Clotiazepam

Clotiazepam
Systematic (IUPAC) name
5-(2-chlorophenyl)-7-ethyl-1-methyl-3H-thieno[2,3-e][1,4]diazepin-2-one
Clinical data
Trade names Veratran, Rize, Clozan
AHFS/Drugs.com International Drug Names
Legal status
Routes of
administration		 Oral, sublingual, liquid drops
Pharmacokinetic data
Bioavailability ~90%
Metabolism Hepatic
Biological half-life 6–18 hours
Excretion Renal
Identifiers
CAS Number 33671-46-4 YesY
ATC code N05BA21
PubChem CID 2811
DrugBank DB01559 YesY
ChemSpider 2709 YesY
UNII ZCN055599V YesY
KEGG D01328 YesY
ChEMBL CHEMBL1697737 N
Chemical data
Formula C16H15ClN2OS
Molar mass 318.8 g/mol
 NYesY (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 The clotiazepam molecule differs from most other benzodiazepines in that the benzene ring has been replaced by a thiophene ring.[2] It possesses anxiolytic,[3] skeletal muscle relaxant,[4] anticonvulsant, sedative properties.[5] Stage 2 NREM sleep is significantly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

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 GABAA receptor where it acts as a full agonist; this action results in an enhanced GABA inhibitory effect at the GABAA 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]

See also

References

  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.
  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.
  5. 1 2 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 (inactive 2015-01-11). PMID 2575522.
  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.
  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. 1 2 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.; Taccola, A. (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

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