Clotiazepam

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Clotiazepam
Clinical data
Trade names	Veratran, Rize, Clozan
AHFS/Drugs.com	International Drug Names
Pregnancy; category	?;
Routes of; administration	Oral, sublingual, liquid drops
ATC code	N05BA21 (WHO) ;
Legal status
Legal status	US: Schedule IV ;
Pharmacokinetic data
Bioavailability	~90%
Metabolism	Hepatic
Elimination half-life	6-18 hr
Excretion	Renal
Identifiers
	IUPAC name 2-(2-chlorophenyl)-9-ethyl-6-methyl-8-thia-3,6-diazabicyclo[5.3.0]deca-2,9,11-trien-5-one;
CAS Number	33671-46-4 ;
PubChem CID	2811;
DrugBank	DB01559 ;
ChemSpider	2709 ;
UNII	ZCN055599V;
KEGG	D01328 ;
ChEMBL	ChEMBL1697737 ;
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
Formula	C16H15ClN2OS
Molar mass	318.8 g/mol
3D model (JSmol)	Interactive image;
	SMILES ClC1=C(C2=NCC(N(C)C3=C2C=C(CC)S3)=O)C=CC=C1;
	InChI InChI=1S/C16H15ClN2OS/c1-3-10-8-12-15(11-6-4-5-7-13(11)17)18-9-14(20)19(2)16(12)21-10/h4-8H,3,9H2,1-2H3 ; Key:CHBRHODLKOZEPZ-UHFFFAOYSA-N ;
(what is this?) (verify)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Clotiazepam^[1] (marketed under brand name Clozan, Distensan, Trecalmo, Rize, Rizen and Veratran) is a thienodiazepine drug which is a benzodiazepine analog. The clotiazepam molecule differs from most other benzodiazepines in that the benzene ring has been replaced by a thiophene ring.^[2] It possesses anxiolytic,^[3] skeletal muscle relaxant,^[4] anticonvulsant, sedative properties.^[5] Stage 2 NREM sleep is significantly increased by clotiazepam.^[6]

Indications

Clotiazepam has been trialed and found to be effective in the short-term management of anxiety.^[7] Clotiazepam is also used as a premedicant in minor surgery in France and Japan, where the drug is commercially available under the brand names Veratran and Rize, respectively.^[8]^[9]

Pharmacokinetics

A cross-over study in six healthy volunteers (median age 28 years) was conducted using single-dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets. The formulations had similar systemic availability. Compared with oral tablets, the sublingual route gave a lower peak concentration and a delayed peak time, while drops gave a greater maximum concentration with a similar peak time. The use of drops is suggested for a more marked initial effect and the sublingual route for easier administration, especially in the elderly.^[10]

Pharmacology

Similar to other benzodiazepines clotiazepam has anxiolytic, sedative, hypnotic, amnesic, anticonvulsant and muscle relaxant pharmacological properties.^[5] Clotiazepam binds to the benzodiazepine site of the GABA_A receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABA_A receptor which results in the pharmacological effects of clotiazepam.^[11]

Clotiazepam has a relatively short elimination half-life and is less prone to accumulation after repeated dosing compared to longer-acting benzodiazepine agents. It is metabolised via oxidation.^[12] Clotiazepam is metabolised to hydroxy-clotiazepam and desmethyl-clotiazepam. After oral ingestion of a single 5 mg dose of clotiazepam by three healthy volunteers the drug was rapidly absorbed.^[13] The elimination half-life of the drug and its metabolites range from 6.5 hours to 18 hours. Clotiazepam is 99 percent bound to plasma protein.^[13] In elderly men the elimination half-life is longer and in elderly women the volume of distribution is increased.^[14] Individuals with liver impairment have a reduced volume of distribution as well as a reduced total clearance of clotiazepam; renal impairment does not affect the kinetics of clotiazepam.^[15]

Side effects

Drowsiness and asthenia are common side effects.^[16] There has been a report of hepatitis caused by clotiazepam.^[17]

Abuse

Clotiazepam is a recognised drug of abuse.^[18]

References

↑ DE Patent 2107356
↑ Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A; Shiraga; Ishii; Kagayama; Takagi (September 2005). "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs" (PDF). Biol. Pharm. Bull. 28 (9): 1711–6. doi:10.1248/bpb.28.1711. PMID 16141545.
↑ Klicpera, C.; Strian, F. (May 1978). "Autonomic perception and responses in anxiety-inducing situations". Pharmakopsychiatr Neuropsychopharmakol. 11 (3): 113–20. doi:10.1055/s-0028-1094569. PMID 27828.
↑ Fukuda, T.; Tsumagari, T. (Aug 1983). "Effects of psychotropic drugs on the rage responses induced by electrical stimulation of the medial hypothalamus in cats" (PDF). Jpn J Pharmacol. 33 (4): 885–90. doi:10.1254/jjp.33.885. PMID 6632385.
↑ ^5.0 ^5.1 Mandrioli, R.; Mercolini, L.; Raggi, MA. (Oct 2008). "Benzodiazepine metabolism: an analytical perspective". Curr Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614.
↑ Nakazawa Y; Kotorii M; Oshima M; Horikawa S; Tachibana H. (October 31, 1975). "Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives". Psychopharmacologia. 44 (2): 165–71. doi:10.1007/BF00421005. PMID 709.
↑ Martucci, N.; Manna, V.; Agnoli, A. (Apr 1987). "A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative". Int Clin Psychopharmacol. 2 (2): 121–8. doi:10.1097/00004850-198704000-00005. PMID 2885366.
↑ Official Japanese Drug Information Sheet (Kusuri-no-Shiori)
↑ French Guide to Medicines - Clotiazepam (Veratran)
↑ C. Benvenuti, V. Bottà, M. Broggini, V. Gambaro, F. Lodi and M. Valenti (1989). "The pharmacokinetics of clotiazepam after oral and sublingual administration to volunteers". European Journal of Clinical Pharmacology. 37 (6): 617–619. doi:10.1007/BF00562556. PMID 2575522. Unknown parameter |doi_brokendate= ignored (help)
↑ Yakushiji, T.; Fukuda, T.; Oyama, Y.; Akaike, N. (Nov 1989). "Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones" (PDF). Br J Pharmacol. 98 (3): 735–40. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC 1854765. PMID 2574062.
↑ Greenblatt, DJ.; Divoll, M.; Abernethy, DR.; Ochs, HR.; Shader, RI. (1983). "Clinical pharmacokinetics of the newer benzodiazepines". Clin Pharmacokinet. 8 (3): 233–52. doi:10.2165/00003088-198308030-00003. PMID 6133664.
↑ ^13.0 ^13.1 Arendt, R.; Ochs, HR.; Greenblatt, DJ. (1982). "Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies". Arzneimittelforschung. 32 (4): 453–5. PMID 6125154.
↑ Ochs, HR.; Greenblatt, DJ.; Verburg-Ochs, B.; Harmatz, JS.; Grehl, H. (1984). "Disposition of clotiazepam: influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol". Eur J Clin Pharmacol. 26 (1): 55–9. doi:10.1007/BF00546709. PMID 6143670.
↑ Ochs, HR.; Greenblatt, DJ.; Knüchel, M. (1986). "Effect of cirrhosis and renal failure on the kinetics of clotiazepam". Eur J Clin Pharmacol. 30 (1): 89–92. doi:10.1007/BF00614202. PMID 2872061.
↑ Colonna, L.; Cozzi, F.; Del Citerna, F.; Di Benedetto, A.; De Divitiis, O.; Furlanello, F.; Milazzotto, F.; Pittalis, M.; Taccola, A. (1990). "[Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology]". Minerva Cardioangiol. 38 (1–2): 45–9. PMID 1971433.
↑ Habersetzer, F.; Larrey, D.; Babany, G.; Degott, C.; Corbic, M.; Pessayre, D.; Benhamou, JP. (Sep 1989). "Clotiazepam-induced acute hepatitis". J Hepatol. 9 (2): 256–9. doi:10.1016/0168-8278(89)90060-3. PMID 2572625.
↑ Shimamine, M.; Masunari, T.; Nakahara, Y. (1993). "[Studies on identification of drugs of abuse by diode array detection. I. Screening-test and identification of benzodiazepines by HPLC-DAD with ICOS software system]". Eisei Shikenjo Hokoku (111): 47–56. PMID 7920567.

External links

Inchem.org - Clotiazepam

Template:Benzodiazepines Template:Anxiolytics Template:GABAAR PAMs

[1] DE Patent 2107356

[2] Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A; Shiraga; Ishii; Kagayama; Takagi (September 2005). "Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs" (PDF). Biol. Pharm. Bull. 28 (9): 1711–6. doi:10.1248/bpb.28.1711. PMID 16141545.

[Klicpera-1978-3] Klicpera, C.; Strian, F. (May 1978). "Autonomic perception and responses in anxiety-inducing situations". Pharmakopsychiatr Neuropsychopharmakol. 11 (3): 113–20. doi:10.1055/s-0028-1094569. PMID 27828.

[Fukuda-1983-4] Fukuda, T.; Tsumagari, T. (Aug 1983). "Effects of psychotropic drugs on the rage responses induced by electrical stimulation of the medial hypothalamus in cats" (PDF). Jpn J Pharmacol. 33 (4): 885–90. doi:10.1254/jjp.33.885. PMID 6632385.

[Mandrioli-2008-5] 5.0 ^5.1 Mandrioli, R.; Mercolini, L.; Raggi, MA. (Oct 2008). "Benzodiazepine metabolism: an analytical perspective". Curr Drug Metab. 9 (8): 827–44. doi:10.2174/138920008786049258. PMID 18855614.

[6] Nakazawa Y; Kotorii M; Oshima M; Horikawa S; Tachibana H. (October 31, 1975). "Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives". Psychopharmacologia. 44 (2): 165–71. doi:10.1007/BF00421005. PMID 709.

[Martucci-1987-7] Martucci, N.; Manna, V.; Agnoli, A. (Apr 1987). "A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative". Int Clin Psychopharmacol. 2 (2): 121–8. doi:10.1097/00004850-198704000-00005. PMID 2885366.

[RIZE-8] Official Japanese Drug Information Sheet (Kusuri-no-Shiori)

[VRTN-9] French Guide to Medicines - Clotiazepam (Veratran)

[PHKTS-10] C. Benvenuti, V. Bottà, M. Broggini, V. Gambaro, F. Lodi and M. Valenti (1989). "The pharmacokinetics of clotiazepam after oral and sublingual administration to volunteers". European Journal of Clinical Pharmacology. 37 (6): 617–619. doi:10.1007/BF00562556. PMID 2575522. Unknown parameter |doi_brokendate= ignored (help)

[Yakushiji-1989-11] Yakushiji, T.; Fukuda, T.; Oyama, Y.; Akaike, N. (Nov 1989). "Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones" (PDF). Br J Pharmacol. 98 (3): 735–40. doi:10.1111/j.1476-5381.1989.tb14600.x. PMC 1854765. PMID 2574062.

[Greenblatt--12] Greenblatt, DJ.; Divoll, M.; Abernethy, DR.; Ochs, HR.; Shader, RI. (1983). "Clinical pharmacokinetics of the newer benzodiazepines". Clin Pharmacokinet. 8 (3): 233–52. doi:10.2165/00003088-198308030-00003. PMID 6133664.

[Arendt-1982-13] 13.0 ^13.1 Arendt, R.; Ochs, HR.; Greenblatt, DJ. (1982). "Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies". Arzneimittelforschung. 32 (4): 453–5. PMID 6125154.

[Ochs-1984-14] Ochs, HR.; Greenblatt, DJ.; Verburg-Ochs, B.; Harmatz, JS.; Grehl, H. (1984). "Disposition of clotiazepam: influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol". Eur J Clin Pharmacol. 26 (1): 55–9. doi:10.1007/BF00546709. PMID 6143670.

[Ochs-1986-15] Ochs, HR.; Greenblatt, DJ.; Knüchel, M. (1986). "Effect of cirrhosis and renal failure on the kinetics of clotiazepam". Eur J Clin Pharmacol. 30 (1): 89–92. doi:10.1007/BF00614202. PMID 2872061.

[Colonna--16] Colonna, L.; Cozzi, F.; Del Citerna, F.; Di Benedetto, A.; De Divitiis, O.; Furlanello, F.; Milazzotto, F.; Pittalis, M.; Taccola, A. (1990). "[Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology]". Minerva Cardioangiol. 38 (1–2): 45–9. PMID 1971433.

[Habersetzer-1989-17] Habersetzer, F.; Larrey, D.; Babany, G.; Degott, C.; Corbic, M.; Pessayre, D.; Benhamou, JP. (Sep 1989). "Clotiazepam-induced acute hepatitis". J Hepatol. 9 (2): 256–9. doi:10.1016/0168-8278(89)90060-3. PMID 2572625.

[Shimamine-1993-18] Shimamine, M.; Masunari, T.; Nakahara, Y. (1993). "[Studies on identification of drugs of abuse by diode array detection. I. Screening-test and identification of benzodiazepines by HPLC-DAD with ICOS software system]". Eisei Shikenjo Hokoku (111): 47–56. PMID 7920567.

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