Chlorpromazine
Classic first generation phenothiazine neuroleptic
Chlorpromazine is the first neuroleptic in history and a central milestone of psychiatric pharmacotherapy. Its introduction by Rhône Poulenc in 1952 under the brand name Largactil fundamentally changed the treatment of patients with schizophrenia and mania. In Germany chlorpromazine is marketed as Propaphenin and Megaphen, with generics also available; prescription numbers have declined because of better tolerated alternatives.
Chlorpromazine is a low potency phenothiazine. Its antipsychotic effect is weaker than that of haloperidol, its sedative and autonomic effect stronger. In current practice the substance is used mainly as a reserve option in acute psychomotor agitation, in treatment resistant schizophrenia, in palliative care and for intractable hiccup. The typical side effects require careful monitoring.
Mechanism of Action
Chlorpromazine blocks a variety of neurotransmitter receptors. The primary effect is antagonism of postsynaptic dopamine D2 receptors, especially in the mesolimbic system, which is held responsible for the antipsychotic effect. In the nigrostriatal system the same blockade produces extrapyramidal side effects; in the tuberoinfundibular system prolactin rises from loss of dopaminergic inhibition.
Chlorpromazine also antagonises histamine H1 receptors (sedation, weight gain), α1 adrenoceptors (orthostasis, hypotension), muscarinic acetylcholine receptors (dry mouth, constipation, urinary disturbances) and 5-HT2A serotonin receptors (possible effect on negative symptoms and sedation). This broad receptor profile explains both the therapeutic versatility and the side effect burden.
The antiemetic action is based on dopamine receptor blockade in the chemoreceptor trigger zone at the floor of the area postrema. At low doses chlorpromazine is effective against nausea and vomiting, especially in palliative care. The antiallergic and sedative potential results from H1 antagonism, which explains use in acute agitation.
Indications
- Schizophrenia and schizoaffective disorders in acute treatment and maintenance therapy, today mostly as a reserve option
- Manic states as adjunct therapy when the response is inadequate
- Acute psychomotor agitation as a psychiatric emergency
- Delirium with pronounced restlessness, as an alternative to haloperidol
- Chronic treatment resistant nausea and vomiting, particularly in palliative care
- Persistent hiccup (singultus) as an off label option after other measures fail
- Tetanus treatment as adjunct for sedation and relaxation
Dosage and Administration
Adults, schizophrenia: start with 25 to 100 mg per day orally in 2 to 4 divided doses, titrated to 300 to 800 mg depending on the clinical picture. In acute treatment, intramuscular doses of 25 to 50 mg are possible; intravenous use is uncommon in Germany and requires strict cardiovascular monitoring.
Antiemetic use: 10 to 25 mg two to four times daily orally. Hiccup: 25 to 50 mg orally three to four times daily for a few days. Older patients: reduce dose by 30 to 50 percent, since orthostatic hypotension and anticholinergic side effects are more pronounced.
Renal impairment: dose reduction in severe impairment, with caution. Hepatic impairment: chlorpromazine is metabolised in the liver, dose adjustment is required. Swallow tablets whole with liquid; store drop solutions protected from light.
Side Effects
Very common: sedation, orthostatic hypotension, dry mouth, constipation, weight gain, blurred vision, voiding difficulty, nasal congestion.
Common: extrapyramidal motor disorders (parkinsonism, early dyskinesia, akathisia), elevated prolactin levels with galactorrhoea, amenorrhoea, gynaecomastia and sexual dysfunction, skin photosensitisation, tachycardia, elevated liver enzymes.
Serious: neuroleptic malignant syndrome (fever, rigidity, impaired consciousness, rhabdomyolysis; immediate discontinuation and intensive care), tardive dyskinesia with long term use, agranulocytosis, cholestatic hepatitis, QT prolongation with torsade de pointes, seizures from a lowered seizure threshold.
Important: in older patients with dementia the risk of cerebrovascular events and overall mortality is increased. Corresponding Dear Healthcare Professional letters apply to all antipsychotics.
Interactions
- Central depressants (opioids, benzodiazepines, alcohol): enhanced sedation, respiratory depression possible
- QT prolonging drugs (amiodarone, quinidine, sotalol, macrolides, ondansetron): additive QT prolongation, torsade risk
- Levodopa and dopamine agonists: mutual loss of effect
- Lithium: possible increased neurotoxicity, close monitoring
- Anticholinergics (biperiden, tricyclic antidepressants): additive anticholinergic effects (urinary retention, paralytic ileus, delirium)
- Antihypertensives: enhanced hypotension
- CYP2D6 substrates and inhibitors (fluoxetine, paroxetine): plasma levels may fluctuate
Special Notes
Contraindications: comatose states, acute intoxication with central depressants, narrow angle glaucoma, bladder emptying disorders, severe bone marrow depression, Parkinson's disease, myasthenia gravis, pheochromocytoma, known QT prolongation, severe heart failure.
Monitoring: before starting treatment obtain ECG (QTc), blood count, liver values, renal values, lipid panel, fasting glucose and prolactin. During long term therapy perform regular checks every 3 to 6 months, with abdominal ultrasound and, where indicated, mammography in the presence of symptoms of hyperprolactinaemia. Consider the increased fall risk from orthostatic hypotension.
Pregnancy: experience is limited; when therapy is essential, use the lowest effective dose. Neonates exposed in the third trimester may show withdrawal or extrapyramidal symptoms, so at least 24 hours of inpatient monitoring is advised. Breastfeeding: passage into breast milk, breastfeeding during therapy is not recommended.
Driving and sun protection: sedation and blurred vision impair driving. Photosensitisation requires consistent light protection, avoidance of direct sunlight and use of high SPF sunscreen.
You might also be interested in
- Chlorprothixene, related thioxanthene neuroleptic
- Levomepromazine, sedating phenothiazine in palliative care
- Aripiprazole, modern atypical antipsychotic
- Prothipendyl, low potency neuroleptic for agitation
- Chlorprothixene, alternative in sleep and agitation states
Frequently Asked Questions
Why is chlorpromazine historically important?
In 1952 chlorpromazine was the first synthetic neuroleptic and initiated the era of psychopharmacological treatment of psychotic disorders. Before its introduction, only barbiturates, insulin coma therapy and electroconvulsive therapy were available for schizophrenia. The substance fundamentally changed psychiatric care.
What is the difference from modern antipsychotics?
Atypical antipsychotics such as risperidone, olanzapine, aripiprazole or clozapine show lower rates of extrapyramidal effects but often more metabolic side effects. Antipsychotic efficacy is comparable when the patient responds, and is somewhat more favourable for negative symptoms. Chlorpromazine is today used mainly in special reserve situations.
Why should I avoid the sun while on chlorpromazine?
Phenothiazines are strong photosensitisers. Unprotected skin reacts to sun exposure with stronger sunburn, discolouration and in some cases persistent pigment changes. Use consistent light protection with clothing and high SPF sunscreen, avoid direct sun, throughout the whole treatment period.
What is neuroleptic malignant syndrome?
It is a rare but life threatening complication with high fever, muscle rigidity, impaired consciousness and a rise in creatine kinase. If suspected, stop therapy immediately and provide intensive care. Untreated mortality is 10 to 20 percent and is markedly lower with timely therapy. Family members should know the warning signs.
Sources
- EMA, European Medicines Agency
- AWMF, S3 Guideline on Schizophrenia
- Gelbe Liste, Chlorpromazine active substance profile
- BfArM, Federal Institute for Drugs and Medical Devices
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