Clobazam

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Clobazam
File:Clobazam-2D-skeletal.png
File:Clobazam3d.png
Clinical data
Pregnancy
category
  • ?
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability90%
MetabolismHepatic
Elimination half-life18 hours
ExcretionRenal
Identifiers
CAS Number
PubChem CID
DrugBank
E number{{#property:P628}}
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Chemical and physical data
FormulaC16H13ClN2O2
Molar mass300.74

Clobazam is a drug which is a benzodiazepine derivative. It has been marketed as an anxiolytic since 1975[2] and an anticonvulsant since 1984.[3]

Pharmacology

Clobazam is a 1,5-benzodiazepine, meaning that its diazepine ring has nitrogen atoms at the 1 and 5 positions (instead of the usual 1 and 4). Like other 1,5-benzodiazepines (arfendazam, lofendazam, e.g.), it has less affinity for the ω1-allosteric binding site on the GABAA receptor compared to the 1,4-benzodiazepines. It has selective affinity for the ω2 site, where it has agonistic activity.[4]

In a double-blind placebo-controlled trial published in 1990 comparing it to clonazepam, 10mg or 20 mg of clobazam was shown to be much less sedating than either 0.5mg or 1 mg of clonazepam.[5]

The ω1-receptor, which is found on the α1 subtype of the GABAA receptor, was shown to be responsible for the sedative effects of diazepam by McKernan et al in 2000, who also showed that its anxiolytic and anticonvulsant properties could still be seen in mice whose α1 receptors were insensitive to diazepam.[6] It would seem, then, that the anticonvulsant properties of clobazam are due to its selective affinity for ω2.

In 1996, Nakamura et al reported that clobazam and its active metabolite, N-desmethylclobazam (norclobazam), work by enhancing GABA-activated chloride currents at GABAA-receptor-coupled Cl- channels. It was also reported that these effects were inhibited by the GABA antagonist flumazenil, and that clobazam acts most efficiently in GABA-deficient brain tissue.[7]

Nine years earlier, Kilpatrick et al noted that there was a correlation between plasma levels of norclobazam and therapeutic effects, although this was not true with the parent compound.[8]

According to Valli and colleagues in 1984, clobazam lowered prolactin levels elevated by sulpiride, a typical antipsychotic[9]. Hyperprolactinemia (i.e. elevated blood prolactin) occurs occasionally in people using antipsychotics, (particularly the typical ones), and can lead to cardiovascular disease, breast cancer, galactorrhea, infertility, amenorrhea, dysmenorrhea, osteopenia, osteoporosis, loss of libido, impotence,[10] and hypogonadism.[11]

Antipsychotics block type 2 dopamine receptors and at least 65% of central D2 receptors need to be occupied to produce a response; >72% D2 receptor occupancy was found to be associated with development of hyperprolactinemia.[12]

Peak plasma protein binding occurs around 83%.

Metabolism

Clobazam has two major metabolites: N-desmethyl-clobazam and 4'-hydroxyclobazam, the former of which is active.[13] The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4'-hydroxyclobazam by CYP2C18 and CYP2C19.[14]

Dependence

Clobazam as with other benzodiazepine drugs can lead to physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from clobazam or other benzodiazepines after regular use often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken for, the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.[15]

Uses

Canada

As of 2005, clobazam (Frisium®) is approved in Canada for adjunctive use in tonic-clonic, complex partial, and myoclonic seizures.[16]

France

Clobazam (Urbanyl®[17]) is approved for adjunctive therapy in complex partial seizures[18] certain types of status epilepticus, specifically the myoclonic, myoclonic-absent, simple partial, complex partial, and tonic varieties[19], and non-status absence seizures.[20] It is also approved for treatment of anxiety.

India

Clobazam (Frisium®, Aventis Pharma India, Ltd.) is approved for use as an adjunctive therapy in epilepsy and in acute and chronic anxiety.[21]

Japan

Clobazam (Mystan®[4]) is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures.[22]

New Zealand

Marketed as: Frisium®[23]

United Kingdom

Clobazam (Frisium®) is approved in the United Kingdom for short-term (2-4 weeks) relief of acute anxiety in patients who have not responded to other drugs, with or without insomnia and without uncontrolled clinical depression.[24]

It is also approved for adjunctive therapy for epilepsy in patients who have not responded to first-line drugs and in children who are refractory to first-line drugs. It is not recommended for use in children between the ages of six months and three years, unless there is a compelling need.[24]

In addition to epilepsy and severe anxiety, clobazam is also approved as an adjunctive agent in schizophrenia and other psychotic disorders.[24]

Clobazam is sometimes used for refractory epilepsies however, long term prophylactic treatment of epilepsy has considerable drawbacks, most importantly loss of antiepileptic effects due to tolerance which may render long term therapy useless.[25] Other antiepileptic drugs may therefore be preferred for the long term management of epielpsy. Also benzodiazepines have the draw back after long term use of causing rebound seizures upon abrupt or over-rapid discontinuation of therapy forming part of the benzodiazepine withdrawal syndrome.

Dosage

Clobazam is available in oral form only, due to its insolubility in water.

Side effects

Common

Rare

Contraindications

Clobazam should be used with great care in patients with the following disorders:

Drug Interactions

Abuse potential

Clobazam in animal studies has been shown to increase reward seeking behaviours which may suggest an increased risk of addictive behavioural patterns.[28]

External links

References

  • Ochoa, Juan G. (2005). "GABA Receptor Agonists". Antiepileptic Drugs: An Overview. eMedicine.com, Inc. Retrieved 10 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)

End Notes

  1. ↑ "MISUSE OF DRUGS ACT 1975". Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Unknown parameter |accessmonthday= ignored (help)
  2. ↑ Freche, C. (1975). "[Study of an anxiolytic, clobazam, in otorhinolaryngology in psychosomatic pharyngeal manifestations]". Semaine des Hopitaux. Therapeutique. 51 (4): 261–3. PMID 5777. [Article in French] [No abstract] List of Library Holdings Worldwide
  3. ↑ No authors listed (1991). "Clobazam in treatment of refractory epilepsy: the Canadian experience. A retrospective study. Canadian Clobazam Cooperative Group". Epilepsia. 32 (3): 407–16. PMID 2044502. List of Library Holdings
  4. ↑ 4.0 4.1 Nakajima H (2001). "[A pharmacological profile of clobazam (Mystan), a new antiepileptic drug]" (PDF). Nippon Yakurigaku Zasshi. 118 (2): 117–22. PMID 11530681. [Article in Japanese]
  5. ↑ Wildin JD, Pleuvry BJ, Mawer GE, Onon T, Millington L (1990). "Respiratory and sedative effects of clobazam and clonazepam in volunteers". British Journal of Clinical Pharmacology. 29 (2): 169–77. PMID 2106335.List of Library Holdings Worldwide
  6. ↑ McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ (2000). "Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype". Nature Neuroscience. 3 (6): 587–92. doi:10.1038/75761. PMID 10816315.
  7. ↑ Nakamura, Fumihiro (1996). "Effects of clobazam and its active metabolite on GABA-activated currents in rat cerebral neurons in culture" (PDF). Epilepsia. 37 (8): 728–35. PMID 8764810. Retrieved 2006-08-03. Unknown parameter |coauthors= ignored (help)
  8. ↑ Kilpatrick C, Bury R, Fullinfaw R, Moulds R (1987). "Clobazam in the treatment of epilepsy". Clinical and Experimental Neurology. 23 (1): 139–44. PMID 3117456. List of Library Holdings Worldwide
  9. ↑ Valli M, Courtiere A, Tamalet C, Jadot G (1984). "[Activity of clobazam on plasma prolactin and gonadotropins after administration of sulpiride in the male rat]". Annales d'Endocrinologie. 45 (6): 409–11. [Article in French] PMID 6152598 List of Library Holdings Worldwide
  10. ↑ Halbreich, Uriel (2003). "Hyperprolactinemia and Schizophrenia: Mechanisms and Clinical Aspects". Journal of Psychiatric Practice. 9 (5): 344–53. PMID 15985953. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  11. ↑ Meaney, Anna Maria (2004). "Effects of long-term prolactin-raising antipsychotic medication on bone mineral density in patients with schizophrenia". British Journal of Psychiatry. 184: 503–508. PMID 15172944. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  12. ↑ Kapur, Shitij (2000). "Relationship Between Dopamine D2 Occupancy, Clinical Response, and Side Effects: A Double-Blind PET Study of First-Episode Schizophrenia". The American Journal of Psychiatry. 157 (4): 514–20. PMID 10739409. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  13. ↑ Contin M, Sangiorgi S, Riva R, Parmeggiani A, Albani F, Baruzzi A (2002). "Evidence of polymorphic CYP2C19 involvement in the human metabolism of N-desmethylclobazam". Therapeutic Drug Monitoring. 24 (6): 737–41. PMID 12451290. List of Library Holdings Worldwide
  14. ↑ Giraud C, Tran A, Rey E, Vincent J, Treluyer JM, Pons G (2004). "In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19". Drug Metabolism and Disposition. 32 (11): 1279–86. PMID 15483195. List of Library Holdings Worldwide
  15. ↑ MacKinnon GL (1982). "Benzodiazepine withdrawal syndrome: a literature review and evaluation". The American journal of drug and alcohol abuse. 9 (1): 19–33. PMID 6133446. Unknown parameter |coauthors= ignored (help)
  16. ↑ Epilepsy Ontario (2005). "Clobazam". Medications. Retrieved March 4. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
  17. ↑ "Liste des médicaments contenant la substance : Clobazam". Retrieved 28 September. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help) Vidal.
  18. ↑ Larrieu JL, Lagueny A, Ferrer X, Julien J (1986). "[Epilepsy with continuous discharges during slow-wave sleep. Treatment with clobazam]". Revue d'Electroencephalographie et de Neurophysiologie Clinique. 16 (4): 383–94. [Article in French] PMID 3103177 List of Library Holdings Worldwide
  19. ↑ Gastaut, Henri (1984). "[Treatment of certain forms of status epilepticus by means of a single oral dose of clobazam]". Revue d'Electroencephalographie et de Neurophysiologie Clinique. 14 (3): 203–6. PMID 6528075. Unknown parameter |coauthors= ignored (help) (Article in French) List of Library Holdings Worldwide
  20. ↑ Biam Database (2001). "CLOBAZAM". Classes Chimiques: BENZODIAZEPINE. Retrieved 28 September. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
  21. ↑ "Frisium Press Kit". Aventis Pharma India. Archived from the original on 2005-03-05. Retrieved 2006-08-02.
  22. ↑ Shimizu, Hisako (2003). "Use of clobazam for the treatment of refractory complex partial seizures". Seizure. 12 (5): 282–6. PMID 12810340. Unknown parameter |coauthors= ignored (help) List of Library Holdings Worldwide
  23. ↑ Epilepsy New Zealand (2000). "Antiepileptic Medication". Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
  24. ↑ 24.0 24.1 24.2 sanofi-aventis (2002). "Frisium Tablets 10 mg, Summary of Product Characteristics from eMC". electronic Medicines Compendium. Medicines.org.uk. Retrieved 11 July. Unknown parameter |accessyear= ignored (|access-date= suggested) (help); Check date values in: |accessdate= (help)
  25. ↑ Isojärvi, JI (1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". J Intellect Disabil Res. 42 (1): 80–92. PMID 10030438. Unknown parameter |coauthors= ignored (help); Unknown parameter |month= ignored (help)
  26. ↑ Iwasaki T (2003). "[A case of intractable epilepsy showing frequent gelastic seizures by administration of clobazam]". No To Hattatsu. 35 (5): 406–10. Unknown parameter |coauthors= ignored (help) [Article in Japanese] PMID 13677950 List of Library Holdings Worldwide
  27. ↑ Monjanel-Mouterde S, Antoni M, Bun H, Botta-Frindlund D, Gauthier A, Durand A, Cano JP (1994). "Pharmacokinetics of a single oral dose of clobazam in patients with liver disease". Annual Review of Pharmacology and Toxicology. 74 (6): 345–50. PMID 7937568. List of Library Holdings Worldwide
  28. ↑ Thiébot MH (1985). "Benzodiazepines reduce the tolerance to reward delay in rats". Psychopharmacology (Berl). 86 (1–2): 147–52. PMID 2862657. Unknown parameter |coauthors= ignored (help)

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