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Pharmacokinetic Optimisation of Benzodiazepine Therapy for Acute Seizures

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  • Review Article
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Abstract

All benzodiazepines enter cerebral tissue rapidly. However, the duration of action is short for diazepam (<2 hours) and midazolam (3 to 4 hours) and longer for clonazepam (24 hours) and lorazepam (up to 72 hours), and is not correlated with the plasma concentration-time profiles of these drugs. Although a relationship between the plasma concentration of diazepam, lorazepam and midazolam and their pharmacodynamic effect has been demonstrated in healthy individuals, some caution is warranted as the clinical relevance of these data has not been clearly established.

The physicochemical properties of benzodiazepines (lipid solubility and protein binding) regulate their rate and extent of entry into the brain and cerebrospinal fluid. However, the duration of the pharmacological activity of benzodiazepines may be in part related to the affinity of these compounds for the benzodiazepine receptors in the brain: midazolam, clonazepam and lorazepam have higher affinities than diazepam.

In the emergency setting, the intravenous route is the most suitable, delivering adequate quantities of benzodiazepines as fast as possible. However, when intravenous administration is not available, rectal administration of a solution is a convenient method for diazepam, midazolam being the only one of these drugs that should be given intramuscularly.

The assessment of the efficacy of benzodiazepines in the management of acute seizures and status epilepticus is mainly based on nonrandomised uncontrolled trials. According to the route of administration, the efficacy was 28.6 to 100% (intrarectal) and 54 to 100% (intravenous) for diazepam, 82 to 100% (intravenous) for lorazepam, and 79% (intranasal), 93 to 100% (intramuscular) and 100% (intravenous) for midazolam.

Although diazepam was initially chosen for the management of refractory status epilepticus, the longer duration of action of lorazepam and clonazepam may favour the use of these 2 drugs. However, double-blind evaluations are necessary to determine which drug is best.

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  1. Pharmacologie Périnatale et Pédiatrique, Université René Descartes, Hôpital Saint-Vincent de Paul, 82 Avenue Denfert Rochereau, 75674, Paris Cédex 14, France

    Elisabeth Rey, Jean-Marc Tréluyer & Gérard Pons

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  1. Elisabeth Rey
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Rey, E., Tréluyer, JM. & Pons, G. Pharmacokinetic Optimisation of Benzodiazepine Therapy for Acute Seizures. Clin Pharmacokinet 36, 409–424 (1999). https://doi.org/10.2165/00003088-199936060-00003

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