Intravenous and Intramuscular Formulations of Antiseizure Drugs in the Treatment of Epilepsy

Abstract

Intravenous and intramuscular antiseizure drugs (ASDs) are essential in the treatment of clinical seizure emergencies as well as in replacement therapy when oral administration is not possible. The parenteral formulations provide rapid delivery and complete (intravenous) or nearly complete (intramuscular) bioavailability. Controlled administration of the ASD is feasible with intravenous but not intramuscular formulations. This article reviews the literature and discusses the chemistry, pharmacology, pharmacokinetics, and clinical use of currently available intravenous and intramuscular ASD formulations as well as the development of new formulations and agents. Intravenous or intramuscular formulations of lorazepam, diazepam, midazolam, and clonazepam are typically used as the initial treatment agents in seizure emergencies. Recent studies also support the use of intramuscular midazolam as easier than the intravenous delivery of lorazepam in the pre-hospital setting. However, benzodiazepines may be associated with hypotension and respiratory depression. Although loading with intravenous phenytoin was an early approach to treatment, it is associated with cardiac arrhythmias, hypotension, and tissue injury at the injection site. This has made it less favored than fosphenytoin, a water-soluble, phosphorylated phenytoin molecule. Other drugs being used for acute seizure emergencies are intravenous formulations of valproic acid, levetiracetam, and lacosamide. However, the comparative effectiveness of these for status epilepticus (SE) has not been evaluated adequately. Consequently, guidelines for the medical management of SE continue to recommend lorazepam followed by fosphenytoin, or phenytoin if fosphenytoin is not available. Intravenous solutions for carbamazepine, lamotrigine, and topiramate have been developed but remain investigational. The current ASDs were not developed for use in emergency situations, but were adapted from ASDs approved for chronic oral use. New approaches for bringing drugs from experimental models to treatment of human SE are needed.

Pre-hospital midazolam for benzodiazepine-treated seizures before and after the Rapid Anticonvulsant Medication Prior to Arrival Trial: A national observational cohort study

“…The increasing use of midazolam could be explained by growing acknowledgment of the benefits of midazolam for the treatment of pre-hospital status epilepticus. Midazolam is not only as effective as alternative intravenous medications [3], but is also easier to administer[8], has better pharmacodynamics than diazepam [9], is cheaper [10–12] and has a longer shelf life than lorazepam [13]. Furthermore, midazolam is subject to far fewer shortages, with diazepam and lorazepam making up 2 of the 10 most susceptible drugs to national shortages [14].…”

Prophylactic Midazolam For Prevention Of Post-Operative Nausea And Vomiting Following Adenoidectomy or Adenotonsillectomy

“…In contrast to other parenteral formulations of benzodiazepines, intramuscular midazolam is rapidly absorbed; with peak serum concentrations achieved at 17.5 ± 6.5 to 25 ± 23 min [20]. The postulated antiemetic mechanism of midazolam includes glycine mimetic inhibitory effects, adenosinergic effects, and inhibition of dopamine release [21].…”

Pre-Hospital Midazolam for Treatment of Status Epilepticus Before and After the Rapid Anticonvulsant Medication Prior to Arrival Trial: A National Observational Cohort Study

“…The increasing use of midazolam could be explained by growing acknowledgement of the benefits of midazolam for the treatment of pre-hospital status epilepticus. Midazolam is not only as effective as alternative intravenous medications [3, 5], but is also easier to administer[8], has better pharmacodynamics than diazepam [9], is cheaper [10-12] and has a longer shelf life than lorazepam [13]. Furthermore, midazolam is subject to far fewer shortages, with diazepam and lorazepam making up 2 of the 10 most susceptible drugs to national shortages [14].…”