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

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.

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.

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. 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.

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.

According to Valli and colleagues in 1984, clobazam lowered prolactin levels elevated by sulpiride, a typical antipsychotic. 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, and hypogonadism.

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.

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. The demethylation is facilitated by CYP2C19, CYP3A4, and CYP2B6 and the 4'-hydroxyclobazam by CYP2C18 and CYP2C19.

Uses

Approved

Canada
As of 2005, clobazam (Frisium®) is approved in Canada for adjunctive use in tonic-clonic, complex partial, and myoclonic seizures.
France
Clobazam (Urbanyl®) is approved for adjunctive therapy in complex partial seizures certain types of status epilepticus, specifically the myoclonic, myoclonic-absent, simple partial, complex partial, and tonic varieties, and non-status absence seizures. 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.

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

New Zealand
Marketed as: Frisium®

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.

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.

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

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

External links

References

End Notes

  1. National Center for Biotechnology Information.
  3. in French abstract PMID 5777 List of Library Holdings Worldwide
  4. List of Library Holdings
  5. in Japanese
  6. List of Library Holdings Worldwide
  7. List of Library Holdings Worldwide
  8. List of Library Holdings Worldwide
  9. List of Library Holdings Worldwide
  10. List of Library Holdings Worldwide
  11. List of Library Holdings Worldwide
  13. Vidal.
  14. in French PMID 3103177 List of Library Holdings Worldwide
  15. }} in French List of Library Holdings Worldwide
  17. Aventis Pharma Ltd. India.
  18. see Nakajima et al., 2001.
  19. | url = http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=12810340&dopt=ExternalLink}} List of Library Holdings Worldwide
  22. see Frisium Tablets 10 mg, Summary of Product Characteristics from eMC, 2002.
  23. see Frisium Tablets 10 mg, Summary of Product Characteristics from eMC, 2002.
  24. in French PMID 6152598 List of Library Holdings Worldwide
  28. in Japanese PMID 13677950 List of Library Holdings Worldwide
  29. List of Library Holdings Worldwide

Anticonvulsants | Anxiolytics | Benzodiazepines | Hypnotics | Muscle relaxants | Schedule IV controlled substances | Sedatives

Клобазам | Klobatsaami

 

This article is licensed under the GNU Free Documentation License. It uses material from the "Clobazam".

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