Benzodiazepines in the Management of Seizures and Status Epilepticus: A Review of Routes of Delivery, Pharmacokinetics, Efficacy, and Tolerability

Abstract

Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and SE is a constant challenge for healthcare professionals, in both the pre-hospital and the in-hospital settings. Benzodiazepines (BZDs) are the first-line treatment for SE worldwide due to their efficacy, tolerability, and rapid onset of action. Although all BZDs act as allosteric modulators at the inhibitory gamma-aminobutyric acid (GABA)_A receptor, the individual agents have different efficacy profiles and pharmacokinetic and pharmacodynamic properties, some of which differ significantly. The conventional BZDs clonazepam, diazepam, lorazepam and midazolam differ mainly in their durations of action and available routes of administration. In addition to the common intravenous, intramuscular and rectal administrations that have long been established in the acute treatment of SE, other administration routes for BZDs-such as intranasal administration-have been developed in recent years, with some preparations already commercially available. Most recently, the intrapulmonary administration of BZDs via an inhaler has been investigated. This narrative review provides an overview of the current knowledge on the efficacy and tolerability of different BZDs, with a focus on different routes of administration and therapeutic specificities for different patient groups, and offers an outlook on potential future drug developments for the treatment of prolonged seizures and SE.

Fig. 1

Overview of the structural forms of the benzodiazepines diazepam, lorazepam, midazolam and clonazepam, which are discussed in this review. Even though the benzodiazepines are structurally very similar and closely related, their different pharmacological and pharmacokinetic properties result in relevant differences that are of particular importance when considering various delivery routes. All structural forms displayed have been released into the public domain by their creators

Fig. 2

Mean time from drug administration to cessation of status epilepticus (SE) in minutes is displayed for different delivery routes, based on literature research, as far as available (n.a. = not available). Intravenous (i.v.) administration showed the fastest onset of action with a latency of less than 3 min, followed by intranasal (i.n.) and intramuscular (i.m.) administration, as well as buccal and rectal delivery. Due to the heterogeneous patient populations and study settings, the displayed values should only serve as a basic guidance [, , , , –190]. MDZ midazolam, LZP lorazepam, DZP diazepam, CZP clonazepam

Fig. 3

Time from therapy administration to cessation of status epilepticus (SE) is displayed to help decide on the clinical use of different delivery routes for benzodiazepines in SE, based on published preparations and process times for drug administration via intravenous injection (i.v.), intramuscular injection (i.m.), rectal, intranasal (i.n.) and buccal administration [48]. For i.v. administration, it was assumed that no peripheral indwelling venous catheter had yet been established analogous to Silbergleit et al. [48]. MDZ midazolam, LZP lorazepam, DZP diazepam, CZP clonazepam