Chlorpromazine
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| Non-proprietary name | Chlorpromazine | ||||||||||||
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| Molecular formula | C 17 H 19 ClN 2 S | ||||||||||||
| Brief description |
oily liquid |
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| Molar mass | 318.86 g · mol -1 | ||||||||||||
| Melting point |
<25 ° C |
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| boiling point |
200–205 ° C (107 Pa ) |
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| pK s value |
9.3 (25 ° C) |
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| solubility |
Water: 2.55 mg l −1 (24 ° C) |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||
Chlorpromazine is a phenothiazine - derivative and a neuroleptic agent of medium potency. Chlorpromazine was the first drug from the group of neuroleptics and is considered the cornerstone of modern psychotropic drugs - therapy . Like the later developed neuroleptics, chlorpromazine has extrapyramidal motor side effects. In order to compare the side effects of neuroleptics, the neuroleptic potency was introduced, which assigns a number to these side effects. As a comparison value, the side effects of chlorpromazine were assigned the value 1.
history
The starting point for the development of “neuroleptics” of the phenothiazine type was the German dye industry around 1900. The “Badische Anilin und Sodafabrik” BASF produced chemical dyes that were soon used in histology. It was soon discovered that certain dyes had antibiotic properties. Some historical examples are:
- Trypan red against trypanosomes (sleeping sickness)
- Arsphenamine against syphilis (P. Ehrlich "Salvarsan")
- Methylene blue , a phenothiazine derivative, tested against malaria .
Malaria drugs in particular were in short supply during World War II , as the only active substance quinine still had to be extracted from the cinchona tree . When using phenothiazine derivatives such as promethazine (1948; available as Atosil to this day), a sedating and antihistaminergic effect was quickly established. This should be an advantage in the case of shock and stress reactions caused by war and in operations. The additional vegetative ( sympathetic and vagolytic ) properties were called "artificial hibernation" and should be helpful in major operations. At that time the term “neuroleptic anesthesia” was used together with opiates. It was soon discovered that the substances had marked antipsychotic effects. The first clinical experiences were made mainly in France, Belgium and Switzerland. In the USA, the spread was slow due to the prevalence of psychoanalysis at the time.
Chlorpromazine was synthesized in 1950 by the chemist Paul Charpentier at the Rhône-Poulenc company . It was shown that chlorpromazine has a strong sedating effect in addition to an antihistamine effect. Between April 1951 and March 1952, 4,000 samples were sent to over 100 researchers in 9 countries. On October 13, 1951, the first article appeared in which chlorpromazine was mentioned publicly. Henri Marie Laborit reported on the success of the new substance in anesthesia. The two French psychiatrists Jean Delay and Pierre Deniker announced on May 26, 1952 that they had seen a calming effect on patients with mania . While chlorpromazine was used against many different disorders in the beginning, schizophrenia later became the most important indication . Some researchers even assumed a specific effect against this disease.
From 1953 the chlorpromazine was marketed as Megaphen (Germany July 1, 1953) or Largactil in Europe, in 1955 it came onto the market in the USA under the name “Thorazine”.
In 1988 Megaphen was withdrawn from the West German market. German doctors have long preferred perazine as a treatment for schizophrenia. In contrast, in the USA, where the brand name Thorazine has entered the vocabulary as a synonym for a strong sedative, chlorpromazine continued to be used frequently. In 1989, full-page advertisements appeared in the trade magazines with the slogan "Trust 35 Years of Proven Experience - Thorazine".
To this day, chlorpromazine is on the list of essential drugs of the World Health Organization .
pharmacology
As a result of the blockade of various neurotransmitter receptors, the spectrum of activity of chlorpromazine is very broad. It has antipsychotic, sedating, antiemetic, local anesthetic ganglion-blocking, anticholinergic, antiadrenergic and antihistaminic effects. The average daily dose is usually well below 400 mg; in acute schizophrenic psychoses, doses of over 400 mg are used. The absolute bioavailability after oral administration is 30 percent, the half-life is 30 hours. More than 75 metabolites are known, one active metabolite is 7-hydroxy-chlorpromazine, which has a half-life of 24 hours.
Chlorpromazine works by reversibly blocking the D 1 and D 2 subtypes of dopamine receptors . Chlorpromazine also acts as FIASMA (functional inhibitor of acid sphingomyelinase ).
unwanted effects
The main side effects of chlorpromazine are sedation and lowering of blood pressure ( hypotension ).
By influencing the heat center, heat regulation is disturbed, which can trigger hypothermia at low temperatures and hyperthermia at high temperatures . Furthermore, the administration of chlorpromazine can lead to allergic skin reactions and liver dysfunction. Cholestatic hepatosis , which can lead to death, is rarely observed .
Furthermore photosensitivity , thrombosis , menstrual - and erectile dysfunction , leukopenia and pronounced anticholinergic effects described. Agranulocytosis occurs very rarely .
An extrapyramidal syndrome is triggered much less frequently by chlorpromazine compared to the highly potent neuroleptics.
Biotransformation
Phenothiazines can form a large number of metabolites. The ring system can be hydroxylated, the side chain can first be hydroxylated and then conjugated with glucuronic acid . The tertiary amine can be N- dealkylated and the sulfidic sulfur atom can be oxidized to the sulfoxide .
synthesis
Starting from 3-chlorodiphenylamine, 2-chlorophenothiazine is obtained by heating with sulfur . 3-Dimethylaminopropyl chloride alkylates the phenothiazine derivative in the basic to chlorpromazine.
Analytics
By oxidation of a colored compound is formed from chlorpromazine. The content can be determined in glacial acetic acid against perchloric acid . A potentiometric measurement as well as crystal violet as an indicator are suitable for endpoint detection .
Prohibition of use
The use of chlorpromazine in food-producing animals is generally prohibited in the European Union in accordance with the EU maximum residue limit regulation for food of animal origin .
Trade names
Megaphen (Germany), Fenactil (PL), Thorazine (USA, GB), Largactil
See also
literature
- Hans Bangen: History of the drug therapy of schizophrenia. Berlin 1992, ISBN 3-927408-82-4 .
- Judith Swazey: Chlorpromazine in Psychiatry. Cambridge 1974, ISBN 0-262-19130-X (One of the first and best books on the history of modern psychotropic drugs).
Web links
- Chlorpromazine . In: Erowid . (English)
- Khaled Selim, Neil Kaplowitz: Hepatotoxicity of Psychotropic Drugs. (PDF; 87 kB) In: Hepatology . Vol. 29, No. 5, 1999, pp. 1347-1351.
Individual evidence
- ↑ a b entry on chlorpromazine. In: Römpp Online . Georg Thieme Verlag, accessed on May 30, 2014.
- ↑ a b c d Entry on chlorpromazine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
- ↑ Entry on 2-chloro-10- (3- (dimethylamino) propyl) phenothiazine in the GESTIS substance database of the IFA , accessed on July 23, 2016(JavaScript required) .
- ↑ Data sheet Chlorpromazin-d6-hydrochloride from Sigma-Aldrich , accessed on May 8, 2017 ( PDF ).
- ^ F. López-Muñoz, C. Alamo, E. Cuenca, WW Shen, P. Clervoy, G. Rubio: History of the discovery and clinical introduction of chlorpromazine . In: Annals of Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists . tape 17 , no. 3 , 2005, p. 113-135 , PMID 16433053 .
- ^ Bangen, Hans: History of the drug therapy of schizophrenia. Berlin 1992, ISBN 3-927408-82-4 p. 104.
- ^ CE Adams, GA Awad, J. Rathbone, B. Thornley, K. Soares-Weiser: Chlorpromazine versus placebo for schizophrenia. In: The Cochrane database of systematic reviews. Volume 1, 2014, pp. CD000284, doi: 10.1002 / 14651858.CD000284.pub3 . PMID 24395698 .
- ^ X. Liu, S. De Haan: Chlorpromazine dose for people with schizophrenia. In: The Cochrane database of systematic reviews. Number 2, 2009, S. CD007778, doi: 10.1002 / 14651858.CD007778 . PMID 19370692 .
- ^ AJ Giannini, C. Nageotte, RH Loiselle, DA Malone, WA Price: Comparison of chlorpromazine, haloperidol and pimozide in the treatment of phencyclidine psychosis: DA-2 receptor specificity. In: Journal of toxicology. Clinical toxicology. Volume 22, Number 6, 1984-1985, pp. 573-579. PMID 6535849 .
- ↑ J. Kornhuber, M. Muehlbacher, S. Trapp, S. Pechmann, A. Friedl, M. Reichel, C. Mühle, L. Terfloth, T. Groemer, G. Spitzer, K. Liedl, E. Gulbins, P Tripal: Identification of novel functional inhibitors of acid sphingomyelinase . In: PLoS ONE . tape 6 , no. 8 , 2011, p. e23852 , doi : 10.1371 / journal.pone.0023852 .
