chlorpromazine

chlorpromazine
IUPAC name	3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethylpropan-1-amine
Tradename	Thorazine, Largactil, others
CAS number	50-53-3
DrugBank	DB00477
UNII	U42B7VYA4P

chlorpromazine. It is a typical antipsychotic medication of the phenothiazine class. First synthesized in 1950, it revolutionized the treatment of schizophrenia and ushered in the modern era of psychopharmacology. Its introduction led to the widespread deinstitutionalization of psychiatric patients and profoundly influenced both medicine and society.

History

The compound was first synthesized on December 11, 1950, by chemist Paul Charpentier at the French pharmaceutical company Rhône-Poulenc. Initially investigated as a potential antihistamine, its profound sedative properties were noted by surgeon Henri Laborit, who pioneered its use to potentiate anesthesia and manage surgical shock. Psychiatrists Jean Delay and Pierre Deniker at Sainte-Anne Hospital in Paris first systematically studied its effects in patients with psychosis in 1952, recognizing its specific antipsychotic action. The drug was marketed as Largactil in Europe and later as Thorazine in the United States by Smith, Kline & French. Its success spurred intense research into neuroleptic drugs and fundamentally altered the landscape of psychiatry, earning Delay and Deniker the prestigious Lasker Award.

Medical uses

Its primary use is in the management of schizophrenia and other psychotic disorders to control symptoms like delusions and hallucinations. It is also used to treat acute mania in bipolar disorder and severe behavioral problems in children. Beyond psychiatry, it has been employed as a potent antiemetic to prevent nausea and vomiting, particularly associated with chemotherapy or surgery. It is also used in the treatment of intractable hiccups and, less commonly, as an adjunct in tetanus management. Its use has declined with the advent of atypical antipsychotics like clozapine and risperidone, which often have a more favorable side-effect profile.

Adverse effects

Common side effects include drowsiness, orthostatic hypotension, and anticholinergic effects such as dry mouth and constipation. Significant and often dose-limiting adverse effects involve the extrapyramidal system, including dystonia, akathisia, parkinsonism, and the potentially irreversible tardive dyskinesia. It can also cause neuroleptic malignant syndrome, a rare but life-threatening condition. Other serious effects include jaundice, agranulocytosis, seizures, and significant weight gain. Its sedation and hypotension pose particular risks for the elderly, and it carries a FDA black box warning for increased mortality in this population with dementia-related psychosis.

Pharmacology

It acts primarily as a potent antagonist at dopamine D2 receptors in the mesolimbic pathway, which is central to its antipsychotic efficacy. It also has high affinity for histamine H1, alpha-1 adrenergic, and muscarinic receptors, contributing to its sedative, hypotensive, and anticholinergic effects. It is well-absorbed orally but undergoes extensive first-pass metabolism in the liver, primarily via the cytochrome P450 system, notably CYP2D6. Its half-life is approximately 30 hours, and it is excreted in the urine as numerous metabolites.

Society and culture

The introduction of the drug is considered a landmark event in the history of psychiatry, enabling the movement away from insulin shock therapy, psychosurgery like lobotomy, and prolonged institutionalization. It facilitated the policy of deinstitutionalization, though this shift also led to challenges with community mental health services. The drug features prominently in cultural critiques, such as in Ken Kesey's novel One Flew Over the Cuckoo's Nest and its film adaptation. It is on the World Health Organization's List of Essential Medicines and remains a critical, low-cost treatment option in global mental health.

Chemistry

Chemically, it is a tricyclic compound belonging to the phenothiazine family, specifically a 2-chloro derivative. Its molecular formula is C₁₇H₁₉ClN₂S, and it is a yellow, crystalline powder that is slightly soluble in water but soluble in chloroform and ethanol. The molecule consists of a central phenothiazine ring system with a chlorine atom at the 2-position and a dimethylaminopropyl side chain at the nitrogen of the 10-position. This side chain is classified as aliphatic, which is associated with a higher incidence of sedation and autonomic side effects compared to piperidine or piperazine phenothiazine derivatives.

Category:Antipsychotics Category:Phenothiazines Category:World Health Organization essential medicines