Chlorpromazine works on a variety of receptors in the central nervous system; these include anticholinergic, antidopaminergic and antihistamine effects as well as some antagonism of adrenergic receptors. Chlorpromazine, along with many of the older antipsychotics which have minimal effect on the serotonergic pathways, is considered a typical antipsychotic.
Its receptor affinities result in a side-effect profile that is predominantly anticholinergic in nature: constipation, sedation, hypotension, and antiemetic properties. It also has anxiolytic (alleviation of anxiety) properties. Extrapyramidal side-effects that are common in many antipsychotics may occur, but are ameliorated by chlorpromazine's anticholinergic activity. They include akathisia and parkinsonian tremor, which can be very unpleasant though reversible. A more chronic side-effect is tardive dyskinesia, which may be irreversible in some patients. Neuroleptic malignant syndrome is a rare though potentially fatal outcome of any antipsychotic use — about one in two thousand (0.05%) patients taking chlorpromazine may develop it. It is often administered in acute settings as a syrup, which has a faster onset of action than tablets. Parenteral administration is not generally recommended.
Its effects on mental state were first reported by the French doctor Henri Laborit as sedation without narcosis. It became possible to cause 'artificial hibernation' in patients, if used as a cocktail together with pethidine and hydergine. Patients with shock, severe trauma or burns, become, if treated so, sedated, without anxiety and unresponsive/indifferent to painful external stimuli like minor surgical interventions. Laborit initially felt its benefit would be in anaethesia and medical stress.
The first published clinical trial was that of Jean Delay and Pierre Deniker at the Hôpital Ste. Anne in Paris in 1952, in which they treated 38 psychotic 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 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.
The drug had been developed by Laboratoires Rhône-Poulenc in 1950 but they sold the rights in 1952 to Smith-Kline & French (today's GlaxoSmithKline). GlaxoSmithKline has since discontinued the drug and it is now only available as a generic drug. The drug was being sold as an antiemetic when its other use was noted. Smith-Kline was quick to encourage clinical trials and in 1954 the drug was approved in the US for psychiatric treatment. The effect of this drug in emptying psychiatric hospitals has been compared to that of penicillin and infectious diseases. 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 neuroleptics were developed such as triflupromazine and trifluoperazine.
Chlorpromazine substituted and eclipsed the old therapies of electro and insulin shocks and other methods such as psychosurgical means (lobotomy) causing permanent brain injury. Before the era of neuroleptics, starting with chlorpromazine, positive long-term results for psychotic patients were only 20%.
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.
Chlorpromazine is derived from phenothiazine, has an aliphatic side chain, typical for low to middle potency neuroleptics. The oral bioavailability is estimated to be 30–50% due to extensive first pass metabolism in the liver. Its elimination half-life is 16–30 hours, due to high lipophilicity, high membrane-binding, and high protein-binding. It has many active metabolites (approximately 75 different ones) with greatly varying halflives and pharmacological profiles. The cytochrome P450 isoenzymes 1A2 and 2D6 are needed for metabolism of chlorpromazine.
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 urine. 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.
Often, due to their high lipophilic character, these and other metabolites may be detected in the urine several months after discontinuation of use. Most metabolites lack any sort of neuroleptic activity, but a few are biologically active. These include 7-hydroxychlorpromazine, mesoridazine, 9-hydroxyresperidone, and a few N-demethylated metabolites.
Chlorpromazine acts as an antagonist (blocking agent) on different postsynaptic receptors:
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).
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.
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.
A particularly severe side effect is neuroleptic malignant syndrome which occurs in approximately 0.05% of those taking chlorpromazine and 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 pigementation of the cornea.
Chlorpromazine is the neuroleptic 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, anecdotally known as 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.
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 neuroleptics may lead to seizures in combination with tramadol (Ultram). Chlorpromazine may increase the insulin needs of diabetic patients.
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.
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.
Use is determined by an attending physician. 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.
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. Afterwards 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.
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).
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.
It still is well recommended for short term management of severe anxiety and aggressive episodes.
It can be used to treat amphetamine overdose.
It has also been used to stimulate the appetite of patients with eating disorders, as most anti-psychotics make patients feel hungrier and thus eat more.
Chlorpromazine is occasionally used off-label for treatment of severe migraine. Sometimes it is used in small doses to improve nausea/emesis opioid-treated cancer patients encounter and to intensify and prolong the analgesic action of the opioids given. Interestingly, 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 the pain much less than before. Other mechanisms may be an interaction with opioid receptors centrally and/or in the spinal cord. Some experts on the contrary 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%.
Some jurisdictions in the United States use Thorazine as a sedative/tranquilizer prior to carrying out a death sentence by lethal injection. The condemned may be offered the sedative and some states require that it be administered, even against the wishes of the condemned.
Was used in the 1970s as a treatment for Hyperactive children as a means of calming them down.
Chlorpromazine: Eye Disorders (First Report of Neurotrophic Corneal Ulcer) in an Elderly Patient: Case Report
Jul 21, 2012; An 80-year-old woman developed chemosis, eyelid oedema, erythema and, later, a neurotrophic corneal ulcer, following retrobulbar...