium bicarbonate as well as conventional arrhythmics such as lidocaine. In the rare patient with torsades de pointes, i.v. magnesium sulfate and/or a pacemaker should be used. Once the patient's airway is adequately protected, 1 dose of activated charcoal can be administered to minimize absorption of orally ingested chlorpromazine. Extrapyramidal reactions may be treated with i.v. benztropine or diphenhydramine.