Rescue therapies for seizure clusters: Pharmacology and target of treatments

The primary goal of treatment for seizure clusters is cessation of the cluster to avoid progression to more severe conditions, such as prolonged seizures and status epilepticus. Rescue therapies are key components of treatment plans for patients with seizure clusters. Three rescue therapies are approved in the United States for the treatment of seizure clusters: diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. This review characterizes the pharmacological function of rescue therapies for seizure clusters, as well as describing γ‐aminobutyric acid A (GABA(A)) receptor functions. GABA(A) receptors are heteropentamers, consisting primarily of α1‐6, β1‐3, γ2, and δ subunits in the central nervous system. These subunits can traffic to and from the membrane to regulate membrane potential. Benzodiazepines, such as diazepam and midazolam, are positive allosteric modulators of GABA(A) receptors, the activation of which leads to an increase in intracellular chloride, hyperpolarization of the cell membrane, and a reduction in excitation. GABA(A) receptor subunit mutations, dysregulation of trafficking, and degradation are associated with epilepsy. Although benzodiazepines are effective GABA(A) receptor modulators, individual formulations have unique profiles in practice. Diazepam rectal gel is an effective rescue therapy for seizure clusters; however, adults and adolescents may have social reservations regarding its administration. Intranasal delivery of midazolam or diazepam is a promising alternative to rectal administration because these formulations offer easy, socially acceptable administration and exhibit a rapid onset. Off‐label benzodiazepines, such as orally disintegrating lorazepam and intranasal use of an intravenous formulation of midazolam via nasal atomizer, are less well characterized regarding bioavailability and tolerability compared with approved agents.