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Chlorprothixene (Cloxan, Taractan, Truxal) is a typical antipsychotic drug of the thioxanthene class and was the first of the series to be synthesized.^[1] It was introduced in 1959 by Lundbeck.^[2]

Chlorprothixene is not approved for use in the United States.

Pharmacology

Chlorprothixene exerts strong antagonism at the following receptors:

5-HT₂: antipsychotic effects, anxiolysis, weight gain
D₁, D₂, D₃: antipsychotic effects, sedation, extrapyramidal side effects, prolactin increase, depression, apathy/anhedonia, weight gain
H₁: sedation, weight gain
mACh: anticholinergic effects, inhibition of extrapyramidal side effects
α₁-adrenergic: hypotension, tachycardia

Chlorprothixene does also act as FIASMA (functional inhibitor of acid sphingomyelinase).^[3]

Indications

Chlorprothixene's principal indications are the treatment of psychotic disorders (e.g. schizophrenia) and of acute mania occurring as part of bipolar disorders.

Other uses are pre- and postoperative states with anxiety and insomnia, severe nausea / emesis (in hospitalized patients), the amelioration of anxiety and agitation due to use of selective serotonin reuptake inhibitors for depression and, off-label, the amelioration of alcohol and opioid withdrawal. It may also be used cautiously to treat nonpsychotic irritability, aggression, and insomnia in pediatric patients.

An intrinsic antidepressant effect of chlorprothixene has been discussed, but not proven yet. Likewise, it is unclear, if chlorprothixene has genuine (intrinsic) analgesic effects. However, chlorprothixene can be used as comedication in severe chronic pain. Also, like most antipsychotics, chlorprothixene has antiemetic effects.

Side effects

Chlorprothixene has a strong sedative activity with a high incidence of anticholinergic side effects. The types of side effects encountered (dry mouth, massive hypotension and tachycardia, hyperhidrosis, substantial weight gain etc.) normally do not allow a full effective dose for the remission of psychotic disorders to be given. So cotreatment with another, more potent, antipsychotic agent is needed.

Chlorprothixene is structurally related to chlorpromazine, with which it shares in principal all side effects. Allergic side effects and liver damage seem to appear with an appreciable lower frequency. The elderly are particularly sensitive to anticholinergic side effects of chlorprothixene (precipitation of narrow angle glaucoma, severe obstipation, difficulties in urinating, confusional and delirant states). In patients >60 years the doses should be particularly low.

Early and late extrapyramidal side effects may occur but have been noted with a low frequency (one study with a great number of participants has delivered a total number of only 1%).

Dosage

The initial doses of chlorprothixene should always be as low as possible (e.g. 30 mg at bedtime, 15 mg morning dose) and be increased gradually. Patients receiving 90 mg daily (and more) of the drug should be hospitalized, particularly during the initial phase of treatment. The theoretical maximum is 800 mg daily which can usually not be given due to side effects as stated above. Elderly and pediatric patients should be treated with particular low initial doses. Dose increments should be done slowly. If chlorprothixene is to be withdrawn, it should not be stopped abruptly, but the dose should be decreased steadily.

Interactions

Chlorprothixene may increase the plasma-level of concomitantly given lithium. In order to avoid lithium intoxication, lithium plasma levels should be monitored closely.

If chlorprothixene is given concomitantly with opioids, the opioid dose should be reduced (by approx. 50%), because chlorprothixene amplifies the therapeutic actions and side effects of opioids considerably.

Avoid the concomitant use of chlorprothixene and tramadol (Ultram). Seizures may be encountered with this combination.

Consider additive sedative effects and confusional states to emerge, if chlorprothixene is given with benzodiazepines or barbiturates. Choose particular low doses of these drugs.

Exert particular caution in combining chlorprothixene with other anticholinergic drugs (tricyclic antidepressants and antiparkinsonian agents): Particularly the elderly may develop delirium, high fever, severe obstipation, even ileus and glaucoma .

Chemistry

Chlorprothixene (2-chloro-9[(1-dimethylamino)-3-propyliden]thioxanthene) is made starting from 2-chlorothixantone. 2-Chlorothixantone, in turn, is prepared from 2-mercaptobenzoic acid, the reaction of which with 1-bromo-4-chlorobenzene forms 2-(4-chlorophenylthio)benzoic acid, which upon reaction with phosphorus pentachloride transforms into acid chloride, and further undergoes intramolecular cyclization with the use of aluminum chloride to give 2-chlorthioxantone.

H. Spiegelberg, K. Doeben, DE 1044103 (1957).

An alternative way of making 2-chlorthioxantone is by making 2-(4-chlorophenylthio)benzoic acid by reacting 2-iodobenzoic acid with 4-chlorothiophenol.

E.L. Engelhardt, J.M. Sprague, U.S. Patent 2,951,082 (1960).

The resulting 2-chlorothioxantone is reacted as a carbonyl component with either 3-dimethylaminopropylmagnesiumbromide (see Engelhardt above), or with allylmagnesiumbromide, giving the corresponding tertiary alcohol.

V.P. Petersen, H.O. Trokil, U.S. Patent 3,116,291 (1963).
Kefalas Aktieselskab, DE 1168446 (1959).
Kefalas Aktieselskabet, DE 1418517 (1959).

Dehydration of the first is accomplished by acylation of the tertiary hydroxyl group using acetyl chloride and the subsequent pyrolysis of the formed acetate, which leads to the desired chlorprothixene. In the second case, dehydration of the tertiary alcohol is accomplished by chlorination of the tertiary alcohol group by thionyl chloride, forming the diene 2-chloro-9-(3-propen-1- iliden)thioxanthene, the addition to which of dimethylamine at high temperature forms the desired chlorprothixene.

References

^ Healy, David (1997). The antidepressant era. Cambridge: Harvard University Press. p. 182. ISBN 0-674-03958-0. http://books.google.com/books?id=6lpHd_P4VOsC&lpg=RA2-PA182&dq=chlorprothixene%20antidepressant&as_brr=3&pg=RA2-PA182#v=onepage&q=chlorprothixene%20antidepressant&f=false.
^ Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 410. ISBN 0-471-89980-1. http://books.google.com/books?id=Cb6BOkj9fK4C&lpg=PA410&dq=chlorprothixene%20introduced%201958&pg=PA410#v=onepage&q=chlorprothixene%20introduced%201958&f=false.
^ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE 6 (8): e23852. doi:10.1371/journal.pone.0023852.

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English Journal

Field-amplified sample injection coupled with pseudo-isotachophoresis technique for sensitive determination of selected psychiatric drugs in human urine samples after dispersive liquid-liquid microextraction.

Dziomba S1, Kowalski P2, Słomińska A1, Bączek T1.
Analytica chimica acta.Anal Chim Acta.2014 Feb 6;811:88-93. doi: 10.1016/j.aca.2013.12.021. Epub 2013 Dec 26.
A field-amplified sample injection (FASI) technique was elaborated for fast and sensitive determination of selected central nervous system drugs in human urine samples. Factors affecting the sensitivity enhancement, such as background electrolyte (BGE) and the analytical matrix composition were opti
PMID 24456599

Quantification of typical antipsychotics in human plasma by ultra-high performance liquid chromatography tandem mass spectrometry for therapeutic drug monitoring.

Gradinaru J1, Vullioud A, Eap CB, Ansermot N.
Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2014 Jan;88:36-44. doi: 10.1016/j.jpba.2013.07.041. Epub 2013 Aug 7.
A selective and sensitive method was developed for the simultaneous quantification of seven typical antipsychotic drugs (cis-chlorprothixene, flupentixol, haloperidol, levomepromazine, pipamperone, promazine and zuclopenthixol) in human plasma. Ultra-high performance liquid chromatography (UHPLC) wa
PMID 24036032

Differential interaction of neuroleptics with apomorphine-induced behavior in rats as a function of changing levels of dopamine receptor stimulation.

Megens AA1, Hendrickx HM, Lavreysen H, Langlois X.
The Journal of pharmacology and experimental therapeutics.J Pharmacol Exp Ther.2013 Dec;347(3):681-96. doi: 10.1124/jpet.113.207506. Epub 2013 Sep 26.
Twenty-two neuroleptic drugs were studied for interaction with the behavior induced by intravenous injection of apomorphine in rats. All compounds dose-dependently shortened the duration of the apomorphine-induced agitation and-with the exception of clozapine-shortened the onset of the de-arousal gr
PMID 24071734

Japanese Journal

Studies on the muscle relaxation effects of ethyl loflazepate (CM6912) and evaluation as an anti-anxiety drug.

,
The Japanese Journal of Pharmacology 36(3), 319-328, 1984
… The potentiating action of CM6912 on chlorprothixene-induced anesthesia was far weaker than that of diazepam. …
NAID 130000835032

新しい睡眠導入剤１Ｈ‐１，２，４‐Ｔｒｉａｚｏｌｙｌ　ｂｅｎｚｏｐｈｅｎｏｎｅ誘導体４５０１９１‐Ｓの薬理　Ｉ　　行動薬理学的研究

山本研一 [他],広瀬勝巳,松下享,吉村弘二,沢田亨,永業正美,城山博邦,藤田明広,松原旦明,月野木祐二,畠山久男,塩見輝雄,伊比井信広,井上譲,広野悟,越田光
日本薬理学雑誌 84(1), 109-154, 1984
… 450191-Sの経口投与後鎮静的で発揚症状は現われず，マウスのAnimexおよびラットのオープンフィールド試験における自発運動にも著変を来たさなかったが，rearing，preeningを対照薬と同様に抑制した．450191-Sのchlorprothixene睡眠およびthiopental-Na 麻酔増強作用はnitrazepamと同程度，diazepam，estazolamより2～6倍強かった．450191-Sのpentylenetetrazol，picrotoxin，bicucullineけいれん抑制作用はnitrazepamと同程度であったが，抗電撃けいれん作用 …
NAID 130000761055

Enhancement of drug withdrawal convulsion by combinations of phenobarbital and antipsychotic agents.

[他], , , ,
The Japanese Journal of Pharmacology 31(5), 689-699, 1981
… In the crossphysical dependence study, two-drug combinations, i.e., phenobarbital (PhB)-chloropromazine (CPZ), PhB-diphenhydramine (DPH) and nitrazepam-chlorprothixene, and 3-drug combinations, i.e., PhBCPZ-promethazine and PhB-CPZ-DPH were evaluated. …
NAID 130000835549

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★リンクテーブル★

リンク元	「クロルプロチキセン」
拡張検索	「chlorprothixene hydrochloride」

「クロルプロチキセン」

Chlorprothixene
Systematic (IUPAC) name
	(Z)-3-(2-chlorothioxanthen-9-ylidene)-N, N-dimethyl-propan-1-amine
Clinical data
AHFS/Drugs.com	Micromedex Detailed Consumer Information
Pregnancy cat.	?
Legal status	Legend drug (US), ℞
Routes	Oral, IM
Pharmacokinetic data
Metabolism	Hepatic
Half-life	8-12 hours
Excretion	Feces/urine
Identifiers
CAS number	113-59-7
ATC code	N05AF03
PubChem	CID 667467
DrugBank	DB01239
ChemSpider	580849
UNII	9S7OD60EWP
KEGG	D00790
ChEBI	CHEBI:50931
ChEMBL	CHEMBL908
Chemical data
Formula	C18H18ClNS
Mol. mass	315.861 g/mol
	SMILES Clc2cc1C(\c3c(Sc1cc2)cccc3)=C/CCN(C)C;
	InChI InChI=1S/C18H18ClNS/c1-20(2)11-5-7-14-15-6-3-4-8-17(15)21-18-10-9-13(19)12-16(14)18/h3-4,6-10,12H,5,11H2,1-2H3/b14-7- ; Key:WSPOMRSOLSGNFJ-AUWJEWJLSA-N ;
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