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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 \u03b3\u2010aminobutyric acid A (GABA<jats:sub>A<\/jats:sub>) receptor functions. GABA<jats:sub>A<\/jats:sub>receptors are heteropentamers, consisting primarily of \u03b11\u20106, \u03b21\u20103, \u03b32, and \u03b4 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<jats:sub>A<\/jats:sub>receptors, the activation of which leads to an increase in intracellular chloride, hyperpolarization of the cell membrane, and a reduction in excitation. GABA<jats:sub>A<\/jats:sub>receptor subunit mutations, dysregulation of trafficking, and degradation are associated with epilepsy. Although benzodiazepines are effective GABA<jats:sub>A<\/jats:sub>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\u2010label 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.<\/jats:p>","DOI":"10.1111\/epi.17341","type":"journal-article","created":{"date-parts":[[2022,8,24]],"date-time":"2022-08-24T02:11:10Z","timestamp":1661307070000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Rescue therapies for seizure clusters: Pharmacology and target of treatments"],"prefix":"10.1111","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6681-7134","authenticated-orcid":false,"given":"Barry","family":"Gidal","sequence":"first","affiliation":[{"name":"School of Pharmacy University of Wisconsin\u2013Madison Madison Wisconsin United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8334-1403","authenticated-orcid":false,"given":"Kamil","family":"Detyniecki","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Miami Miller School of Medicine Miami Florida United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,8,23]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1528-1157.1999.tb01607.x"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2018.05.013"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yebeh.2020.107391"},{"issue":"1","key":"e_1_2_12_5_1","first-page":"S14","article-title":"Consequences: bench to home","volume":"63","author":"Kapur J","year":"2022","journal-title":"Epilepsia"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1212\/CPJ.0000000000000099"},{"key":"e_1_2_12_7_1","volume-title":"LLC. 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