Chlorpromazine
Encyclopedia
Chlorpromazine is a typical antipsychotic
. First synthesized on December 11, 1950, chlorpromazine was the first drug developed with specific antipsychotic
action, and would serve as the prototype for the phenothiazine
class of drugs, which later grew to comprise several other agents. The introduction of chlorpromazine into clinical use has been described as the single greatest advance in psychiatric care, dramatically improving the prognosis of patients in psychiatric hospitals worldwide; the availability of antipsychotic drugs curtailed indiscriminate use of electroconvulsive therapy
and psychosurgery
, and was one of the driving forces behind the deinstitutionalization movement.
Chlorpromazine works on a variety of receptors in the central nervous system
, producing anticholinergic
, antidopaminergic, antihistaminic, and weak antiadrenergic effects. Both the clinical indications and side effect profile
of CPZ are determined by this broad action: its anticholinergic properties cause constipation
, sedation
, and hypotension
, and help relieve nausea. It also has anxiolytic
(anxiety-relieving) properties. Its antidopaminergic properties can cause extrapyramidal symptoms
such as akathisia
(restlessness, aka the 'largactil shuffle' where the patient walks almost constantly, despite having nowhere to go due to mandatory confinement, and takes small, shuffling steps) and dystonia
. It is known to cause tardive dyskinesia
, which can be irreversible. In recent years, chlorpromazine has been largely superseded by the newer atypical antipsychotic
s, which are usually better tolerated, and its use is now restricted to fewer indications. In acute settings, it is often administered as a syrup, which has a faster onset of action than tablets, and can also be given by intramuscular injection
. IV
administration is very irritating and is not advised; its use is limited to severe hiccups, surgery, and tetanus.
, a phenothiazine
derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs. 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. 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. Laborit trialled the medicine on at the Val-de-Grâce
military hospital in Paris, using it as an anaesthetic booster in intravenous doses of 50 to 100 mg on surgery patients and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterwards. He also noted its hypothermic 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. 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.
Following on, Laborit considered whether chlorpromazine may have a role in managing patients with severe burns, Raynaud's phenomenon
, or psychiatric disorders. At the Villejuif Mental Hospital in November 1951, he and Montassut administered an intravenous dose to psychiatrist Cornelio 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. Despite this, Laborit continued to push for testing in psychiatric patients during early 1952. Psychiatrists were reluctant initially, but on January 19, 1952, it was administered (alongside pethidine, penthothal and ECT) to Jacques Lh. a 24 year old manic patient, who responded dramatically, and was discharged after three weeks having received 855 mg of the drug in total.
Pierre Deniker
had heard about Laborit's work from his brother in law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the Hôpital Sainte-Anne in Paris where he was Men's Service Chief. Together with the Director of the hospital, Professor Jean Delay
, they published first clinical trial 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. They also found that doses higher than those used by Laborit were required, giving patients 75–100 mg daily.
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.
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. But the popularity of the drug fell from the late 1960s as newer drugs came on the scene. From chlorpromazine a number of other similar antipsychotic
s were developed. It led to the discovery of antidepressants.
Chlorpromazine largely replaced electroconvulsive therapy
, psychosurgery
, and insulin shock therapy
. By 1964, about 50 million people worldwide had taken it. 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 and their reintegration into the community. 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 and 120,000 patients.
Chlorpromazine, in widespread use for 50 years, remains a "benchmark" drug in the treatment of schizophrenia, an effective drug although not perfect. The relative strengths or potencies of other antipsychotics are often ranked or measured against chlorpromazine in aliquots of 100 mg, termed chlorpromazine equivalents or CPZE.
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. Low-potency antipsychotics have more anticholinergic side effects such as dry mouth, sedation and constipation, and lower rates of extrapyramidal side effects, while high-potency antipsychotics (such as haloperidol
) have the reverse profile.
The use of chlorpromazine and other typical antipsychotics 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.
Chlorpromazine has also been used in porphyria
and as part of tetanus
treatment. It still is recommended for short term management of severe anxiety and aggressive episodes. Resistant and severe hiccups, severe nausea
/emesis and preanesthetic conditioning are other uses. Symptoms of delirium
in medically hospitalized AIDS
patients have been effectively treated with low doses of chlorpromazine.
. 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.
It has a unique action in cholera
, reducing the loss of water by approximately 30 percent.
In Germany, chlorpromazine still carries label indications for insomnia
and severe pruritus, as well as preanesthesia.
in dogs and cats, and it is commonly used to decrease nausea in animals that are too young for other common anti-emetics. 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.
s 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, and Glucose tolerance
may be impaired. It lowers blood pressure with accompanying dizziness. Memory loss
and amnesia
has also been reported. Chlorpromazine, which has sedating effects, will increase sleep time when given at high doses or when first administered, although tolerance usually develops. Sleep cycles or REM sleep is not altered by antipsychotics.
Dermatological reactions are frequently observed. In fact three types of skin disorders are observed: hypersensitivity reaction, contact dermatitis, and photosensitivity
. During long-term therapy of schizophrenic patients chlorpromazine can induce abnormal pigmentation of the skin. This can be manifested as gray-blue pigmentation in regions exposed to sunlight.
There are 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 gynaecomastia, lactation
, 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. 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.
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.
Even therapeutically low doses may trigger seizures in susceptible patients, such as those with an abnormally low genetically determined seizure threshold, presumably by lowering the seizure threshold. The incidence of the first unprovoked seizure in the general population is from 0.07 to 0.09%, but in patients treated with commonly used antipsychotic drugs it reportedly ranges from 0.1 to 1.5%. In overdose, the risk reaches 4 to 30%. This wide variability among studies may be due to methodological differences. The risk is greatly influenced by the individual's inherited seizure threshold, and particularly by a history of epilepsy, brain damage or other conditions. The triggering of seizures by antipsychotic drugs is generally agreed to be a dose-dependent adverse effect.
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, with conservative dosing, the incidence of such effects for chlorpromazine may be comparable to that of newer agents such as risperidone
or olanzapine
.
A particularly severe side effect is neuroleptic malignant syndrome
, which 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.
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 is 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.
s, barbiturate
s, narcotics, antihistamines, OTC antiemetics). It also intensifies the actions and undesired side effects of antihypertensive
and anticholinergic
drugs. The combination of chlorpromazine with other antipsychotics may result in increased central depression
, hypotension
and extrapyramidal side effects, but may 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. Chorpromazine enhances the CNS depressant effects of alcohol.
Chlorpromazine is able to inhibit dextromethorphan 0-demethylation, a selective marker for CYP2D6
, in a concentration dependent manner. It inhibits 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 antidepressant
s and selective serotonin reuptake inhibitor
s 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 co-administered. These increases in concentration may in turn lead to the development of antipsychotic-induced side effects, developing pharmacokinetic interactions with other antipsychotics and antidepressant drugs that are coadministered. 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.
As chlorpromazine can enhance the central nervous system depression produced by other CNS depressant drugs, its administration with alcohol results in increased sedative effects and impaired co-ordination. An interaction between phenothiazine and caffeinated beverages has been reported. Addition of coffee or tea to phenothiazine or butyrophenone 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 precipitation. 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.
Chlorpromazine has been shown to inhibit the human ether-a-go-go related gene (hERG
) potassium channels. This is a serious side effect of the drug and could lead to death. When this occurs long QT syndrome
(aLQTS) is acquired by the prolongation of the cardiac action potential due to a block in the cardiac ion channels and delayed repolarization of the heart. Patients with aLQTS are exposed to a higher chance of torsade de pointes arrhythmias and sudden cardiac arrest.
Chlorpromazine is notorious for depositing ocular tissues when taken in high dosages for long periods of time. In one specific case a 59 year old schizophrenic man on chlorpromazine therapy with cumulative dosage of 2500 g resulted in multiple white deposits in the endothelium of both corneas. Confocal microscopy revealed significant pleomorphism and polymegethism of endothelial cells. The anterior lens capsules opacities were star- shaped and concentrated in the centre. In this patient chlorpromazine deposited mainly in the corneal endothelium, central anterior lens capsule and epithelial cells. This is common with many patients that receive high dosages of chlorpromazine.
derivatives, are highly lipophilic molecules that readily bind with membranes and proteins. Around 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 unconjugated chlorpromazine metabolites are found in the lungs and the liver. It is a dopamine inhibitor, increases dopamine turnover in the brain, and stimulates prolactin release. The increased brain turnover of dopamine may be related to its therapeutic effects; it achieves a higher concentration in the brain than in the blood stream.
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.
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.
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 (range 1.5–8 hours), after an oral dose.
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), 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.) 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. 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.
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. 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 up to 18 months. after discontinuation of use. Most metabolites lack any sort of antipsychotic activity, but a few are biologically active. These include 7-hydroxychlorpromazine, mesoridazine
, and a few N-demethylated metabolites.
Chlorpromazine acts as an antagonist
(blocking agent) on different postsynaptic receptors:
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 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.
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.
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.
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.
s (dry mouth, reduction in forming of gastric juice) and some 5-HT receptor
s (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.
recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse. While withdrawal symptoms can occur, 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, parkinsonian and other neuroleptic effects, although this is debatable.
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.
. In the US 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, and is more difficult to spit out to avoid taking.
Chlorpromazine and other antipsychotic drugs need to be taken long-term to prevent the symptoms of the disease from reappearing. Abuse of antipsychotics is unlikely due to their unpleasant effects, in fact these effects often lead patients to 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. The technique involves an IM dose injected into a muscle (usually the gluteus medius) of the buttocks or deltoid muscle
in the shoulder. The drug slowly diffuses into the body fluids. A single depot injection of an antipsychotic drug can be effective for as long as four weeks. Chlorpromazine is not available as a depot medication.
Previously, higher doses, up to 1200 mg daily or more, were used in acute psychosis. However, this range has markedly decreased in recent years, and dosing aims for the lowest possible with good therapeutic effect. 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 intravenous 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.
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 such as tardive dyskinesia
can appear over time.
of chlorpromazine begins with the reaction of 1,4-dichloro-2-nitrobenzene with 2-bromobenzenethiol. Hydrogen chloride
is evolved as a by-product
of this step and a thioether
is formed as the product. Although not verified, it appears that the ortho-chlorine is eliminated preferentially. In the second step the nitrogroup is reduced with hydrogen gas. Upon heating in DMF
solvent, ring cyclization occurs. In an analogous manner to what was done in the preparation of promazine
, the 2-chloro-10H-phenothiazine of the last step is combined with 3-chloro-N,N-dimethylpropan-1-amine in the presence of sodamide base.
Typical antipsychotic
Typical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis...
. First synthesized on December 11, 1950, chlorpromazine was the first drug developed with specific antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
action, and would serve as the prototype for the phenothiazine
Phenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
class of drugs, which later grew to comprise several other agents. The introduction of chlorpromazine into clinical use has been described as the single greatest advance in psychiatric care, dramatically improving the prognosis of patients in psychiatric hospitals worldwide; the availability of antipsychotic drugs curtailed indiscriminate use of electroconvulsive therapy
Electroconvulsive therapy
Electroconvulsive therapy , formerly known as electroshock, is a psychiatric treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect. Its mode of action is unknown...
and psychosurgery
Psychosurgery
Psychosurgery, also called neurosurgery for mental disorder , is the neurosurgical treatment of mental disorder. Psychosurgery has always been a controversial medical field. The modern history of psychosurgery begins in the 1880s under the Swiss psychiatrist Gottlieb Burckhardt...
, and was one of the driving forces behind the deinstitutionalization movement.
Chlorpromazine works on a variety of receptors in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, producing anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
, antidopaminergic, antihistaminic, and weak antiadrenergic effects. Both the clinical indications and side effect profile
Adverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
of CPZ are determined by this broad action: its anticholinergic properties cause constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, and hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, and help relieve nausea. It also has anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
(anxiety-relieving) properties. Its antidopaminergic properties can cause extrapyramidal symptoms
Extrapyramidal symptoms
The extrapyramidal system can be affected in a number of ways, which are revealed in a range of extrapyramidal symptoms , also known as extrapyramidal side-effects , such as akinesia and akathisia .Extrapyramidal symptoms are various movement disorders such as acute dystonic reactions,...
such as akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
(restlessness, aka the 'largactil shuffle' where the patient walks almost constantly, despite having nowhere to go due to mandatory confinement, and takes small, shuffling steps) and dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
. It is known to cause tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
, which can be irreversible. In recent years, chlorpromazine has been largely superseded by the newer atypical antipsychotic
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
s, which are usually better tolerated, and its use is now restricted to fewer indications. In acute settings, it is often administered as a syrup, which has a faster onset of action than tablets, and can also be given by intramuscular injection
Intramuscular injection
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...
. IV
Intravenous therapy
Intravenous therapy or IV therapy is the infusion of liquid substances directly into a vein. The word intravenous simply means "within a vein". Therapies administered intravenously are often called specialty pharmaceuticals...
administration is very irritating and is not advised; its use is limited to severe hiccups, surgery, and tetanus.
History
In 1933, the French pharmaceutical company Laboratoires Rhône-Poulenc began to search for new anti-histamines. In 1947, it synthesized promethazinePromethazine
Promethazine is a first-generation antihistamine of the phenothiazine family. The drug has anti-motion sickness, antiemetic, and anticholinergic effects, as well as a strong sedative effect and in some countries is prescribed for insomnia when benzodiazepines are contraindicated...
, a phenothiazine
Phenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
derivative, which was found to have more pronounced sedative and antihistaminic effects than earlier drugs. A year later, the French surgeon Pierre Huguenard used promethazine together with pethidine
Pethidine
Pethidine or meperidine Pethidine (INN) or meperidine (USAN) Pethidine (INN) or meperidine (USAN) (commonly referred to as Demerol but also referred to as: isonipecaine; lidol; pethanol; piridosal; Algil; Alodan; Centralgin; Dispadol; Dolantin; Mialgin (in Indonesia); Petidin Dolargan (in Poland);...
as part of a lytic cocktail to induce relaxation and indifference in surgical patients. Another surgeon, Henri Laborit
Henri Laborit
Henri Laborit was a French physician, writer and philosopher.Laborit was born in Hanoi, Vietnam and started his career as a neurosurgeon in the Marines and then moved on to fundamental research. He won the prestigious Albert Lasker Award for Clinical Medical Research in 1957...
, believed the compound stabilized the central nervous system by causing 'artificial hibernation', and described this state as 'sedation without narcosis
Narcosis
Narcosis may refer to:* Narcosis, the unconsciousness induced by a narcotic drug* Nitrogen narcosis, an effect of diving deep with nitrogen* Hydrogen narcosis, an effect of diving deep with hydrogenIn music:* Narcosis , an English metal band...
'. He suggested to Rhône-Poulenc that they develop a compound with better stabilizing properties. 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
Aversives
In psychology, aversives are unpleasant stimuli that induce changes in behavior through punishment; by applying an aversive immediately following a behavior, the likelihood of the behavior occurring in the future is reduced. Aversives can vary from being slightly unpleasant or irritating to...
in rats. Chlorpromazine was distributed for testing to physicians between April and August 1951. Laborit trialled the medicine on at the Val-de-Grâce
Val-de-Grâce
This article describes the hospital and former abbey. For the main article on Mansart and Lemercier's central church, see Church of the Val-de-Grâce....
military hospital in Paris, using it as an anaesthetic booster in intravenous doses of 50 to 100 mg on surgery patients and confirming it as the best drug to date in calming and reducing shock, with patients reporting improved well being afterwards. He also noted its hypothermic 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. 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.
Following on, Laborit considered whether chlorpromazine may have a role in managing patients with severe burns, Raynaud's phenomenon
Raynaud's phenomenon
In medicine, Raynaud's phenomenon is a vasospastic disorder causing discoloration of the fingers, toes, and occasionally other areas. This condition can also cause nails to become brittle with longitudinal ridges. Named for French physician Maurice Raynaud , the phenomenon is believed to be the...
, or psychiatric disorders. At the Villejuif Mental Hospital in November 1951, he and Montassut administered an intravenous dose to psychiatrist Cornelio 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. Despite this, Laborit continued to push for testing in psychiatric patients during early 1952. Psychiatrists were reluctant initially, but on January 19, 1952, it was administered (alongside pethidine, penthothal and ECT) to Jacques Lh. a 24 year old manic patient, who responded dramatically, and was discharged after three weeks having received 855 mg of the drug in total.
Pierre Deniker
Pierre Deniker
Pierre Deniker was involved, jointly with Jean Delay and J. M. Harl, in the introduction of chlorpromazine , the first antipsychotic used in the treatment of schizophrenia, in the 1950's. Thorazine had been used in surgical procedures peri-operatively as an anti-nausea medication in France....
had heard about Laborit's work from his brother in law, who was a surgeon, and ordered chlorpromazine for a clinical trial at the Hôpital Sainte-Anne in Paris where he was Men's Service Chief. Together with the Director of the hospital, Professor Jean Delay
Jean Delay
Jean Delay was a French psychiatrist, neurologist and writer. He discovered, jointly with J. M...
, they published first clinical trial 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. They also found that doses higher than those used by Laborit were required, giving patients 75–100 mg daily.
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
Douglas Hospital
The Douglas Mental Health University Institute is a Canadian psychiatric hospital located in the borough of Verdun in the city of Montreal, Quebec. It is also a teaching hospital affiliated with McGill University...
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
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, mania
Mania
Mania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
, psychomotor excitement, and other psychotic
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
disorders.
Rhône-Poulenc licensed chlorpromazine to Smith Kline & French (today's GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline plc is a global pharmaceutical, biologics, vaccines and consumer healthcare company headquartered in London, United Kingdom...
) 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
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
and infectious diseases. But the popularity of the drug fell from the late 1960s as newer drugs came on the scene. From chlorpromazine a number of other similar antipsychotic
Antipsychotic
An antipsychotic is a tranquilizing psychiatric medication primarily used to manage psychosis , particularly in schizophrenia and bipolar disorder. A first generation of antipsychotics, known as typical antipsychotics, was discovered in the 1950s...
s were developed. It led to the discovery of antidepressants.
Chlorpromazine largely replaced electroconvulsive therapy
Electroconvulsive therapy
Electroconvulsive therapy , formerly known as electroshock, is a psychiatric treatment in which seizures are electrically induced in anesthetized patients for therapeutic effect. Its mode of action is unknown...
, psychosurgery
Psychosurgery
Psychosurgery, also called neurosurgery for mental disorder , is the neurosurgical treatment of mental disorder. Psychosurgery has always been a controversial medical field. The modern history of psychosurgery begins in the 1880s under the Swiss psychiatrist Gottlieb Burckhardt...
, and insulin shock therapy
Insulin shock therapy
Insulin shock therapy or insulin coma therapy was a form of psychiatric treatment in which patients were repeatedly injected with large doses of insulin in order to produce daily comas over several weeks...
. By 1964, about 50 million people worldwide had taken it. 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 and their reintegration into the community. 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 and 120,000 patients.
Chlorpromazine, in widespread use for 50 years, remains a "benchmark" drug in the treatment of schizophrenia, an effective drug although not perfect. The relative strengths or potencies of other antipsychotics are often ranked or measured against chlorpromazine in aliquots of 100 mg, termed chlorpromazine equivalents or CPZE.
Indications
Chlorpromazine is classified as a low-potency typical antipsychoticTypical antipsychotic
Typical antipsychotics are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis...
and in the past was used in the treatment of both acute and chronic psychoses
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, including schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
and the manic phase of bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
as well as amphetamine-induced psychoses. Low-potency antipsychotics have more anticholinergic side effects such as dry mouth, sedation and constipation, and lower rates of extrapyramidal side effects, while high-potency antipsychotics (such as haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
) have the reverse profile.
The use of chlorpromazine and other typical antipsychotics 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.
Chlorpromazine has also been used in porphyria
Porphyria
Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...
and as part of tetanus
Tetanus
Tetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...
treatment. It still is recommended for short term management of severe anxiety and aggressive episodes. Resistant and severe hiccups, severe nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
/emesis and preanesthetic conditioning are other uses. Symptoms of delirium
Delirium
Delirium or acute confusional state is a common and severe neuropsychiatric syndrome with core features of acute onset and fluctuating course, attentional deficits and generalized severe disorganization of behavior...
in medically hospitalized AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
patients have been effectively treated with low doses of chlorpromazine.
Off-label and controversial uses
Chlorpromazine is occasionally used off-label for treatment of severe migraineMigraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
. Sometimes it is used in small doses to improve the nausea that opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
-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
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
properties. Analgesic properties may result from a central action on the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
; 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
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
. Some experts even say that chlorpromazine, like other phenothiazines, may even have antianalgesic properties.
It has a unique action in cholera
Cholera
Cholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission occurs primarily by drinking or eating water or food that has been contaminated by the diarrhea of an infected person or the feces...
, reducing the loss of water by approximately 30 percent.
In Germany, chlorpromazine still carries label indications for insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
and severe pruritus, as well as preanesthesia.
Veterinary uses
Chlorpromazine is not registered for animal uses, but may be prescribed legally by veterinarians for animal use. It is primarily used as an antiemeticAntiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer....
in dogs and cats, and it is commonly used to decrease nausea in animals that are too young for other common anti-emetics. It is also sometimes used as a preanesthetic and muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
in cattle, swine, sheep, and goats. It is generally contraindicated for use with horses, due to a high incidence of ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
and altered mentation. Its use in food-producing animals has been banned in the EU according to the Council's regulation 2377/90.
Adverse effects
The main side effectAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s of chlorpromazine are due to its anticholinergic properties; these effects overshadow and counteract, to some extent, the extrapyramidal
Extrapyramidal symptoms
The extrapyramidal system can be affected in a number of ways, which are revealed in a range of extrapyramidal symptoms , also known as extrapyramidal side-effects , such as akinesia and akathisia .Extrapyramidal symptoms are various movement disorders such as acute dystonic reactions,...
side effects typical of many early generation antipsychotics. These include sedation, slurred speech, dry mouth, constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, urinary retention and possible lowering of seizure threshold. Appetite may be increased with resultant weight gain, and Glucose tolerance
Glucose tolerance test
A glucose tolerance test is a medical test in which glucose is given and blood samples taken afterward to determine how quickly it is cleared from the blood. The test is usually used to test for diabetes, insulin resistance, and sometimes reactive hypoglycemia and acromegaly, or rarer disorders of...
may be impaired. It lowers blood pressure with accompanying dizziness. Memory loss
Memory loss
Memory loss can be partial or total and it is normal when it comes with aging. Sudden memory loss is usually a result of brain trauma and it may be permanent or temporary. When it is caused by medical conditions such as Alzheimers, the memory loss is gradual and tends to be permanent.Brain trauma...
and amnesia
Amnesia
Amnesia is a condition in which one's memory is lost. The causes of amnesia have traditionally been divided into categories. Memory appears to be stored in several parts of the limbic system of the brain, and any condition that interferes with the function of this system can cause amnesia...
has also been reported. Chlorpromazine, which has sedating effects, will increase sleep time when given at high doses or when first administered, although tolerance usually develops. Sleep cycles or REM sleep is not altered by antipsychotics.
Dermatological reactions are frequently observed. In fact three types of skin disorders are observed: hypersensitivity reaction, contact dermatitis, and photosensitivity
Photosensitivity
Photosensitivity is the amount to which an object reacts upon receiving photons, especially visible light.- Human medicine :Sensitivity of the skin to a light source can take various forms. People with particular skin types are more sensitive to sunburn...
. During long-term therapy of schizophrenic patients chlorpromazine can induce abnormal pigmentation of the skin. This can be manifested as gray-blue pigmentation in regions exposed to sunlight.
There are adverse effects on the reproductive system. Phenothiazines are known to cause hyperprolactinaemia
Hyperprolactinaemia
Hyperprolactinaemia or hyperprolactinemia is the presence of abnormally-high levels of prolactin in the blood. Normal levels are less than 500 mIU/L for women, and less than 450 mIU/L for men....
leading to amenorrhea, cessation of normal cyclic ovarian function, loss of libido, occasional hirsutism
Hirsutism
Hirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
, false positive pregnancy tests, and long-term risk of osteoporosis in women. The effects of hyperprolactinemia in men are gynaecomastia, lactation
Lactation
Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process occurs in all female mammals, however it predates mammals. In humans the process of feeding milk is called breastfeeding or nursing...
, impotence, loss of libido
Libido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
, and hypospermatogenesis
Spermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
. 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. 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.
Antipsychotic drugs may cause priapism
Priapism
Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
, 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.
Even therapeutically low doses may trigger seizures in susceptible patients, such as those with an abnormally low genetically determined seizure threshold, presumably by lowering the seizure threshold. The incidence of the first unprovoked seizure in the general population is from 0.07 to 0.09%, but in patients treated with commonly used antipsychotic drugs it reportedly ranges from 0.1 to 1.5%. In overdose, the risk reaches 4 to 30%. This wide variability among studies may be due to methodological differences. The risk is greatly influenced by the individual's inherited seizure threshold, and particularly by a history of epilepsy, brain damage or other conditions. The triggering of seizures by antipsychotic drugs is generally agreed to be a dose-dependent adverse effect.
Tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
and akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
are less commonly seen with chlorpromazine than they are with high potency typical antipsychotics such as haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
or trifluoperazine
Trifluoperazine
Trifluoperazine is a typical antipsychotic of the phenothiazine chemical class.- Uses :...
, 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 risperidone
Risperidone
Risperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism...
or olanzapine
Olanzapine
Olanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
.
A particularly severe side effect is neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
, which 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
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
—or, in extreme cases, even agranulocytosis
Agranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
, which may occur in 0.01% of patients and lead to death via uncontrollable infections and/or sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...
. Chlorpromazine is also known to accumulate in the eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
—in the posterior corneal stroma, lens
Lens (anatomy)
The crystalline lens is a transparent, biconvex structure in the eye that, along with the cornea, helps to refract light to be focused on the retina. The lens, by changing shape, functions to change the focal distance of the eye so that it can focus on objects at various distances, thus allowing a...
, and uveal tract
Uvea
The uvea , also called the uveal layer, uveal coat, uveal tract, or vascular tunic, is the pigmented middle of the three concentric layers that make up an eye. The name is possibly a reference to its reddish-blue or almost black colour, wrinkled appearance and grape-like size and shape when...
. 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.
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 is 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.
Interactions
Chlorpromazine intensifies the central depressive action of drugs with such activity (such as tranquilizerTranquilizer
A tranquilizer, or tranquilliser , is a drug that induces tranquility in an individual.The term "tranquilizer" is imprecise, and is usually qualified, or replaced with more precise terms:...
s, barbiturate
Barbiturate
Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, as hypnotics, and as anticonvulsants...
s, narcotics, antihistamines, OTC antiemetics). It also intensifies the actions and undesired side effects of antihypertensive
Antihypertensive
The antihypertensives are a class of drugs that are used to treat hypertension . Evidence suggests that reduction of the blood pressure by 5 mmHg can decrease the risk of stroke by 34%, of ischaemic heart disease by 21%, and reduce the likelihood of dementia, heart failure, and mortality from...
and anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
drugs. The combination of chlorpromazine with other antipsychotics may result in increased central depression
Depression (physiology)
Depression in physiology and medicine refers to a lowering, in particular a reduction in a particular biological variable or the function of an organ...
, hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
and extrapyramidal side effects, but may enhance the clinical results of therapy. The anti-worm drug (antihelminthic) piperazine
Piperazine
Piperazine is an organic compound that consists of a six-membered ring containing two opposing nitrogen atoms. Piperazine exists as small alkaline deliquescent crystals with a saline taste....
may intensify extrapyramidal side effects. In general, all antipsychotics may lead to seizures in combination with tramadol
Tramadol
Tramadol hydrochloride is a centrally acting synthetic opioid analgesic used in treating moderate pain. The drug has a wide range of applications, including treatment for restless legs syndrome and fibromyalgia...
(Ultram). Chlorpromazine may increase the insulin needs of diabetic patients. Chorpromazine enhances the CNS depressant effects of alcohol.
Chlorpromazine is able to inhibit dextromethorphan 0-demethylation, a selective marker for CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
, in a concentration dependent manner. It inhibits 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 antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s and selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s 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 co-administered. These increases in concentration may in turn lead to the development of antipsychotic-induced side effects, developing pharmacokinetic interactions with other antipsychotics and antidepressant drugs that are coadministered. 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.
As chlorpromazine can enhance the central nervous system depression produced by other CNS depressant drugs, its administration with alcohol results in increased sedative effects and impaired co-ordination. An interaction between phenothiazine and caffeinated beverages has been reported. Addition of coffee or tea to phenothiazine or butyrophenone 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 precipitation. 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.
Chlorpromazine has been shown to inhibit the human ether-a-go-go related gene (hERG
HERG
hERG is a gene that codes for a protein known as Kv11.1 potassium ion channel...
) potassium channels. This is a serious side effect of the drug and could lead to death. When this occurs long QT syndrome
Long QT syndrome
The long QT syndrome is a rare inborn heart condition in which delayed repolarization of the heart following a heartbeat increases the risk of episodes of torsade de pointes . These episodes may lead to palpitations, fainting and sudden death due to ventricular fibrillation...
(aLQTS) is acquired by the prolongation of the cardiac action potential due to a block in the cardiac ion channels and delayed repolarization of the heart. Patients with aLQTS are exposed to a higher chance of torsade de pointes arrhythmias and sudden cardiac arrest.
Chlorpromazine is notorious for depositing ocular tissues when taken in high dosages for long periods of time. In one specific case a 59 year old schizophrenic man on chlorpromazine therapy with cumulative dosage of 2500 g resulted in multiple white deposits in the endothelium of both corneas. Confocal microscopy revealed significant pleomorphism and polymegethism of endothelial cells. The anterior lens capsules opacities were star- shaped and concentrated in the centre. In this patient chlorpromazine deposited mainly in the corneal endothelium, central anterior lens capsule and epithelial cells. This is common with many patients that receive high dosages of chlorpromazine.
Pharmacokinetics
Chlorpromazine, and many other phenothiazinePhenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
derivatives, are highly lipophilic molecules that readily bind with membranes and proteins. Around 95-98% of the drug is bound in the plasma; 85% of the drug is bound to the plasma protein albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
. Renal disease may cause this range to expand significantly. Highest concentrations of unconjugated chlorpromazine metabolites are found in the lungs and the liver. It is a dopamine inhibitor, increases dopamine turnover in the brain, and stimulates prolactin release. The increased brain turnover of dopamine may be related to its therapeutic effects; it achieves a higher concentration in the brain than in the blood stream.
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
Phenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
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.
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.
Bioavailability
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
: 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 (range 1.5–8 hours), after an oral dose.
Phenothiazine
Phenothiazine is an organic compound that occurs in various antipsychotic and antihistaminic drugs. It has the formula S2NH. This yellow tricyclic compound is soluble in acetic acid, benzene, and ether. The compound is related to the thiazine-class of heterocyclic compounds...
, has an aliphatic side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...
, 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
Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered...
is estimated to be 30–50% that of intramuscular doses and about 10% that of intravenous doses due to extensive first pass metabolism
First pass effect
The first-pass effect is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation. It is the fraction of lost drug during the process of absorption which is generally related to the liver and gut wall...
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), 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.) 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. 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
CYP1A2
Cytochrome P450 1A2 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body...
and 2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
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.
Chlorpromazine is typically degraded by the liver by the action of cytochrome-P450 family enzymes, usually CYP2D6
CYP2D6
Cytochrome P450 2D6 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. Also, many substances are bioactivated by CYP2D6 to form their active compounds...
. 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. 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 up to 18 months. after discontinuation of use. Most metabolites lack any sort of antipsychotic activity, but a few are biologically active. These include 7-hydroxychlorpromazine, mesoridazine
Mesoridazine
Mesoridazine is a piperidine neuroleptic drug belonging to the class of drugs called phenothiazines, used in the treatment of schizophrenia. It is a metabolite of thioridazine...
, and a few N-demethylated metabolites.
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.Chlorpromazine acts as an antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
(blocking agent) on different postsynaptic receptors:
- dopamine receptorDopamine receptorDopamine receptors are a class of metabotropic G protein-coupled receptors that are prominent in the vertebrate central nervous system . The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors....
s (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 receptorHistamine receptorThe histamine receptors are a class of G protein-coupled receptors with histamine as their endogenous ligand.There are four known histamine receptors:*H1 receptor*H2 receptor*H3 receptor*H4 receptor-Comparison:...
s (H1 receptors, accounting for sedation, antiemetic effect, vertigo, fall in blood pressure and weight gain), - α1- and α2-adrenergic receptorAdrenergic receptorThe adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
s (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 receptorMuscarinic acetylcholine receptorMuscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographicElectrocardiogramElectrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...
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 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.
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.
Chlorpromazine and other antipsychotics with sedative properties such as promazine
Promazine
Promazine is a medication that belongs to the phenothiazine class of antipsychotics. An older medication used to treat schizophrenia, it is still prescribed, alongside newer agents such as olanzapine and quetiapine...
and thioridazine
Thioridazine
Thioridazine is a piperidine typical antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis...
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.
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.
Peripheral effects
Chlorpromazine is an antagonist to H1 receptors (provoking antiallergic effects), H2 receptors (reduction of forming of gastric juice), M1 and M2 receptorMuscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
s (dry mouth, reduction in forming of gastric juice) and some 5-HT receptor
5-HT receptor
The serotonin receptors, also known as 5-hydroxytryptamine receptors or 5-HT receptors, are a group of G protein-coupled receptors and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neurotransmission...
s (different anti-allergic/gastrointestinal actions).
Because it acts on so many receptors, chlorpromazine is often referred to as a "dirty drug
Dirty drug
A dirty drug is an informal term used in pharmacology to describe drugs that may bind to many different molecular targets or receptors in the body, and so tend to have a wide range of effects and possibly negative side effects...
", whereas the atypical antipsychotic amisulpride
Amisulpride
Amisulpride , is an atypical antipsychotic used to treat psychosis in schizophrenia and episodes of mania in bipolar disorder. In small doses it is also used to treat depression. It was introduced by Sanofi-Aventis in the 1990s.-Pharmacology:Amisulpride functions primarily as a D2 and D3 receptor...
, 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.
Tolerance and withdrawal
The British National FormularyBritish National Formulary
The British National Formulary is a medical and pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about all medicines available on the National Health Service , including indication,...
recommends a gradual withdrawal when discontinuing antipsychotic treatment to avoid acute withdrawal syndrome or rapid relapse. While withdrawal symptoms can occur, 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, parkinsonian and other neuroleptic effects, although this is debatable.
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.
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. Initial doses should be low and be increased gradually. It is recommended that most of the daily dose is given at bedtime for maximum hypnotic activity and minimal daytime sedation and hypotensionHypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
. In the US 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, and is more difficult to spit out to avoid taking.
Chlorpromazine and other antipsychotic drugs need to be taken long-term to prevent the symptoms of the disease from reappearing. Abuse of antipsychotics is unlikely due to their unpleasant effects, in fact these effects often lead patients to 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
Injection (medicine)
An injection is an infusion method of putting fluid into the body, usually with a hollow needle and a syringe which is pierced through the skin to a sufficient depth for the material to be forced into the body...
which slowly releases the drug and maintains the appropriate blood levels. The technique involves an IM dose injected into a muscle (usually the gluteus medius) of the buttocks or deltoid muscle
Deltoid muscle
In human anatomy, the deltoid muscle is the muscle forming the rounded contour of the shoulder. Anatomically, it appears to be made up of three distinct sets of fibers though electromyography suggests that it consists of at least seven groups that can be independently coordinated by the central...
in the shoulder. The drug slowly diffuses into the body fluids. A single depot injection of an antipsychotic drug can be effective for as long as four weeks. Chlorpromazine is not available as a depot medication.
Previously, higher doses, up to 1200 mg daily or more, were used in acute psychosis. However, this range has markedly decreased in recent years, and dosing aims for the lowest possible with good therapeutic effect. Dosage in ambulatory patients should be particularly low (minimizing sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
and hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
). Intravenous injection of undiluted solution is contraindicated due to risk of massive fall in blood pressure, cardiovascular collapse. For intravenous 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.
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
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
-values, blood cell counts
Complete blood count
A complete blood count , also known as full blood count or full blood exam or blood panel, is a test panel requested by a doctor or other medical professional that gives information about the cells in a patient's blood...
, ECG and EEG
EEG
EEG commonly refers to electroencephalography, a measurement of the electrical activity of the brain.EEG may also refer to:* Emperor Entertainment Group, a Hong Kong-based entertainment company...
. Some side effects seem to appear more frequently during the first months of therapy (sedation
Sedation
Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...
, hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, liver damage
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
) while others such as tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
can appear over time.
Discontinuation
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, stomach pain, dizziness, nausea and vomiting. Preferably the dose should be gradually reduced.Synthesis
The synthesisOrganic synthesis
Organic synthesis is a special branch of chemical synthesis and is concerned with the construction of organic compounds via organic reactions. Organic molecules can often contain a higher level of complexity compared to purely inorganic compounds, so the synthesis of organic compounds has...
of chlorpromazine begins with the reaction of 1,4-dichloro-2-nitrobenzene with 2-bromobenzenethiol. Hydrogen chloride
Hydrogen chloride
The compound hydrogen chloride has the formula HCl. At room temperature, it is a colorless gas, which forms white fumes of hydrochloric acid upon contact with atmospheric humidity. Hydrogen chloride gas and hydrochloric acid are important in technology and industry...
is evolved as a by-product
By-product
A by-product is a secondary product derived from a manufacturing process or chemical reaction. It is not the primary product or service being produced.A by-product can be useful and marketable or it can be considered waste....
of this step and a thioether
Thioether
A thioether is a functional group in organosulfur chemistry with the connectivity C-S-C as shown on right. Like many other sulfur-containing compounds, volatile thioethers have foul odors. A thioether is similar to an ether except that it contains a sulfur atom in place of the oxygen...
is formed as the product. Although not verified, it appears that the ortho-chlorine is eliminated preferentially. In the second step the nitrogroup is reduced with hydrogen gas. Upon heating in DMF
Dimethylformamide
Dimethylformamide is an organic compound with the formula 2NCH. Commonly abbreviated as DMF , this colourless liquid is miscible with water and the majority of organic liquids. DMF is a common solvent for chemical reactions...
solvent, ring cyclization occurs. In an analogous manner to what was done in the preparation of promazine
Promazine
Promazine is a medication that belongs to the phenothiazine class of antipsychotics. An older medication used to treat schizophrenia, it is still prescribed, alongside newer agents such as olanzapine and quetiapine...
, the 2-chloro-10H-phenothiazine of the last step is combined with 3-chloro-N,N-dimethylpropan-1-amine in the presence of sodamide base.