Clotiazepam

Clotiazepam

Systematic (IUPAC) name
2-(2-chlorophenyl)-9-ethyl-6-methyl-8-thia-3,6-diazabicyclo[5.3.0]deca-2,9,11-trien-5-one
Clinical data
Trade names	Veratran, Rize, Clozan
AHFS/Drugs.com	International Drug Names
Pregnancy cat.	?
Legal status	Schedule IV (US)
Routes	Oral, sublingual, liquid drops
Pharmacokinetic data
Bioavailability	~90%
Metabolism	Hepatic
Half-life	6-18 hr
Excretion	Renal
Identifiers
CAS number	33671-46-4 Y
ATC code	N05BA21
PubChem	CID 2811
DrugBank	DB01559
ChemSpider	2709 Y
UNII	ZCN055599V Y
KEGG	D01328 Y
Chemical data
Formula	C16H15ClN2OS
Mol. mass	318.8 g/mol
SMILES	eMolecules & PubChem
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 Y Key:CHBRHODLKOZEPZ-UHFFFAOYSA-N Y
Y(what is this?)  (verify)

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 The clotiazepam molecule differs from most other benzodiazepines in that the benzene ring has been replaced by a thiophene ring.^[2] It possesses anxiolytic,^[3] skeletal muscle relaxant,^[4] anticonvulsant, sedative properties.^[5] Stage 2 NREM sleep is significantly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

Single dose pharmacokinetics of 5 mg clotiazepam drops, oral tablets, and sublingual tablets in a cross-over study in six healthy volunteers (median age 28 years) was conducted. 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 effect 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]

See also

• List of benzodiazepines
• Etizolam

References

1. ^ DE Patent 2107356
2. ^ Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A (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. http://www.jstage.jst.go.jp/article/bpb/28/9/1711/_pdf. 
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. 
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. http://www.journalarchive.jst.go.jp/jnlpdf.php?cdjournal=jphs1951&cdvol=33&noissue=4&startpage=885&lang=en&from=jnlabstract. 
5. ^ ^{a b} 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. 
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. 
8. ^ Official Japanese Drug Information Sheet (Kusuri-no-Shiori)
9. ^ French Guide to Medicines - Clotiazepam (Veratran)
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. http://resources.metapress.com/pdf-preview.axd?code=v72413q7v4781472&size=largest. 
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. PMC 1854765. PMID 2574062. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1854765. 
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. 
13. ^ ^{a b} 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. 
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. 
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. 
16. ^ Colonna, L.; Cozzi, F.; Del Citerna, F.; Di Benedetto, A.; De Divitiis, O.; Furlanello, F.; Milazzotto, F.; Pittalis, M. et al. (1990). "[Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology]". Minerva Cardioangiol 38 (1–2): 45–9. PMID 1971433. 
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. 
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. 

External links

• Inchem.org - Clotiazepam

This drug article relating to the nervous system is a stub. You can help Wikipedia by expanding it.v · Categories: Thienodiazepines Lactams Organochlorides Nervous system drug stubs Wikimedia Foundation. 2010. Игры ⚽ Нужен реферат? WiL Francis Orlando "Cachaito" López Look at other dictionaries: Clotiazépam — Général Nom IUPAC 5 (2 chlorophényl) 7 éthyl 1 méthyl 1,3 dihydro 2H thiéno[2,3 e][1,4]diazépin 2 one No …   Wikipédia en Français clotiazepam — noun A thienodiazepine drug with anxiolytic, anticonvulsant and sedative properties …   Wiktionary 33671-46-4 — Clotiazépam Clotiazépam Général No CAS …   Wikipédia en Français C16H15ClN2OS — Clotiazépam Clotiazépam Général No CAS …   Wikipédia en Français Veratran — Clotiazépam Clotiazépam Général No CAS …   Wikipédia en Français Clazolam — Systematic (IUPAC) name 2 chloro 5 methyl 5,9,10,14b tetrahydroisoquino[2,1 d][1,4]benzodiazepin 6(7H) one Clinical data Pregnancy cat …   Wikipedia Benzodiazepine — Benzodiazepines …   Wikipedia Diazepam — Systematic (IUPAC) name 7 chlo …   Wikipedia Alprazolam — Alprazolam …   Wikipedia Lorazepam — Systematic (IUPAC) name (RS) 9 chloro 6 (2 chlorophenyl) 4 hydroxy …   Wikipedia 18+ © Academic, 2000-2024 Contact us: Technical Support, Advertising Dictionaries export, created on PHP, Joomla, Drupal, WordPress, MODx. Mark and share Search through all dictionaries Translate… Search Internet Share the article and excerpts Direct link … Do a right-click on the link above and select “Copy Link”