Clobazam

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]

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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 GABA_A 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 GABA_A 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 GABA_A-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]

Indications

As of 2005, clobazam (Frisium®) is approved in Canada for adjunctive use in tonic-clonic, complex partial, and myoclonic seizures.^[16] 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. In India, clobazam (Frisium®, Aventis Pharma India, Ltd.) is approved for use as an adjunctive therapy in epilepsy and in acute and chronic anxiety.^[21] In Japan, clobazam (Mystan®^[4]) is approved for adjunctive therapy in treatment-resistant epilepsy featuring complex partial seizures.^[22] In New Zealand, clobazam is marketed as Frisium®^[23] In the 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

• Ataxia
• Somnolence
• Diplopia
• Dysarthria

Rare

• Gelastic seizures^[26]
• Urticaria
• Rashes

Contraindications

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

• Myasthenia gravis
• Sleep apnea
• Severe liver diseases such as cirrhosis and hepatitis^[27]
• Respiratory problems, including hypoventilation

Drug Interactions

• Alcohol increases bioavailability by 50%
• Cimetidine increases the effects of clobazam
• valproates

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]

References

• Ochoa, Juan G. (2005). GABA Receptor Agonists. Antiepileptic Drugs: An Overview. eMedicine.com, Inc. Retrieved on 10 July, 2005.

End Notes