Clotiazepam Explained

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 The clotiazepam molecule differs from benzodiazepines in that the benzene ring has been replaced by a thiophene ring.[2] It possesses anxiolytic,[3] skeletal muscle relaxant,[4] anticonvulsant, sedative properties.[5] Stage 2 NREM sleep is significantly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

The dose equivalent to 10 mg diazepam is thought to be between 5 and 10 mg clotiazepam.

Side effects

Side effects experienced with this product will resemble those of other benzodiazepines.Drowsiness and asthenia are common side effects.[16] There has been a report of reversible hepatitis caused by clotiazepam.[17]

Abuse

Clotiazepam is a recognised drug of abuse.[18]

See also

External links

Notes and References

  1. DE . 2107356 . Thieno-(2,3-E)(1,4)diazepin-2-ones . Nakanishi M, Kazuhiko A, Tetsuya T, Shiroki M . 3 May 1978 . Yoshitomi Pharmaceutical Industries, Ltd. .
  2. Niwa T, Shiraga T, Ishii I, Kagayama A, Takagi A . Contribution of human hepatic cytochrome p450 isoforms to the metabolism of psychotropic drugs . Biological & Pharmaceutical Bulletin . 28 . 9 . 1711–1716 . September 2005 . 16141545 . 10.1248/bpb.28.1711 . free .
  3. Klicpera C, Strian F . Autonomic perception and responses in anxiety-inducing situations . Pharmakopsychiatrie, Neuro-Psychopharmakologie . 11 . 3 . 113–120 . May 1978 . 27828 . 10.1055/s-0028-1094569 .
  4. Fukuda T, Tsumagari T . Effects of psychotropic drugs on the rage responses induced by electrical stimulation of the medial hypothalamus in cats . Japanese Journal of Pharmacology . 33 . 4 . 885–890 . August 1983 . 6632385 . 10.1254/jjp.33.885 .
  5. Mandrioli R, Mercolini L, Raggi MA . Benzodiazepine metabolism: an analytical perspective . Current Drug Metabolism . 9 . 8 . 827–844 . October 2008 . 18855614 . 10.2174/138920008786049258 .
  6. Nakazawa Y, Kotorii M, Oshima M, Horikawa S, Tachibana H . Effects of thienodiazepine derivatives on human sleep as compared to those of benzodiazepine derivatives . Psychopharmacologia . 44 . 2 . 165–171 . October 1975 . 709 . 10.1007/BF00421005 . 13365554 .
  7. Martucci N, Manna V, Agnoli A . A clinical and neurophysiological evaluation of clotiazepam, a new thienodiazepine derivative . International Clinical Psychopharmacology . 2 . 2 . 121–128 . April 1987 . 2885366 . 10.1097/00004850-198704000-00005 .
  8. Web site: RIZE TABLETS 5mg . Official Japanese Drug Information Sheet (Kusuri-no-Shiori) . February 2016 .
  9. Web site: Clotiazepam (Veratran) . French Guide to Medicines .
  10. Benvenuti C, Bottà V, Broggini M, Gambaro V, Lodi F, Valenti M . The pharmacokinetics of clotiazepam after oral and sublingual administration to volunteers . European Journal of Clinical Pharmacology . 37 . 6 . 617–619 . 1989 . 2575522 . 10.1007/BF00562556 . 29397932 .
  11. Yakushiji T, Fukuda T, Oyama Y, Akaike N . Effects of benzodiazepines and non-benzodiazepine compounds on the GABA-induced response in frog isolated sensory neurones . British Journal of Pharmacology . 98 . 3 . 735–740 . November 1989 . 2574062 . 1854765 . 10.1111/j.1476-5381.1989.tb14600.x .
  12. Greenblatt DJ, Divoll M, Abernethy DR, Ochs HR, Shader RI . Clinical pharmacokinetics of the newer benzodiazepines . Clinical Pharmacokinetics . 8 . 3 . 233–252 . 1983 . 6133664 . 10.2165/00003088-198308030-00003 . 19691487 .
  13. Arendt R, Ochs HR, Greenblatt DJ . Electron capture GLC analysis of the thienodiazepine clotiazepam. Preliminary pharmacokinetic studies . Arzneimittel-Forschung . 32 . 4 . 453–455 . 1982 . 6125154 .
  14. Ochs HR, Greenblatt DJ, Verburg-Ochs B, Harmatz JS, Grehl H . Disposition of clotiazepam: influence of age, sex, oral contraceptives, cimetidine, isoniazid and ethanol . European Journal of Clinical Pharmacology . 26 . 1 . 55–59 . 1984 . 6143670 . 10.1007/BF00546709 . 44321356 .
  15. Ochs HR, Greenblatt DJ, Knüchel M . Effect of cirrhosis and renal failure on the kinetics of clotiazepam . European Journal of Clinical Pharmacology . 30 . 1 . 89–92 . 1986 . 2872061 . 10.1007/BF00614202 . 21304989 .
  16. Colonna L, Cozzi F, Del Citerna F, Di Benedetto A, De Divitiis O, Furlanello F, Milazzotto F, Pittalis M, Taccola A . 6 . [Multicenter study of the effectiveness and tolerance of clotiazepam in cardiology] . Minerva Cardioangiologica . 38 . 1–2 . 45–49 . 1990 . 1971433 .
  17. Habersetzer F, Larrey D, Babany G, Degott C, Corbic M, Pessayre D, Benhamou JP . Clotiazepam-induced acute hepatitis . Journal of Hepatology . 9 . 2 . 256–259 . September 1989 . 2572625 . 10.1016/0168-8278(89)90060-3 .
  18. Shimamine M, Masunari T, Nakahara Y . [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. Bulletin of National Institute of Hygienic Sciences . 111 . 47–56 . 1993 . 7920567 .

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