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.

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“…The plasma half-life is 24–48 h and shows individual differences, especially in the elderly population. The half-life of diazepam increases after a drug overdose, with significant prolongation of the half-life of diazepam and its metabolites, and drug accumulation, leading to adverse drug reactions ( Kienitz et al, 2022 ).…”

“…Establishing peripheral venous catheters during poor venous status or seizures or outside the hospital may result in delayed drug administration. ( Kienitz et al, 2022 ). Rectal diazepam licensed in the United States in 1997.…”

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“…Reduction in anti-seizure medication is known to directly (i.e., modulate sleep efficiency) ( 18 , 19 ) and indirectly (i.e., gradually increase seizure risk which in turn reduces sleep efficiency) ( 4 ) affect sleep. Lorazepam, a benzodiazepine sometimes prescribed to PWE in the EMU as a rescue medication with a relatively short half-life, increases sleep efficiency and reduces seizure risk in a relatively short amount of time as compared to other anti-seizure medications which have a longer half-life ( 20 ). Lorazepam is the only rescue medication which was prescribed to patients in the cohort either to prevent a seizure during nuclear imaging or to treat a seizure cluster.…”