Benzodiazepines

OTHER DRUGS USED IN MANAGEMENT OF EPILEPSY

Some drugs not classifiable by application to seizure type are dis-cussed in this section.

BENZODIAZEPINES

Six benzodiazepines play prominent roles in the therapy of epilepsy. Although many benzodiazepines are similar chemically, subtle structural alterations result in differences in activity and pharmacokinetics. They have two mechanisms of antiseizure action, which are shown to different degrees by the six compounds. This is evident from the fact that diazepam is rela-tively more potent against electroshock and clonazepam against pentylenetetrazol (the latter effect correlating with an action at the GABA-benzodiazepine allosteric receptor sites).

Diazepam given intravenously or rectally is highly effective forstopping continuous seizure activity, especially generalized tonic-clonic status epilepticus . The drug is occasionally given orally on a long-term basis, although it is not considered very effective in this application, probably because of the rapid development of tolerance. A rectal gel is available for refractory patients who need acute control of bouts of seizure activity. Lorazepam appears in some studies to be more effective and lon-ger acting than diazepam in the treatment of status epilepticus and is preferred by some experts.

Clonazepam is a long-acting drug with documented efficacyagainst absence seizures; on a milligram basis, it is one of the most potent antiseizure agents known. It is also effective in some cases of myoclonic seizures and has been tried in infantile spasms. Sedation is prominent, especially on initiation of therapy; starting doses should be small. Maximal tolerated doses are usually in the range of 0.1–0.2 mg/kg, but many weeks of gradually increasing daily doses may be needed to achieve these dosages in some patients. Nitrazepam is not marketed in the USA but is used in many other countries, especially for infantile spasms and myoclo-nic seizures. It is less potent than clonazepam, and superiority to that drug has not been documented.Clorazepate dipotassium is approved in the USA as an adjunctto treatment of complex partial seizures in adults. Drowsiness and lethargy are common adverse effects, but as long as the drug is increased gradually, dosages as high as 45 mg/d can be given.Clobazam is not available in the USA but is marketed in mostcountries and is widely used in a variety of seizure types. It is a 1,5-benzodiazepine (other marketed benzodiazepines are 1,4-benzodiaz-epines) and reportedly has less sedative potential than benzodiazepines marketed in the USA. Whether the drug has significant clinical advantages is not clear. It has a half-life of 18 hours and is effective at dosages of 0.5–1 mg/kg/d. It does interact with some other anti-seizure drugs and causes adverse effects typical of the benzodiaz-epines; efficacy, in some patients, is limited by the development of tolerance. It has an active metabolite, norclobazam.

Limitations

Two prominent aspects of benzodiazepines limit their usefulness. The first is their pronounced sedative effect, which is unfortunate both in the treatment of status epilepticus and in chronic therapy. Children may manifest a paradoxical hyperactivity, as with barbiturates. The second problem is tolerance, in which seizures may respond initially but recur within a few months. The remark-able antiseizure potency of these compounds often cannot be realized because of these limiting factors.