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Chlorpromazine ( CPZ), marketed under the brand names Thorazine and Largactil among others, is an medication. It is primarily used to treat psychotic disorders such as . Other uses include the treatment of , severe behavioral problems in children including those with attention deficit hyperactivity disorder, and , anxiety before surgery, and that do not improve following other measures. It can be given orally (by mouth), by (injection into a muscle), or (injection into a vein).

Chlorpromazine is in the typical antipsychotic class, and, chemically, is one of the . Its mechanism of action is not entirely clear but is believed to be related to its ability as a dopamine antagonist. It has and antihistaminergic properties.

Common side effects include movement problems, , dry mouth, low blood pressure upon standing, and . Serious side effects may include the potentially permanent movement disorder tardive dyskinesia, neuroleptic malignant syndrome, severe lowering of the seizure threshold, and . In older people with psychosis as a result of , it may increase the risk of death. It is unclear if it is safe for use in .

Chlorpromazine was developed in 1950 and was the first antipsychotic on the market. It is on the World Health Organization's List of Essential Medicines. Its introduction has been labeled as one of the great advances in the history of psychiatry.

(2025). 9780198039235, Oxford University Press. .
It is available as a generic medication.


Medical uses
Chlorpromazine is used in the treatment of both acute and chronic , including and the manic phase of , as well as -induced psychosis.

Controversially, some psychiatric patients may be given chlorpromazine by force, even if they do not suffer any of the typical conditions the drug is prescribed for.

In a 2013 comparison of fifteen antipsychotics in schizophrenia, chlorpromazine demonstrated mild-standard effectiveness. It was 13% more effective than and , approximately as effective as and , and 12–16% less effective than , , and .

A 2014 systematic review carried out by Cochrane included 55 trials that compared the effectiveness of chlorpromazine versus placebo for the treatment of schizophrenia. Compared to the placebo group, patients under chlorpromazine experienced less relapse during 6 months to 2 years follow-up. No difference was found between the two groups beyond two years of follow-up. Patients under chlorpromazine showed a global improvement in symptoms and functioning. The systematic review also highlighted the fact that the side effects of the drug were 'severe and debilitating', including sedation, considerable weight gain, a lowering of blood pressure, and an increased risk of acute movement disorders. They also noted that the quality of evidence of the 55 included trials was very low and that 315 trials could not be included in the systematic review due to their poor quality. They called for further research on the subject, as chlorpromazine is a cheap benchmark drug and one of the most used treatments for schizophrenia worldwide.

Chlorpromazine has also been used in and as part of treatment. It is still recommended for short-term management of severe anxiety and psychotic aggression. Resistant and severe , severe /, and conditioning are other uses. Symptoms of in hospitalized patients have been effectively treated with low doses of chlorpromazine.


Other uses
Chlorpromazine is occasionally used off-label for treatment of severe . It is often, particularly as , used in small doses to reduce nausea by -treated cancer patients and to intensify and prolong the analgesia of the opioids as well. Efficacy has been shown in treatment of symptomatic hypertensive emergency.

In Germany, chlorpromazine still carries label indications for , severe , and preanesthesia.

Chlorpromazine has been used as a to block the effects of serotonergic psychedelics like , lysergic acid diethylamide (LSD), and .

(1975). 9780856080111, Wright-Scientechnica. .
However, it was said to not be completely effective and could exacerbate symptoms under certain situations. The results of clinical studies of chlorpromazine for this use have been inconsistent, with reduced effects, no change in effects, and even enhanced effects all reported. Intravenous chlorpromazine is described as completely abolishing the autonomic and psychoactive effects of LSD, whereas oral chlorpromazine is said to be much less effective.
(1978). 9783642667770, Springer Berlin Heidelberg. .

Chlorpromazine and other phenothiazines have been demonstrated to possess antimicrobial properties, but are not currently used for this purpose except for a very small number of cases. For example, Miki et al. 1992 trialed daily doses of chlorpromazine, reversing chloroquine resistance in Plasmodium chabaudi isolates in .

Weeks et al., 2018 find that it also possesses a wide spectrum effect.

Chlorpromazine is an antagonist of several insect monoamine receptors. It is the most active antagonist known of silk moth ( ) octopamine receptor α, intermediate for Bm tyramine receptors 1 & 2, weak for Drosophila octopamine receptor β, high for Drosophila tyramine receptor 1, intermediate for migratory locust ( Locusta migratoria) tyramine receptor 1, and high for American cockroach ( Periplaneta americana) octopamine receptor α and tyramine receptor 1.

+ Comparison of chlorpromazine to placebo
Very low (estimate of effect uncertain)
RR 0.7 CI 0.5 to 0.9


Contraindications
Absolute contraindications include:

  • Previous (including jaundice, agranulocytosis, etc.) to phenothiazines, especially chlorpromazine, or any of the excipients in the formulation being used.

Relative contraindications include:

  • Epilepsy
  • Parkinson's disease
  • Myasthenia gravis
  • Hypoparathyroidism
  • Prostatic hypertrophy

Very rarely, elongation of the QT interval, due to blockade, may occur, increasing the risk of potentially fatal arrhythmias.


Adverse effects
There appears to be a dose-dependent risk for seizures with chlorpromazine treatment. Tardive dyskinesia (involuntary, repetitive body movements) and (a feeling of inner restlessness and inability to stay still) are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as or , and some evidence suggests that, with conservative dosing, the incidence of such effects for chlorpromazine may be comparable to that of newer agents such as or .

Chlorpromazine stably and for life alters natural processes in the biological systems of the mitochondria of the nervous system, and inhibits the efficiency of the electron transport chain.A number of doctors and scientists, including psychiatrist and Narcological doctor Alexander Danilin and biochemist Albert Szent-Györgyi, claim that Chlorpromazine stably and for life alters natural processes in the biological systems of the mitochondria of the nervous system, and inhibits the efficiency of the electron transport chain.

Chlorpromazine may deposit in ocular tissues when taken in high dosages for long periods of time.

+ Comparison of chlorpromazine to placebo
Very low (estimate of effect uncertain)
RR 2.8 CI 2.3 to 3.5
RR 3.5 CI 1.5 to 8.0
RR 2.1 CI 1.6 to 2.8
RR 2.4 CI 1.7 to 3.3


Discontinuation
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.
(2009). 9780853698456, Royal Pharmaceutical Society of Great Britain.
Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.
(2025). 9780198527480, OUP Oxford. .
Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly, there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated.

(2025). 9788847026797, Springer Science & Business Media. .
Rarely, tardive dyskinesia can occur when the medication is stopped.


Interactions
Consuming food prior to taking chlorpromazine orally limits its absorption; likewise, cotreatment with can also reduce chlorpromazine absorption. Alcohol can also reduce chlorpromazine absorption. Antacids slow chlorpromazine absorption. Lithium and chronic treatment with can increase chlorpromazine clearance significantly. Tricyclic antidepressants (TCAs) can decrease chlorpromazine clearance and hence increase chlorpromazine exposure. Cotreatment with CYP1A2 inhibitors like , or can reduce chlorpromazine clearance and hence increase exposure and potentially also adverse effects. Chlorpromazine can also potentiate the CNS depressant effects of drugs like , , , lithium and anesthetics and hence increase the potential for adverse effects such as respiratory depression and .

Chlorprozamine is also a moderate inhibitor of CYP2D6 and a substrate for CYP2D6 and hence can inhibit its own metabolism. It can also inhibit the clearance of CYP2D6 substrates such as , potentiating their effects. Other drugs like and , which require CYP2D6-mediated activation into their respective active metabolites, may have their therapeutic effects attenuated. Likewise, CYP2D6 inhibitors such as or can reduce chlorpromazine clearance, increasing serum levels of chlorpromazine and potentially its adverse effects. Chlorpromazine also reduces levels and increases levels. It also reduces clearance and antagonizes the therapeutic effects of agents, (a Parkinson's medication. This is likely because chlorpromazine antagonizes the D2 receptor which is one of the receptors dopamine, a levodopa metabolite, activates), and . It may also interact with anticholinergic drugs such as to produce (low blood sugar).

Chlorpromazine may also interact with (adrenaline) to produce a paradoxical fall in blood pressure. Monoamine oxidase inhibitors (MAOIs) and diuretics may also accentuate the orthostatic hypotension experienced by those receiving chlorpromazine treatment. Quinidine may interact with chlorpromazine to increase depression. Likewise, it may also antagonize the effects of and . It also may reduce the seizure threshold and hence a corresponding titration of anticonvulsant treatments should be considered. and may also interact with chlorpromazine to produce transient metabolic .

Other drugs that prolong the QT interval, such as , , , and , may also interact with chlorpromazine to produce additive prolongation.

Chlorpromazine is a 5-HT2A receptor antagonist and has been found to reduce the effects of serotonergic psychedelics like .


Pharmacology
Chlorpromazine is classified as a low-potency typical antipsychotic. Low-potency antipsychotics have more side effects, such as dry mouth, sedation, and constipation, and lower rates of extrapyramidal side effects, while high-potency antipsychotics (such as ) have the reverse profile.


Pharmacodynamics
+Chlorpromazine !Site !Ki !Species !Ref
5-HT1A3115Human
5-HT1B1489Human
5-HT1D452Human
5-HT1E344Human
5-HT2A2.75Human
5-HT2B6.0Bovine
5-HT2C25Human
5-HT3776Human
5-HT5A118Human
5-HT619.5Human
5-HT721Human
α1A0.28Human
α1B0.81Human
α2A184Human
α2B28Human
α2C46Human
β110000+Human
β210000+Human
M147Human
M2433Human
M347Human
M4151Human
D1114.8Human
D27.244Human
D36.9Human
D432.36Human
H14.25Human
H2174Human
H31000Human
H45048Human
NET2,443Human
DAT10000+Human

Chlorpromazine is a very effective antagonist of D2 receptors and similar receptors, such as D3 and D5. Unlike most other drugs of this genre, it also has a high affinity for D1 receptors. Blocking these receptors causes diminished neurotransmitter binding in the forebrain, resulting in many different effects. , unable to bind with a receptor, causes a feedback loop that causes dopaminergic neurons to release more dopamine. Therefore, upon first taking the drug, patients will experience an increase in dopaminergic neural activity. Eventually, dopamine production in the neurons will drop substantially and dopamine will be removed from the . At this point, neural activity decreases greatly; the continual blockade of receptors only compounds this effect.

Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic and presynaptic receptors:

  • Dopamine receptors (subtypes D1, D2, D3 and D4), which account for its different antipsychotic properties on productive and unproductive symptoms, in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects
  • Serotonin receptors (5-HT2, 5-HT6 and 5-HT7), with anxiolytic, antidepressant and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain and ejaculation difficulties.
  • Histamine receptors (H1 receptors, accounting for sedation, antiemetic effect, vertigo, and weight gain)
  • α1- and α2-adrenergic receptors (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism – controversial. Also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor as well as with intraoperative floppy iris syndrome due to its effect on the iris dilator muscle.
    (2025). 9781681044491, American Academy of Ophthalmology.
  • M1 and M2 muscarinic acetylcholine receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).

The presumed effectiveness of the antipsychotic drugs relied on their ability to block dopamine receptors. This assumption arose from the dopamine hypothesis that maintains that both schizophrenia and bipolar disorder are a result of excessive dopamine activity. Furthermore, psychomotor stimulants like cocaine that increase dopamine levels can cause psychotic symptoms if taken in excess.

Chlorpromazine and other typical are primarily blockers of D2 receptors. An almost perfect correlation exists between the therapeutic dose of a typical antipsychotic and the drug's affinity for the D2 receptor. Therefore, a larger dose is required if the drug's affinity for the D2 receptor is relatively weak. A correlation exists between average clinical potency and affinity of the antipsychotics for receptors.

(2025). 9780132197885, Prentice Hall.
Chlorpromazine tends to have a greater effect at receptors than at D2 receptors, which is notably the opposite effect of the other typical antipsychotics. Therefore, chlorpromazine's effects on dopamine and serotonin receptors are more similar to the atypical antipsychotics than to the typical antipsychotics.

Chlorpromazine and other antipsychotics with properties such as and are among the most potent agents at α-adrenergic receptors. Furthermore, they are also among the most potent antipsychotics at H1 receptors. This finding is in agreement with the pharmaceutical development of chlorpromazine and other antipsychotics as anti-histamine agents. Furthermore, the brain has a higher density of histamine H1 receptors than any body organ examined which may account for why chlorpromazine and other antipsychotics are as potent at these sites as the most potent classical .

In addition to influencing the neurotransmitters dopamine, serotonin, , , and it has been reported that antipsychotic drugs could achieve glutamatergic effects. This mechanism involves the direct effects of antipsychotic drugs on receptors. By using the technique of functional neurochemical assay chlorpromazine and phenothiazine derivatives have been shown to have inhibitory effects on receptors that appeared to be mediated by action at the Zn site. It was found that there is an increase of NMDA activity at low concentrations and suppression at high concentrations of the drug. No significant difference in activity from the effects of chlorpromazine was reported. Further work will be necessary to determine if the influence in NMDA receptors by antipsychotic drugs contributes to their effectiveness.

Chlorpromazine does also act as a (functional inhibitor of acid sphingomyelinase).

Chlorpromazine is an antagonist to H1 receptors (provoking antiallergic effects), H2 receptors (reduction of forming of gastric juice), M1 and M2 receptors (dry mouth, reduction in forming of gastric juice) and some 5-HT receptors (different anti-allergic/gastrointestinal actions).

Because it acts on so many receptors, chlorpromazine is often referred to as a "".


Pharmacokinetics
+ Pharmacokinetic parameters of chlorpromazine ! Bioavailability !! tmax !! CSS !! Protein bound !! Vd !! t1/2 !! Details of metabolism !! Excretion !! Notes
Its high degree of (fat solubility) allows it to be detected in the urine for up to 18 months. Less than 1% of the unchanged drug is excreted via the kidneys in the urine, in which 20–70% is excreted as conjugated or unconjugated metabolites, whereas 5–6% is excreted in feces.


History
In 1933, the French pharmaceutical company Laboratoires Rhône-Poulenc began to search for new . In 1947, it synthesized , a derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs.
(2025). 9780674015999, Harvard University Press. .
A year later, the French surgeon Pierre Huguenard used promethazine together with as part of a cocktail to induce relaxation and indifference in surgical patients. Another surgeon, , believed the compound stabilized the central nervous system by causing "artificial hibernation" and described this state as "sedation without ". He suggested to Rhône-Poulenc that they develop a compound with better-stabilizing properties.
(2025). 9780674015999, Harvard University Press.
In December 1950, the chemist Paul Charpentier produced a series of compounds that included RP4560 or chlorpromazine.

Chlorpromazine was distributed for testing to physicians between April and August 1951. Laborit trialled the medicine at the Val-de-Grâce military hospital in Paris, using it as an anaesthetic booster in intravenous doses of 50 to 100 mg in surgery patients and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterward. He also noted its effect and suggested it may induce artificial hibernation. Laborit thought this would allow the body to better tolerate major surgery by reducing shock, a novel idea at the time.

Following on, Laborit considered whether chlorpromazine may have a role in managing patients with severe , Raynaud's phenomenon, or psychiatric disorders. At the Villejuif Mental Hospital in November 1951, he and Montassut administered an dose to psychiatrist Cornelia Quarti, who was acting as a volunteer. Quarti noted the indifference but fainted upon getting up to go to the toilet, and so further testing was discontinued. (Orthostatic hypotension is a known side effect of chlorpromazine). Despite this, Laborit continued to push for testing in psychiatric patients during early 1952. Psychiatrists were reluctant initially, but on 19 January 1952, it was administered (alongside pethidine, and ECT) to Jacques Lh., a 24-year-old patient, who responded dramatically; he was discharged after three weeks, having received 855 mg of the drug in total.

had heard about Laborit's work from his brother-in-law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the Sainte-Anne Hospital Center in Paris where he was chief of the men's service. Together with the hospital director , they published their first clinical trial in 1952, in which they treated thirty-eight patients with daily injections of chlorpromazine without the use of other sedating agents. The response was dramatic; treatment with chlorpromazine went beyond simple sedation, with patients showing improvements in and behaviour.

(2025). 9780674015999, Harvard University Press. .
They also found that doses higher than those used by Laborit were required, giving patients 75–100 mg daily. Known colloquially as "Laborit's drug", chlorpromazine was released onto the market in 1953 by Rhône-Poulenc and given the trade name Largactil, derived from large "broad" and acti* "activity".

Deniker then visited America, where the publication of their work alerted the American psychiatric community that the new treatment might represent a real breakthrough. Heinz Lehmann of the in Montreal trialled it in seventy patients and also noted its striking effects, with patients' symptoms resolving after many years of unrelenting psychosis. By 1954, chlorpromazine was being used in the United States to treat , , psychomotor excitement, and other disorders.

(2025). 9780071624428, McGraw-Hill Professional.
(1992). 9780062715340, HarperPerennial.
Rhône-Poulenc licensed chlorpromazine to Smith Kline & French (today's ) in 1953. In 1955 it was approved in the United States for the treatment of emesis (vomiting). The effect of this drug in emptying psychiatric hospitals has been compared to that of on infectious diseases.

The popularity of the drug fell in the late 1960s as newer drugs came on the scene. From chlorpromazine several other similar antipsychotics were developed, leading to the discovery of .

(2025). 9780674015999, Harvard University Press. .

Chlorpromazine largely replaced electroconvulsive therapy, , , and insulin shock therapy. By 1964, about fifty million people worldwide had taken it. Chlorpromazine, in widespread use for fifty years, remains a "benchmark" drug in the treatment of , an effective drug although not a perfect one.


Society and culture

In literature
Thorazine was often depicted in Tom Wolfe's The Electric Kool-Aid Acid Test to abort bad trips on . Thorazine is also mentioned in Fear and Loathing in Las Vegas, where it was reported to negate the effects of LSD.


Names
Brand names include Thorazine, Largactil, Hibernal, and Megaphen (sold by in West-Germany since July 1953).Bangen, Hans (1992). Geschichte der medikamentösen Therapie der Schizophrenie. Verlag für Wissenschaft und Bildung. p. 98. .


Research
Chlorpromazine has tentative benefit in animals infected with Naegleria fowleri and shows and activity .


Veterinary use
The veterinary use of chlorpromazine has generally been superseded by the use of .
(2025). 9781118911921, John Wiley & Sons.

Chlorpromazine may be used as an in dogs and cats, or, less often, as a sedative before anesthesia.

(2025). 9780813820613, Wiley-Blackwell.
In horses, it often causes and and is therefore seldom used.

It is commonly used to decrease nausea in animals that are too young for other common antiemetics. It is sometimes used as a and in cattle, swine, sheep, and goats.

The use of chlorpromazine in is not permitted in the , as a maximum residue limit could not be determined following assessment by the European Medicines Agency.

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