Benzodiazepines: use in epilepsy

Introduction

The antiepileptic action of benzodiazepines involves modulation of the GABAA receptor, which opens the chloride channel and hyperpolarises the cell, leading to postsynaptic inhibition. Benzodiazepines are the preferred option in patients presenting with active generalised convulsive status epilepticus since they rapidly terminate seizures.

Clonazepam

The sedative effect and the development of tolerance substantially reduce the usefulness of clonazepam in the chronic treatment of epilepsy. Apart from the treatment of status epilepticus, the therapeutic role of clonazepam is limited; it is used mostly for refractory myoclonic seizures.

Common adverse effects are drowsiness, ataxia, excess salivary and bronchial secretions, and behavioural and personality changes. Behavioural adverse effects are particularly common in children.

Diazepam

Although diazepam has a long elimination half-life, it redistributes out of the central nervous system rapidly. It therefore has a relatively short duration of action (only 20 to 30 minutes) against seizures when given acutely. While it is highly effective in stopping seizures, its short duration of action requires that a longer-acting antiepileptic drug (eg phenytoin) be given after status epilepticus ceases.

Intravenous diazepam usually stops seizures within a few minutes. Intravenous diazepam should be administered undiluted. If diazepam for injection is diluted with sodium chloride 0.9% before administration, a fine white precipitate may form. The safety of administration with such a solution is not established.

Intramuscular diazepam is not recommended because of its variable and relatively inefficient absorption. Rectally administered diazepam is effective in terminating seizures in high-risk situations. [Note 1]

Midazolam

Effective midazolam plasma concentrations can be obtained after intramuscular, buccal or intranasal administration making it a useful option when intravenous access is difficult. The effect of a single dose wears off quickly because of its short elimination half-life.

Care needs to be exercised if midazolam is given intravenously because it may cause transient apnoea and hypotension. An active metabolite relies on renal excretion and may accumulate in patients with renal impairment. Enhanced effects may result from drug interactions with diltiazem, erythromycin, itraconazole, ketoconazole and possibly fluconazole.

Note 1: There is no rectal formulation of diazepam marketed in Australia. A formulation for rectal use is prepared in some hospital pharmacies and provided under specialist advice to parents and carers who have been trained in its use. See, for example, the Melbourne Royal Children's Hospital website.