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Chlorpromazine: Wikis


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Systematic (IUPAC) name
CAS number 50-53-3 (free base)
69-09-0 (hydrochloride)
ATC code N05AA01
PubChem 2726
DrugBank APRD00482
ChemSpider 2625
Chemical data
Formula C17H19ClN2S 
Mol. mass 318.86 g/mol (free base)
355.33 g/mol (hydrochloride)
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability Oral, 30 to 50% (interindividual variations 10–70%)
Metabolism Hepatic, mostly CYP2D6-mediated
Half life 16 to 30 hours. In long term treatment, CPZ induces its own metabolism
Excretion Biliary and renal, as metabolites (only traces of unchanged drug)
Therapeutic considerations
Pregnancy cat. C—only when benefit for the mother exceeds risk to unborn child
Legal status Prescription only
Routes Oral, rectal (suppository), IM, IV infusion
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Chlorpromazine (as chlorpromazine hydrochloride, abbreviated CPZ, marketed in the US as Thorazine, as Largactil in Europe) is the oldest typical antipsychotic. The molecular structure is 2-chloro-10-(3-dimethylaminopropyl)-phenothiazine. Synthesized on December 11, 1950, chlorpromazine was the first drug developed with specific antipsychotic action. Its use has been described as the single biggest advance in psychiatric treatment, dramatically improving the prognosis of patients in psychiatric hospitals worldwide. It was the prototype for the phenothiazine class, which later grew to comprise several other agents. It is now used less commonly than the newer atypical antipsychotics such as olanzapine, quetiapine, and risperidone.

Chlorpromazine works on a variety of receptors in the central nervous system, producing anticholinergic, antidopaminergic, antihistaminic, and antiadrenergic effects. Its anticholinergic properties cause constipation, sedation, and hypotension and relieve nausea. It also has anxiolytic (anxiety-relieving) properties. Its antidopaminergic properties can cause extrapyramidal symptoms such as akathisia (restlessness), dystonia, and Parkinsonism. Chlorpromazine inhibits clathrin-mediated endocytosis.[1] Chlorpromazine is known to cause tardive dyskinesia, which can be irreversible.[2] It is often administered in acute settings as a syrup, which has a faster onset of action than tablets. Subcutaneous injection is not advised, and administration is limited to severe hiccups, surgery, and tetanus.[3]



In 1933, the French pharmaceutical company Laboratoires Rhône-Poulenc began to search for new antihistamines. In 1947, it synthesized promethazine, a phenothiazine derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs.[4] A year later, the French surgeon Pierre Huguenard used promethazine together with pethidine as part of a lytic cocktail to induce relaxation and indifference in surgical patients. Another surgeon, Henri Laborit, believed the compound stabilized the central nervous system by causing 'artificial hibernation', and described this state as 'sedation without narcosis'. He suggested to Rhône-Poulenc that they develop a compound with better stabilizing properties.[5] The chemist Paul Charpentier produced a series of compounds and selected the one with the least peripheral activity, known as RP4560 or chlorpromazine, on 11 December 1950. Simone Courvoisier conducted behavioural tests and found chlorpromazine produced indifference to aversive stimuli in rats. Chlorpromazine was distributed for testing to physicians between April and August 1951.

The first published clinical trial was that of Jean Delay and Pierre Deniker at the Hôpital Sainte-Anne in Paris in 1952, in which they treated 38 psychotic patients with daily injections of chlorpromazine without the use of other sedating agents.[6] The response was dramatic; treatment with chlorpromazine went beyond simple sedation with patients showing improvements in thinking and emotional behaviour.

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 Verdun Protestant Hospital in Montreal trialled it in 70 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 schizophrenia, mania, psychomotor excitement, and other psychotic disorders.[7][8][9] Rhône-Poulenc licensed chlorpromazine to Smith Kline & French (today's GlaxoSmithKline) 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 penicillin and infectious diseases.[6] Over 100 million people were treated but the popularity of the drug fell from the late 1960s as the severe extrapyramidal side effects and tardive dyskinesia became more of a concern. From chlorpromazine a number of other similar antipsychotics were developed such as triflupromazine and trifluoperazine.

Chlorpromazine largely replaced electroconvulsive therapy, psychosurgery, and insulin shock therapy. The development and use of antipsychotic drugs like chlorpromazine was one of the forces that propelled deinstitutionalization, the systematic removal of people with severe mental illness from institutions like psychiatric hospitals. In 1955 there were 558,922 resident patients in American state and county psychiatric hospitals. By 1970, the number dropped to 337,619; by 1980 to 150,000; and by 1990 between 110,000 to 120,000 patients.[10]



Chlorpromazine, and many other phenothiazine derivatives, are very lipophilic molecules that readily bind with membranes and proteins. Approximately 95-98% of the drug is bound in the plasma; 85% of the drug is bound to the plasma protein albumin. Renal disease may cause this range to expand significantly. Highest concentrations of the drug can be found in the brain, lung, and other tissues that receive a high supply of blood.

The drug can also enter fetal circulation and breast milk, so pregnant and nursing mothers must beware, especially since fetuses have a low rate of phenothiazine metabolism. With gas chromatography, levels of chlorpromazine and some of its metabolites can be measured in the milk and plasma of nursing mothers. In one case study of nursing mothers on chlorpromazine therapy, the drug itself was detected in milk samples and ranged from 7 ng/ml to 98 ng/ml. The metabolite chlorpromazine sulphoxide was present in all samples. Plasma levels of CPZ ranged from 16 ng/ml to 52 ng/ml. However, there was no clear or consistent relationship between plasma and milk levels of CPZ. In one mother who did in fact feed her baby her breast milk, the milk CPZ level was 92 ng/ml and the baby was reported to be drowsy and lethargic. Therefore, there should be some caution in allowing nursing mothers currently on CPZ therapy and presumably related antipsychotics to breast feed their children.[11]

Chlorpromazine is able to cross the placental barrier and it has been shown that drug doses higher than 500 mg daily in late pregnancy are associated with an increased incidence of respiratory distress in newborns. One case study reported that a newborn who was not breast fed but was exposed to CPZ in utero had detectably large amounts of the drug in its urine. This indicated the drug can in fact cross the placental barrier and is slowly cleared out of the body due to the infant's immature liver. Pregnant women and nursing mothers should thus be advised of the effects of CPZ on their newborn's health.[12]

The elderly also have a slower rate of metabolism, but it seems that children have the highest. The anticholinergic properties only slightly influence chlorpromazine's absorption from the gastrointestinal tract, compared to other antipsychotics such as fluphenazine.

Bioavailability: Only about 32% of the administered dose is available to the systemic circulation in the active form. Over time and multiple administrations, bioavailability may drop to 20%. Peak concentrations are achieved in 1 to 4 hours [7] (range 1.5–8 hours), after an oral dose [13]

Three Common Metabolites of Chlorpromazine

Chlorpromazine is derived from phenothiazine, has an aliphatic side chain, typical for low to middle potency antipsychotics. Chlorpromazine is slowly absorbed from the intramuscular injection site with the peak plasma concentration occurring 6–24 hours after administration of the drug. The oral bioavailability is estimated to be 30–50% that of intramuscular doses and about 10% that of intravenous doses due to extensive first pass metabolism in the liver. Its elimination half-life is 16–30 hours (8–35 hours, although it is as short as 2 hours or as long as 60 hours in some individuals)[13] , due to high lipophilicity, high membrane-binding, and high protein-binding. It has many active metabolites (more than 100 metabolites being theoretically possible) with greatly varying halflives and pharmacological profiles.A number of the metabolites may contribute to the pharmacological effects of chlorpromazine including 7-hydroxychlorpromazine, chlorpromazine-N-oxide, 3-hydroxychlorpromazine and desmethylchlorpromazine.)[13] Although the metabolite chlorpromazine-N-oxide does not possess activity in vitro, it can exert an indirect pharmacological effect in vivo by reverting back to chlorpromazine. The major routes of metabolism include hydroxylation, N-oxidation, sulphoxidation, demethylation, deamination and conjugation. There is little evidence supporting the development of metabolic tolerance or an increase in the metabolism of chlorpromazine due to microsomal liver enzymes following multiple doses of the drug.[14] The mechanism of action of chlorpromazine is that the drug can act as an uncoupling agent of oxidative phosphorylation and also as an inhibitor of ATP-ase and cytochrome oxidase. However, the relationship that may exist between these mechanisms are not entirely understood.

The cytochrome P450 isoenzymes 1A2 and 2D6 are needed for metabolism of chlorpromazine. CYP 2D6 is the main enzyme catalyzing 7-hydroxylation of chlorpromazine, the reaction being partially catalyzed by CYP 1A2.[15]

Chlorpromazine is typically degraded by the liver by the action of cytochrome-P450 family enzymes, usually CYP2D6. 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.[13] There are on the order of 10 or more major metabolites generated by the hepatic pathway in appreciable concentrations. The three most common appear in the following image. The first is the doubly N-demethylated species, followed by the 7-hydroxylated form, and finally chlorophenothiazine, in which the entire R1 side chain is missing.[16]

Often, due to their high lipophilic character, these and other metabolites may be detected in the urine up to 18 months.[13] after discontinuation of use. Most metabolites lack any sort of antipsychotic activity, but a few are biologically active. These include 7-hydroxychlorpromazine, mesoridazine, 9-hydroxyresperidone, and a few N-demethylated metabolites.[7]

Pharmacodynamics and central effects

Chlorpromazine is a very effective antagonist of D2 dopamine 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. Dopamine, 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 activity of dopaminergic neural activity. Eventually, dopamine production of the neurons will drop substantially and dopamine will be removed from the synaptic cleft. At this point, neural activity decreases greatly; the continual blockade of receptors only compounds this effect.[7]

Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic 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-HT1 and 5-HT2), with anxiolytic, and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties),
  • histamine receptors (H1 receptors, accounting for sedation, antiemetic effect, vertigo, fall in blood pressure and weight gain),
  • α1- and α2-adrenergic receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism—controversial), and
  • 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 efficacy 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 antipsychotics are primarily blockers of D2 receptors. In fact 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 dopamine receptors.[17] Chlorpromazine tends to have greater effect at serotonin receptors than at D2 receptors, which is notably the opposite effect of the other typical antipsychotics. Therefore, chlorpromazine with respect to its effects on dopamine and serotonin receptors is similar to the atypical antipsychotics than the typical antipsychotics.[17]

Chlorpromazine and other antipsychotics with sedative properties such as promazine and thioridazine are among the most potent agents at α-adrenergic receptors. Furthermore, they are also among the most potent antipsychotics at histamine 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 phenothiazine antipsychotics are as potent at these sites as the most potent classical antihistamines.[18]

Additionally, chlorpromazine is a presynaptic inhibitor of dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use).

In addition to influencing the neurotransmitters dopamine, serotonin, epinephrine, norepinephrine, and acetylcholine it has been reported that antipsychotic drugs could achieve glutamatergic effects. This mechanism involves direct effects on antipsychotic drugs on glutamate receptors. By using the technique of functional neurochemical assay chlorpromazine and phenothiazine derivatives have been shown to have inhibitory effects on NMDA 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 glutamate and glycine activity from the effects of chlorpromazine were reported. Further work will be necessary to determine if the influence in NMDA receptors by antipsychotic drugs contributes to their effectiveness.[19]

Peripheral effects

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 "dirty drug", whereas the atypical antipsychotic amisulpride, for example, acts only on central D2 and D3 receptors and is therefore a "clean drug". Research still needs to be done to understand the implications of this fact.

Adverse effects

The main side effects of chlorpromazine are due to its anticholinergic properties; these effects overshadow and counteract, to some extent, the extrapyramidal side effects typical of many early generation antipsychotics. These include sedation, slurred speech, dry mouth, constipation, urinary retention and possible lowering of seizure threshold. Appetite may be increased with resultant weight gain, Glucose tolerance may be impaired.[20] Dermatological reactions are frequently observed. In fact three types of skin disorders are observed: hypersensitivity reaction, contact dermatitis, and photosensitivity. During long-term therapy in schizophrenic patients chlorpromazine can induce abnormal pigmentation of the skin. This can be manifested as gray-blue pigmentation in regions exposed to sunlight.

Chlorpromazine, which has sedating effects, will increase sleep time when given at high doses or when first administered. Sleep cycles or REM sleep is not altered by antipsychotics.[17]

There are striking adverse effects on the reproductive system. Phenothiazines are known to cause hyperprolactinaemia leading to amenorrhea, cessation of normal cyclic ovarian function, loss of libido, occasional hirsutism, false positive pregnancy tests, and long-term risk of osteoporosis in women. The effects of hyperprolactinemia in men are impotence, loss of libido, and hypospermatogenesis. These antipsychotics have significant effects on gonadal hormones including significantly lower levels of estradiol and progesterone in women whereas men display significantly lower levels of testosterone and DHEA when undergoing antipsychotic drug treatment compared to controls.[21]

According to one study of the effects on the reproductive system in rats treated with chlorpromazine there were significant decreases in the weight of the testis, epididymis, seminal vesicles, and prostate gland. This was accompanied by a decline in sperm motility, sperm counts, viability, and serum levels of testosterone in chlorpromazine rats compared to control rats. It has been reported that a change in either the absolute or relative weight of an organ after a chemical is administered is an indication of the toxic effect of the chemical. Therefore, the observed change in the relative weight of the testis and other accessory reproductive organs in rats treated with chlorpromazine indicates that the drug might be toxic to these organs at least during the period of treatments. Furthermore, the weights of the kidney, heart, liver, and adrenal glands of these treated rats were not affected both during administration of the drug and recovery periods, suggesting that the drug is not toxic to these organs.[21]

Antipsychotic drugs may cause priapism, a pathologically prolonged and painful penile erection, which is usually unassociated with sexual desire or intercourse. Although this effect is rare it is a potentially serious complication that can lead to permanent impotence and other serious complications.[22]

Doses of antipsychotics that are considered therapeutically low are sufficient to trigger an epileptic seizure in particularly vulnerable patients for example those with an abnormally low genetically determined seizure threshold. The drug dose ability to provoke seizures is presumably due to a reduced seizure threshold. The incidence of the first unprovoked seizure in the general population is 0.07 to 0.09%, whereas the incidence rates have been reported to range from 0.1 to 1.5% in patients treated with therapeutic doses of the most commonly used antipsychotic drugs. Furthermore, the seizure risk rises markedly to a range of 4 to 30% in patients who have taken an overdose. This most notable variability among studies may possibly be due to methodological differences which makes the research data that much harder to interpret. The risk of a seizure being provoked during antipsychotic drug medication is greatly influenced by the individuals inherited seizure threshold and particularly by the presence of a history of epilepsy, brain damage or other conditions. There is an agreement however that seizures triggered by drugs are a dose-dependent adverse effect.[23]

Tardive dyskinesia and akathisia are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as haloperidol or trifluoperazine, and some evidence suggests that, in conservative dosing, the incidence of such effects with chlorpromazine may be comparable with that of newer agents such as risperidone or olanzapine.[24]

A particularly severe side effect is neuroleptic malignant syndrome[25]. NMS can be fatal.

Other reported side effects are rare, though severe; these include a reduction in the number of white blood cells—referred to as leukopenia—or, in extreme cases, even agranulocytosis, which may occur in 0.01% of patients and lead to death via uncontrollable infections and/or sepsis. Chlorpromazine is also known to accumulate in the eye—in the posterior corneal stroma, lens, and uveal tract. Because it is a phototoxic compound, the potential exists for it to cause cellular damage after light exposure. Research confirms a significant risk of blindness from continued use of chlorpromazine, as well as other optological defects such as color blindness and benign pigmentation of the cornea.[26][27]

Chlorpromazine is the antipsychotic drug with the highest rates (0.5% to 1%) of liver toxicity of the cholestatic type.

The sedation effect combined with indifference to physical stimuli, more commonly called the "Thorazine shuffle," has long been associated with the drug. The image of psychiatric patients staggering mute around a padded cell has earned those particular side effects a place in mainstream pop culture. However, heavy sedation is usually due to excessive doses of Chlorpromazine aimed at pacifying difficult patients in institutional settings. The dose required to treat psychotic symptoms is smaller and therefore less sedative than is commonly depicted.

In some rare cases psychosis or death can result from the paradoxical lowering of blood pressure, or death due to cardiac arrest attributed to dysrhythmia.[28]

Cardiotoxic effects of phenothiazines in overdose are similar to that of the tricyclic antidepressants. Cardiac arrhythmia and apparent sudden death have been associated with therapeutic doses of chlorpromazine, however they are rare cases. The sudden cardiovascular collapse being attributable to ventricular dysrhythmia. Supraventricular tachycardia may also develop. Patients on chlorpromazine therapy exhibit abnormalities on the electrocardiographic T and U waves. These major cardiac arrhythmias that are lethal are a potential hazard even in patients without heart disease who are receiving therapeutic doses of antipsychotic drugs. In order to quantify the risk of cardiac complications to patients receiving therapeutic doses of phenothiazines a prospective clinical trial is suggested.[29]


Chlorpromazine intensifies the central depressive action of drugs with such activity (tranquilizers, barbiturates, narcotics, antihistamines, OTC antiemetics etc.) A dose reduction of chlorpromazine or the other drug may be necessary. Chlorpromazine also intensifies the actions and undesired side effects of antihypertensive drugs and anticholinergic drugs. The combination of chlorpromazine with other antipsychotics may result in increased central depression, hypotension and extrapyramidal side effects, but may sometimes enhance the clinical results of therapy. The anti-worm drug (antihelminthic) piperazine may intensify extrapyramidal side effects. In general, all antipsychotics may lead to seizures in combination with tramadol (Ultram). Chlorpromazine may increase the insulin needs of diabetic patients.

Chlorpromazine is able to inhibit dextromethorphan 0-demethylation a selective marker for CYP2D6 in a concentration dependent manner. Chlorpromazine is able to inhibit the catalytic activity of cytochrome P450 isoforms. CYP2D6 enzyme is not only important in the metabolism of chlorpromazine and associated antipsychotics but is also important in the metabolism of tricyclic antidepressants and selective serotonin reuptake inhibitors that are commonly prescribed to patients with psychiatric disorders. This may result in significant drug interactions which may put these people at a heightened risk for side effects that may be masked by the positive effects or side effects of antipsychotic drugs themselves. Therefore, drugs that inhibit the enzymes that metabolize chlorpromazine would be expected to cause increases in the concentration of other antipsychotic drugs that are coadministered. These increases in concentration may in turn lead to the development of antipsychotic induced side effects. Therefore, chlorpromazine may develop pharmacokinetic interactions with other antipsychotics and antidepressant drugs that are coadministered.[30]

Differential expression of various CYP isoforms in specific brain locations leads to the conclusion that antipsychotic drugs could be metabolized to different products in different regions of the brain. The varying levels of expression of the CYP isoforms between individuals and for each particular antipsychotic as well as the possibility of differential metabolism in the brain provides one possible reason why there is such a wide range of adverse effects and therapeutic effects of chlorpromazine and the other antipsychotic drugs in the population of patients currently using.[30]

Pharmacokinetic variation in the interaction with other drugs and the variation in patient compliance may represent the variability in response to antipsychotic drug treatment between patients. Monitoring plasma levels by specific chemical assay methods may offer some guidance to the variability in the pharmacokinetics and metabolism of antipsychotic drugs in order to individualize drug doses, consequently perhaps alleviating the risk of the adverse effects. Furthermore if plasma levels are monitored then any form of drug induced toxicity can be suspected as well as controlling for the lack of compliance by the patient.

Chlorpromazine impairs the metabolism of tricyclic antidepressants which can thus increase the risk of toxicity.

Combination with other antidopaminergic agents such as metoclopramide and prochlorperazine increases the risk of extrapyramidal symptom effects.

Chlorpromazine can enhance the central nervous system depression produced by other CNS depressent drugs. For example administration of chlorpromazine with ethanol results in potentiated sedative effects and impaired co-ordination.

An interaction between phenothiazine and caffeinated beverages has been reported. Addition of coffee or tea to phenothiazine or butyrphenone antipsychotics forms a precipitant in vitro. This finding was of initial concern as many psychiatric patients might drink coffee or tea immediately after receiving oral medication. However in humans caffeine use was only slightly related to antipsychotic levels. These negative findings between in vitro studies and human epidemiological studies can be attributable to the stomach acidity which reverses any preciptation. It still remains unclear whether the caffeine-antipsychotic precipitation phenomenon has any clinical significance. The neurophysiology of this relationship is derived from the fact that cytochrome P450 CYP1A2 isoenzyme is responsible for metabolism of caffeine as well as chlorpromazine, thus they may compete for the isoenzyme. Support of this possible competition of the isoenzyme comes from the observation that high doses of caffeine can cause tremors and restless legs both of which could be mistaken for or could aggravate neuroleptic induced extrapyramidal effects[15]

Drugs such as SSRIs, St. John's Wort and barbiturates can inhibit various CYP isoenzymes, such as CYP2D6, which are needed for the metabolization of chlorpromazine and/or its metabolites. Theoretically, this should increase the half-lives of chlorpromazine and possibly its metabolites, making dosing changes necessary. The exact clinical significance of this enzyme induction and its therapeutic consequences are unknown at present time and remain to be evaluated as.

Tolerance and Withdrawal

There is no evidence that tolerance develops to the drug's antipsychotic effects. A patient can be maintained for years on a therapeutically effective dose without any decrease in effectiveness being reported. Tolerance appears to develop to the sedating effects of chlorpromazine when it is first administered. Tolerance also appears to develop to the extrapyramidal, antipsychotic or parkinsonian effects, although this is debatable.[17]

A failure to notice withdrawal symptoms may be due to the relatively long half life of the drug resulting in the extremely slow excretion from the body. However, there are reports of muscular discomfort, exaggeration of psychotic symptoms and movement disorders, and difficulty sleeping when the antipsychotic drug is suddenly withdrawn, but after years of normal doses these effects are not normally seen. Physical dependence, if it occurs at all, is rare due to compliance problems and the subjective experience of antipsychotics being never described as pleasant.[17]

Veterinary uses

Chlorpromazine is primarily used as an antiemetic in dogs and cats. It is also sometimes used as a preanesthetic and muscle relaxant in cattle, swine, sheep, and goats. It is generally contraindicated for use with horses, due to a high incidence of ataxia and altered mentation. Its use in food-producing animals has been banned in the EU according to the Council's regulation 2377/90.

Dosage and administration

A wide range is covered from 25 mg oral or intramuscular for mild sedation, every 8 hours, up to 100 mg every 6 hours for severely ill patients. Different qualified sources give 800 mg/day to 1,200 mg/day as highest dose. There has been at least one small clinical trial in treatment-resistant patients with a daily dose of 1,200 mg chlorpromazine (and 4 mg Benztropine to counteract early extrapyramidal side effects, which were anticipated with this unusual high chlorpromazine dose). Initial doses should be low and be increased gradually. It is recommended that most of the daily dose (e.g. 2/3) is given at bedtime for maximum hypnotic activity and minimal daytime sedation and hypotension. In the USA there are controlled release forms of chlorpromazine (e.g. 300 mg). After the individual dose is well established, such a CR capsule can be given with the evening meal as a single dose, covering the next 24 hours. It is often administered in acute settings as a syrup, which has a faster onset of action than tablets.

Chlorpromazine and other antipsychotic drugs need to be taken continuously or chronically to prevent the symptoms of the disease from reappearing. While abuse of antipsychotics is unlikely due to their unpleasant effects, they are rather a class of drugs with considerable compliance problems because prescribed patients often stop taking them. For this reason various administration techniques have been developed that do not depend on a patient's compliance. Among them is administration of depot injections which slowly releases the drug and maintains the appropriate blood levels. Depot injections usually only work with drugs that are highly lipid-soluble, otherwise they would be released too quickly. The technique involves the drug being dissolved in a high concentration in a viscous oil (often sesame oil), which is then injected into a muscle (usually the gluteus maximus) of the buttocks. The drug slowly diffuses from the oil into the body fluids. A single depot injection of a antipsychotic drug can be effective for as long as 4 weeks.[17]

The lowest dosage compatible with good therapeutic effect should be given. Dosage in ambulatory patients should be particularly low (minimizing sedation and hypotension). Intravenous injection of undiluted solution is contraindicated due to risk of massive fall in blood pressure, cardiovascular collapse. For i.v.-infusion of dilutions the (hospitalized) patient should be lying and the infusion rate should be as slow as possible. Afterward the patient should rest in the lying position for at least 30 minutes.

Intramuscular administration is generally not recommended due to the unpredictable absorption and hence widely varying effect. The injection has been reported to be uncomfortable or painful and cause sterile abscesses.[citation needed]

All patients treated with chlorpromazine on a long-term-basis should have the following checked regularly: blood-pressure, pulse rate, laboratory-tests (liver function tests, kidney-values, blood cell counts, ECG and EEG. Some side effects seem to appear more frequently during the first months of therapy (sedation, hypotension, liver damage) while others do not (e.g. tardive dyskinesia).


At regular intervals the treating physician should evaluate whether continued treatment is needed. The drug should never be discontinued suddenly, due to unpleasant withdrawal-symptoms, such as agitation, sleeplessness, states of anxiety, etc. Rather, the dose should be slowly reduced at a rate of approximately 20 percent to 25 percent per week.


Chlorpromazine is classified as a low-potency antipsychotic and in the past was used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of bipolar disorder as well as amphetamine-induced psychoses. The use of chlorpromazine has been largely replaced by newer generation of atypical antipsychotics which are generally better tolerated. Recent global review of data supports its effectiveness as an antipsychotic.[31]

Chlorpromazine formerly was the drug of choice to treat LSD (and other psychedelic/hallucinogen) intoxication in a hospital setting, resulting in it gaining an erroneous reputation as the LSD antidote. Now risperidone is more commonly used in such situations.[32]

Other uses

It has also been used in porphyria and as part of tetanus treatment.

It still is well recommended for short term management of severe anxiety and aggressive episodes.

Resistant and severe hiccups, severe nausea/emesis and preanesthetic conditioning have been other indications in the past.

It can be used to treat amphetamine overdose.[33]

It has also been used to stimulate the appetite of patients with eating disorders, as most anti-psychotics make patients feel hungrier.

It is commonly used in animal medicine to decrease nausea in puppies that are too young for other common anti-emetics.

Off-label and controversial uses

Chlorpromazine is occasionally used off-label for treatment of severe migraine. Sometimes it is used in small doses to improve the nausea that opioid-treated cancer patients encounter and to intensify and prolong the analgesic action of the opioids given. It remains controversial whether or not chlorpromazine has its own analgesic properties. Analgesic properties may result from a central action on the hypothalamus; the patient may feel pain much less than before. Other mechanisms may be an interaction with opioid receptors centrally and/or in the spinal cord. Some experts even say that chlorpromazine, like other phenothiazines, may even have antianalgesic properties. Chlorpromazine has been proposed as useful in newborns for the treatment of opioid withdrawal, if the mother was opioid-dependent. The latter indication remains highly controversial.

It has a unique action in cholera, reducing the loss of water by approximately 30 percent.

In Germany, the brand of chlorpromazine drug Propaphenin had additional indications for insomnia and itching skin disease.

Some jurisdictions in the United States use Chlorpromazine as a sedative/tranquilizer prior to carrying out a death sentence by lethal injection.[34]

Pop Culture References

In John Carpenter's Halloween, Dr. Loomis (Donald Pleasance) is asked by a nurse what to give to his patient, Michael Myers, when taken in front of a judge. He replies, "Thorazine". It is again referenced in Halloween III when Dr. Dan Challis (Tom Atkins) requests 100 milligrams of Thorazine to be administered intravenously to a patient in hysterics.

In the 1984 comedy film, Ghostbusters, Peter Venkman (Bill Murray) administers a massive dose of Thorazine to a possessed Dana Barrett (Sigourney Weaver).

The heavy metal band Savatage recorded a song entitled "Thorazine Shuffle" on their 1989 album Gutter Ballet.

During a show in Pittsburgh, comedian Bill Hicks once joked that his audience must be "all on Thorazine" due to their lack of response to his material.

In 1999 Andrew Bird released a song with his band Andrew Bird's Bowl Of Fire called "Tea & Thorazine"

In a verse on Jay-Z's song "Reservoir Dogs", rapper Sheek Louch raps that "you'd think [my team] was on Thorazine".

In 2010 the movie Shutter Island was released directed by Martin Scorsese and starring Leonardo DiCaprio. In the movie psychiatrist Dr. Crawley, played by Ben Kingsley, mentions Thorazine as part of groundbreaking pharmaceutical treatments for psychosis, an alternative to psychosurgery.


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External links

Simple English

Chlorpromazine is an antipsychotic drug. It is the oldest such drug. It was developed in 1950. It is typically used to treat Schizophrenia. It has also been used to treat bipolar disorder. It has been shown to help uncontrollable hiccups disappear.

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