Chlorprothixene

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Chlorprothixene
Chlorprothixene structure.svg
Chlorprothixene3Dan.gif
Clinical data
Trade names Truxal, others
AHFS/Drugs.com Micromedex Detailed Consumer Information
Routes of
administration
Oral, intramuscular injection
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Metabolism Hepatic
Biological half-life 8–12 hours
Excretion Feces, urine
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.003.666
Chemical and physical data
Formula C18H18ClNS
Molar mass 315.861 g/mol
3D model (JSmol)
  (verify)

Chlorprothixene, sold under the brand name Truxal among others, is a typical antipsychotic of the thioxanthene group.

Medical uses[edit]

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[edit]

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 principle, 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%).

Overdose[edit]

Overdose symptoms can be confusion, hypotension, and tachycardia, and several fatalities have been reported with concentrations in postmortem blood ranging from 0.1 to 7.0 mg/L compared to non-toxic levels in postmortem blood which can extend to 0.4 mg/kg.[1]

Interactions[edit]

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 .

Pharmacology[edit]

Pharmacodynamics[edit]

Chlorprothixene[2]
Site Ki (nM) Species Ref
SERT 110 ND [3]
NET 21–532 Human [3][4]
DAT 1,699 ND [3]
5-HT1A 138–230 Human [5][3]
5-HT2A 0.30–0.43 Human [5][3]
5-HT2B ND ND ND
5-HT2C 4.5 ND [3]
5-HT3 398 ND [3]
5-HT6 3.0–3.2 Rat [3][6][7]
5-HT7 5.0–5.6 Rat [3][6][7]
α1 1.0 ND [3]
α2 186 ND [3]
β >10,000 Mammal [8]
D1 12–18 Human [9][3]
D2 3.0–5.6 Human [9][10][3]
D3 1.9–4.6 Human [3][9]
D4 0.65 Human [10][3]
D5 9.0 Human [9]
H1 0.89–3.8 Human [3][9]
H3 >1,000 Human [9]
mACh 41 ND [3]
  M1 11–26 Human [11][3]
  M2 28–79 Human [11][3]
  M3 22 Human [11][3]
  M4 18 Human [11]
  M5 25 Human [11]
σ 603 ND [3]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Chlorprothixene is an antagonist of 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
  • Muscarinic acetylcholine receptors: anticholinergic effects, inhibition of extrapyramidal side effects
  • α1-Adrenergic: hypotension, tachycardia

Because of its potent serotonin 5-HT2A and muscarinic acetylcholine receptor antagonism, chlorprothixene causes relatively mild extrapyramidal symptoms.[12] This is in contrast to most other typical antipsychotics.[12] For this reason, chlorprothixene has sometimes been described instead as an atypical antipsychotic.[12]

Chlorprothixene has also been found to act as FIASMA (functional inhibitor of acid sphingomyelinase).[13]

Pharmacokinetics[edit]

One metabolite of chlorprothixene is N-desmethylchlorprothixene.

Structure of N-desmethylchlorprothixene

Chemistry[edit]

Synthesis[edit]

Chlorprothixene (2-chloro-9[(1-dimethylamino)-3-propyliden]thioxanthene) is made starting from 2-chlorothioxanthone. 2-Chlorothioxantone, in turn, is prepared from 2-mercaptobenzoic acid (1), the reaction of which with 1-bromo-4-chlorobenzene (2) forms 2-(4-chlorophenylthio)benzoic acid 5, which upon reaction with phosphorus pentachloride transforms into acid chloride (6), and further undergoes intramolecular cyclization with the use of aluminum chloride to give 2-chlorthioxantone (6).[14]

An alternative way of making 2-chlorthioxantone (7) is by making 2-(4-chlorophenylthio)benzoic acid (5) by reacting 2-iodobenzoic acid (3) with 4-chlorothiophenol (4).[15]

2-Chlorothioxantone synthesis: DE 1044103  U.S. Patent 2,951,082

The resulting 2-chlorothioxantone is reacted as a carbonyl component with either 3-dimethylaminopropylmagnesiumbromide (see Engelhardt above), or with allylmagnesiumbromide, giving the corresponding tertiary alcohols 8, and 9.

Chlorprothixene synthesis:U.S. Patent 3,116,291 DE 1168446  DE 1418517 

Dehydration of the tertiary (8) 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 (9) is accomplished by chlorination of the tertiary alcohol group by thionyl chloride, forming the diene 2-chloro-9-(3-propen-1-iliden)thioxanthene (10), the addition to which of dimethylamine at high temperature forms the desired chlorprothixene (11).

History[edit]

Chlorprothixene was the first of the thioxanthene antipsychotics to be synthesized.[16] It was introduced in 1959 by Lundbeck.[17]

Lometraline, tametraline, and sertraline were reportedly derived via structural modification of chlorprothixene.[citation needed]

Society and culture[edit]

Brand names[edit]

Chlorprothixene is sold mainly under the brand name Truxal.[18][19]

Availability[edit]

Chlorprothixene is widely available throughout Europe and elsewhere in the world.[18][19] The drug was previously available in the United States under the brand name Taractan, but this formulation has since been discontinued and the drug is no longer available in this country.[20]

References[edit]

  1. ^ Skov L, Johansen SS, Linnet K (Jan 2015). "Postmortem Femoral Blood Reference Concentrations of Aripiprazole, Chlorprothixene, and Quetiapine". Journal of Analytical Toxicology. 39 (1): 41–44. doi:10.1093/jat/bku121. PMID 25342720. 
  2. ^ Roth, BL; Driscol, J. "PDSP Ki Database" (HTML). Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017. 
  3. ^ a b c d e f g h i j k l m n o p q r s t u Silvestre JS, Prous J (2005). "Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes". Methods Find Exp Clin Pharmacol. 27 (5): 289–304. doi:10.1358/mf.2005.27.5.908643. PMID 16082416. 
  4. ^ Haunsø A, Buchanan D (2007). "Pharmacological characterization of a fluorescent uptake assay for the noradrenaline transporter". J Biomol Screen. 12 (3): 378–84. doi:10.1177/1087057107299524. PMID 17379857. 
  5. ^ a b Wander TJ, Nelson A, Okazaki H, Richelson E (1987). "Antagonism by neuroleptics of serotonin 5-HT1A and 5-HT2 receptors of normal human brain in vitro". Eur. J. Pharmacol. 143 (2): 279–82. PMID 2891550. 
  6. ^ a b Roth BL, Craigo SC, Choudhary MS, Uluer A, Monsma FJ, Shen Y, Meltzer HY, Sibley DR (1994). "Binding of typical and atypical antipsychotic agents to 5-hydroxytryptamine-6 and 5-hydroxytryptamine-7 receptors". J. Pharmacol. Exp. Ther. 268 (3): 1403–10. PMID 7908055. 
  7. ^ a b Glusa E, Pertz HH (2000). "Further evidence that 5-HT-induced relaxation of pig pulmonary artery is mediated by endothelial 5-HT(2B) receptors". Br. J. Pharmacol. 130 (3): 692–8. doi:10.1038/sj.bjp.0703341. PMC 1572101Freely accessible. PMID 10821800. 
  8. ^ Bylund DB, Snyder SH (1976). "Beta adrenergic receptor binding in membrane preparations from mammalian brain". Mol. Pharmacol. 12 (4): 568–80. PMID 8699. 
  9. ^ a b c d e f von Coburg Y, Kottke T, Weizel L, Ligneau X, Stark H (2009). "Potential utility of histamine H3 receptor antagonist pharmacophore in antipsychotics". Bioorg. Med. Chem. Lett. 19 (2): 538–42. doi:10.1016/j.bmcl.2008.09.012. PMID 19091563. 
  10. ^ a b Seeman P, Tallerico T (1998). "Antipsychotic drugs which elicit little or no parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors". Mol. Psychiatry. 3 (2): 123–34. PMID 9577836. 
  11. ^ a b c d e Bolden C, Cusack B, Richelson E (1992). "Antagonism by antimuscarinic and neuroleptic compounds at the five cloned human muscarinic cholinergic receptors expressed in Chinese hamster ovary cells". J. Pharmacol. Exp. Ther. 260 (2): 576–80. PMID 1346637. 
  12. ^ a b c John G. Csernansky (6 December 2012). Antipsychotics. Springer Science & Business Media. pp. 360–. ISBN 978-3-642-61007-3. 
  13. ^ 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. PMC 3166082Freely accessible. PMID 21909365. 
  14. ^ H. Spiegelberg, K. Doeben, DE 1044103  (1957).
  15. ^ E.L. Engelhardt, J.M. Sprague, U.S. Patent 2,951,082 (1960).
  16. ^ Healy, David (1997). The antidepressant era. Cambridge: Harvard University Press. p. 182. ISBN 0-674-03958-0. 
  17. ^ Sneader, Walter (2005). Drug discovery: a history. New York: Wiley. p. 410. ISBN 0-471-89980-1. 
  18. ^ a b Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 224–. ISBN 978-3-88763-075-1. 
  19. ^ a b https://www.drugs.com/international/chlorprothixene.html
  20. ^ https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=012486