chlorpromazine

クロルプロマジン 　

WordNet

1. a drug (trade name Thorazine) derived from phenothiazine that has antipsychotic effects and is used as a sedative and tranquilizer (同)Thorazine

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/02/21 21:30:31」(JST)

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Chlorpromazine

Systematic (IUPAC) name
3-(2-chloro-10H-phenothiazin-10-yl)-N,N-dimethyl-propan-1-amine
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a682040
Pregnancy cat.	C—only when benefit for the mother exceeds risk to unborn child
Legal status	℞ Prescription only
Routes	Oral, rectal (suppository), IM, IV infusion
Pharmacokinetic data
Bioavailability	Oral, 30 to 50% (interindividual variations 10–70%)
Metabolism	Hepatic, mostly CYP2D6-mediated
Half-life	16 to 30 hours. In long term treatment, CPZ induces its own metabolism
Excretion	Biliary and renal, as metabolites (only traces of unchanged drug)
Identifiers
CAS number	50-53-3 Y (free base) 69-09-0 (hydrochloride)
ATC code	N05AA01
PubChem	CID 2726
IUPHAR ligand	83
DrugBank	DB00477
ChemSpider	2625 Y
UNII	U42B7VYA4P Y
KEGG	D00270 Y
ChEBI	CHEBI:3647 Y
ChEMBL	CHEMBL71 Y
Chemical data
Formula	C17H19ClN2S
Mol. mass	318.86 g/mol (free base) 355.33 g/mol (hydrochloride)
SMILES CN(C)CCCN1c2ccccc2Sc3c1cc(cc3)Cl
InChI InChI=1S/C17H19ClN2S/c1-19(2)10-5-11-20-14-6-3-4-7-16(14)21-17-9-8-13(18)12-15(17)20/h3-4,6-9,12H,5,10-11H2,1-2H3 Y Key:ZPEIMTDSQAKGNT-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

Chlorpromazine (as chlorpromazine hydrochloride, abbreviated CPZ; marketed in the United States as Thorazine and elsewhere as Largactil or Megaphen) is a dopamine antagonist of the typical antipsychotic class of medications possessing additional antiadrenergic, antiserotonergic, anticholinergic and antihistaminergic properties used to treat schizophrenia. 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^{[citation needed]}; the availability of antipsychotic drugs curtailed indiscriminate use of electroconvulsive therapy and psychosurgery^{[citation needed]}, 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 'Thorazine 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 antipsychotics, 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.

Medical uses

Chlorpromazine is classified as a low-potency typical antipsychotic and in the past was used in the treatment of both acute and chronic psychoses, including schizophrenia and the manic phase of bipolar disorder as well as amphetamine-induced psychoses. 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^{[citation needed]}.

The use of chlorpromazine and other typical antipsychotics has been largely replaced by newer generation of atypical antipsychotics which are generally better tolerated^{[citation needed]}. 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.

Off-label and controversial uses

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

Chlorpromazine has been shown to be the most effective substance against human infection by the brain-eating amoeba. One study concluded: "Chlorpromazine had the best therapeutic activity against Naegleria fowleri in vitro and in vivo. Therefore, it may be a more useful therapeutic agent for the treatment of primary amoebic meningoencephalitis than amphotericin B."

In Germany, chlorpromazine still carries label indications for insomnia and severe pruritus, as well as preanesthesia. It is also used in the withdrawal of heroin, but under medical supervision.

Adverse effects

The main side effects of chlorpromazine are due to its anticholinergic properties; these effects overshadow and counteract, to some extent, the extrapyramidal side effects typical of many early generation antipsychotics. These include sedation, slurred speech, dry mouth, constipation, urinary retention and possible lowering of seizure threshold. Appetite may be increased with resultant weight gain, and Glucose tolerance may be impaired. It lowers blood pressure with accompanying dizziness. Memory loss and amnesia have 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. Antipsychotics do not alter sleep cycles or REM sleep.

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. These effects were 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.

Interactions

Chlorpromazine intensifies the central depressive action of drugs with such activity (such as tranquilizers, barbiturates, Benzodiazepines, 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. Chlorpromazine 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 antidepressants and selective serotonin reuptake inhibitors that are commonly prescribed to patients with psychiatric disorders. This may result in significant drug interactions which may put these people at a heightened risk for side effects that may be masked by the positive effects or side effects of antipsychotic drugs themselves. Therefore, drugs that inhibit the enzymes that metabolize chlorpromazine would be expected to cause increases in the concentration of other antipsychotic drugs that are 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.

Tolerance and withdrawal

The British National Formulary 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.

Pharmacology

Pharmacokinetics

Chlorpromazine, and many other phenothiazine 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^{[citation needed]}; it achieves a higher concentration in the brain than in the blood stream.

This accelerated release and catabolism of dopamine may also be related to its permanently damaging effects. Younger people are more likely to develop akthasia. Dopaminergic neuron apoptosis may be linked to the rapid catabolism of dopamine which can produce oxidative stress through 6-OHDA, and also an interference with the protein folding which occurs in the synthesis of melanin, which occurs in the substantia nigra. The rapid turn over of dopamine may lead to oxidative damage, cytotoxicity, and has been shown to cause apoptosis of dopaminergic neurons. Certain agents, such as benzodiazapines and calcium channel blockers, are routinely used to mask the signals indicating apoptosis, such as creatine phosphokinase. Elevated creatine phosphokinase indicates neuroleptic malignant syndrome, the degree to which lower levels of apoptosis occur is difficult to measure. Long term inhibition of neurogenesis has been shown via dopamine antagonisism at D4 receptors on multipotent neural progenators in the subventricular zone.

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.

Three Common Metabolites of Chlorpromazine

Chlorpromazine is derived from phenothiazine, has an aliphatic side chain, typical for low to middle potency antipsychotics. Chlorpromazine is slowly absorbed from the intramuscular injection site with the peak plasma concentration occurring 6–24 hours after administration of the drug. The oral bioavailability is estimated to be 30–50% that of intramuscular doses and about 10% that of intravenous doses due to extensive first pass metabolism in the liver. Its elimination half-life is 16–30 hours (8–35 hours, although it is as short as 2 hours or as long as 60 hours in some individuals), 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.

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 (blocking agent) on different postsynaptic receptors:

• Dopamine receptors (subtypes D₁, D₂, D₃ and D₄), which account for its different antipsychotic properties on productive and unproductive symptoms;in the mesolimbic dopamine system accounts for the antipsychotic effect whereas the blockade in the nigrostriatal system produces the extrapyramidal effects

• Serotonin receptors (5-HT₁ and 5-HT₂), with anxiolytic, and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties.

• Histamine receptors (H₁ receptors, accounting for sedation, antiemetic effect, vertigo, fall in blood pressure and weight gain)

• α₁- and α₂-adrenergic receptors (accounting for sympatholytic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism—controversial. Also associated with weight gain as a result of blockage of the adrenergic alpha 1 receptor)

• M₁ and M₂ muscarinic acetylcholine receptors (causing anticholinergic symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, sinus tachycardia, electrocardiographic changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects).

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

Chlorpromazine and other typical 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.

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

Peripheral effects

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

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

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 hypotension. 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.^{[citation needed]}

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.

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 synthesis 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 nitro group is reduced with hydrogen gas. Upon heating in Dimethylformamide (DMF) solvent, ring cyclization occurs. The 2-chloro-10H-phenothiazine thus produced is combined with 3-chloro-N,N-dimethylpropan-1-amine in the presence of sodamide base to form chlorpromazine.

History

Advertisement for Thorazine (chlorpromazine) from the early 1960s

In 1933, the French pharmaceutical company Laboratoires Rhône-Poulenc began to search for new anti-histamines. In 1947, it synthesized promethazine, 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 fromlarge "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 (orthostatic hypotension is a possible side effect of chlorpromazine). 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^{[citation needed]}. 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 antipsychotics were developed. It also 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^{[citation needed]}. 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.

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 antiemetic 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^{[citation needed]}. 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 37/2010.

References

Bibliography

• Baldessarini, Ross J.; Frank I. Tarazi (2006). "Pharmacotherapy of Psychosis and Mania". In Laurence Brunton, John Lazo, Keith Parker (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill. ISBN 978-0-07-142280-2.
• Bezchlibnyk-Butler, K. Z. Clinical Handbook of Psychotropic Drugs (German Edition)
• Rote Liste (German Drug Compendium)
• Benkert, O. and H. Hippius. Psychiatrische Pharmakotherapie (German. 6th Edition, 1996)
• Physician's Desktop Reference (2004)
• Heinrich, K. Psychopharmaka in Klinik und Praxis (German, 2nd Edition, 1983)
• Römpp, Chemielexikon (German, 9th Edition)
• NINDS Information Homepage (see External links section)
• Plumb, Dondal C. Plumb's Veterinary Drug Handbook (Blackwell, 5th Edition, 2005)
• "Methods of Execution". Clark County, IN Prosecuting Attorney web page. http://www.clarkprosecutor.org/html/death/methods.htm. Retrieved 2008-08-03.

External links

• Medlineplus article on chlorpromazine
• National Institute of Neurological Disorders and Stroke (NINDS) Tardive Dyskinesia information page
• U.S. National Library of Medicine: Drug Information Portal - Chlorpromazine
• Collection of advertisements for Thorazine (antipsychoticad.blogspot.com.au)

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English Journal

• Trimethyl and carboxymethyl chitosan carriers for bio-active polymer-inorganic nanocomposites.

• Geisberger G, Gyenge EB, Maake C, Patzke GR.SourceInstitute of Inorganic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
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• Neuropharmacology.Neuropharmacology.2013 Jan;64:254-63. doi: 10.1016/j.neuropharm.2012.07.017. Epub 2012 Jul 21.
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• PMID 22824189

Japanese Journal

• 私のカルテから 拒薬を伴うがん終末期のせん妄に対しchlorpromazineを経静脈的に使用した1症例

• 石川 博康,？清水 清治,横山 直弘 [他]
• 精神医学 54(7), 731-733, 2012-07
• NAID 40019334996

• D-アミノ酸代謝酵素システムの機能と構造に関する疾患酸素学研究

• 福井 清
• ビタミン 86(2), 63-73, 2012-02-25
• … Here we show the inhibitory effect of antipsychotic drugs, chlorpromazine and risperidone, on human DAO activity. …
• NAID 110009419211

Related Links

• Chlorpromazineとは - goo Wikipedia (ウィキペディア)

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 ...

• クロルプロマジン:ウインタミン,コントミン

ウインタミン,コントミンとは?クロルプロマジンの効能,副作用等を説明,ジェネリックや薬価も調べられる(おくすり110番:薬事典版) ... 用法用量は医師・薬剤師の指示を必ずお守りください。 すべての副作用を掲載しているわけ ...

• クロルプロマジン - BIGLOBE百科事典

クロルプロマジン（Chlorpromazine）は、フランスの生化学者アンリ・ラボリ（Henri Laborit,1914-1995）が1952年に発見した、フェノチアジン系の抗精神病薬である。精神安定剤としてはメジャートランキライザーに分類される。メチレン ...

Related Pictures

---

★リンクテーブル★

リンク元	「薬理学」「クロルプロマジン」「ドパミン受容体」「フェノチアジン誘導体」「other than」
拡張検索	「chlorpromazine phenolphthalinate」「chlorpromazine hibenzate」「chlorpromazine hydrochloride」

「薬理学」

　　[★]

英

pharmacology

関

drug entries

定義

• 生物系と化学物質の選択的な相互作用を研究する学問 (SPC.2)

生物系と薬の相互作用

• 薬の生物系に対する相互作用：薬理作用 <-化学の視点
• 生物系の薬に対する相互作用：薬物動態 <-生物の視点

関連分野

• 薬物学 materia medica
• 生薬学
• 実験薬理学
• 臨床薬理学
• 動物薬理学
• 人体薬理学
• 比較薬理学
• 薬理作用学(薬力学)
• 薬物動態学
• 中毒学、毒科学
• 薬物治療学
• 処方学

薬品の命名

Ending of the drug name	Category	Example
～afil	Erectile dysfunction	sildenafil
～ane	Inhalatinal general anesthetic	halothane
～azepam	Benzodiaizepine	diazepam
～azine	Phenothiazine (neuroleptic, antiemetic)	chlorpromazine
～azole	Ailtifungal	ketoconazole
～barbital	Barbiturate	phenobarbital
～caine	Local anesthetic	lidocaine
～cillin	Penicillin	methicillin
～cycline	Antibiotic, protein syntlesis inhibitor	tetracycline
～ipramine	TCA	iimipramine
～navir	Protease inhibitor	saquinavir
～olol	β-antagonist	propranolol
～operidol	Butyrophenone ( neuroleptic )	haloperidol
～oxin	Cardiac glycoside ( inotropic agent )	digoxin
～phylline	Methylxanthine	theophylline
～pril	ACE inhibitor	captopril
～terol	β2 agonist	albuterol
～tidine	H2 antagonist	cimtidine
～triptyline	TCA	amitriptyline
～tropine	Pituitary hormone	somatotropine
～zosin	a1 antagonist	prazosin

薬一覧

神経筋接合部遮断薬(筋弛緩薬)

• 非脱分極性筋弛緩薬 競合的筋弛緩薬

• ベクロニウム vecuronium
• パンクロニウム pancuronium
• アトラクリウム atracurium
• d-ツボクラリン tubocurarine

• 脱分極性筋弛緩薬

• スキサメトニウム suxamethonium
• デカメトニウム decamethonium

交感神経作動薬

→アドレナリン受容体

交感神経遮断薬

→アドレナリン受容体

副交感神経作動薬

→アセチルコリン受容体

副交感神経遮断薬

→アセチルコリン受容体

甲状腺関連物質

• 甲状腺ホルモン製剤

• レボチロキシン levothyroxine
• リオチニシン liothyronine

• 抗甲状腺薬

• プロピルチオウラシル propylthiouracil
• チアマゾール thiamazole

痛風治療薬

• 痛風発作予防薬

• コルヒチン colchicine

• 尿酸排泄促進薬

• ベンズブロマロン benzbromarone
• プロベネシド probenecid

• 尿酸生成抑制薬

• アロプリノール allopurinol

「クロルプロマジン」

　　[★]

英

chlorpromazine, CPZ

同

塩酸クロルプロマジン

商

コントミン、ウインタミン、Thorazine、ベゲタミン-A配合

関

精神神経用剤

• 抗精神病薬

• フェノチアジン系

特徴

• 抗ヒスタミン薬の開発の過程で見いだされた
• 統合失調症患者に強い鎮静、睡眠作用を必要とする場合に使う

構造

• フェノチアジン系

作用機序

• ドーパミンD₂受容体拮抗作用
• ムスカリン性アセチルコリン受容体拮抗作用

→錐体外路症状は少ない。末梢性抗コリン作用による副作用が生じやすい

• α1受容体拮抗作用

→鎮静、催眠作用：強。興奮や不眠を示す患者によい。

薬理作用 (SPC.193)

• 鎮静作用(ノルアドレナリンが関与)
• 抗幻覚・抗妄想作用(ドーパミンが関与)
• 感情の安定化
• 賦活作用(セロトニンが関与)

適応

• 統合失調症、躁病
• 吃逆

副作用 (SPC.193)

• 抗コリン作用(口渇、かすみ目、便秘、尿閉、発汗減少)
• α-ブロック作用(頻脈、起立性低血圧、射精障害)
• 内分泌作用
• 体温調節以上
• けいれん誘発
• 錐体外路症状

• 急性：振戦、筋剛直、アカシジア、ジストニア、悪性症状
• 慢性：遅発性ジスキネジア、舞踏様不随意運動

末梢

• 抗ヒスタミン作用
• 抗セロトニン作用
• 局所麻酔作用

「ドパミン受容体」

　　[★]

英

dopamine receptor DA-R

同

ドーパミン受容体

関

ドパミン、ドーパミン作動性ニューロン、受容体、カテコールアミン受容体

[show details]

ドーパミン受容体 : 約 37,500 件
ドパミン受容体 : 約 21,600 件

• GOO.249
• ７回膜貫通型Gタンパク共役型受容体
• D₁受容体

G_s：アデニル酸シクラーゼ活性化→[cAMP]_i↑

低用量での血管拡張はこの受容体を介して起こる

大脳基底核の神経回路では直接路にかかわる(SP.377)。

• D₂受容体

G_i：アデニル酸シクラーゼ抑制→[cAMP]_i↓、K⁺チャネル活性化、Ca²⁺チャネル抑制

中枢神経系に存在

シナプス後ニューロン、ドーパミン作動性ニューロンの細胞体・樹状突起・軸索・終末部に存在し、興奮性の調節に関わる

autoreceptor

大脳基底核の神経回路では間接路にかかわる(SP.377)。

作動薬(アゴニスト)

• タンドスピロン tandospirone

拮抗薬(アンタゴニスト)

• クロルプロマジン chlorpromazine

「フェノチアジン誘導体」

　　[★]

英

phenothiazine derivative, phenothiazines

関

フェノチアジン phenothiazine、抗精神病薬

• フェノチアジン核/骨格を有する化合物

作用機序

• D2受容体拮抗

適応

• 抗精神病薬：統合失調症、躁病

副作用

• 錐体外路症状、意識障害、血圧低下(自律神経遮断作用による？)

所属する薬物

• 抗精神病薬

• クロルプロマジン chlorpromazine (コントミン、ベゲタミン-A配合)
• チオリダジン thioridazine(メレリル)
• レボメプロマジン levomepromazine(ヒルナミン)
• プロペリシアジン propericiazine(ニューレプチル)
• フルフェナジン fluphenazine(フルデカシン、フルメジン)
• ペルフェナジン perphenazine(トリラホン)
• トリフロペラジン trifluoperazine

「other than」

　　[★]

• ～のほかに(besides)、～をのぞいて(except for)

patients with a penicillin allergy other than anaphylaxis may receive a cephalosporin.

This serious complication occurs in not more than 1 in 10,000 patients receiving chlorpromazine or other low-potency agents (other than clozapine).

「chlorpromazine phenolphthalinate」

　　[★]

• フェノールフタリン酸クロルプロマジン、フェノールフタレイン酸クロルプロマジン

関

chlorpromazine、chlorpromazine hibenzate、chlorpromazine hydrochloride

「chlorpromazine hibenzate」

　　[★]

• ヒベンズ酸クロルプロマジン

関

chlorpromazine、chlorpromazine hydrochloride、chlorpromazine phenolphthalinate

「chlorpromazine hydrochloride」

　　[★]

• 塩酸クロルプロマジン

関

chlorpromazine、chlorpromazine hibenzate、chlorpromazine phenolphthalinate