Clotiazepam

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Clotiazepam
Clotiazepam.svg
Clotiazepam3d.png
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 YesY
ATC code N05BA21
PubChem CID 2811
DrugBank DB01559
ChemSpider 2709 YesY
UNII ZCN055599V YesY
KEGG D01328 YesY
ChEMBL CHEMBL1697737
Chemical data
Formula C16H15ClN2OS 
Mol. mass 318.8 g/mol
 YesY (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 The clotiazepam molecule differs from most other benzodiazepines in that the benzene ring has been replaced by a thiophene ring.[2] It possesses anxiolytic,[3] skeletal muscle relaxant,[4] anticonvulsant, sedative properties.[5] Stage 2 NREM sleep is significantly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[edit]

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[edit]

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[edit]

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[edit]

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

Abuse[edit]

Clotiazepam is a recognised drug of abuse.[18]

See also[edit]

References[edit]

  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. 
  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. ^ 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 (inactive 2014-03-24). 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. ^ 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.; 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. 

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