Rescue therapies for seizure emergencies: New modes of administration

A subgroup of patients with drug-resistant epilepsy have seizure clusters, which are a part of the continuum of seizure emergencies that includes prolonged episodes and status epilepticus. When the patient or caregiver can identify the beginning of a cluster, the condition is amenable to certain treatments, an approach known as rescue therapy. Intravenous drug administration offers the fastest onset of action, but this route is usually not an option because most seizure clusters occur outside of a medical facility. Alternate routes of administration have been used or are proposed including rectal, buccal, intrapulmonary, subcutaneous, intramuscular, and intranasal. The objective of this narrative review is to describe the (1) anatomical, physiologic, and drug physicochemical properties that need to be considered when developing therapies for seizure emergencies and (2) products currently in development. New therapies must consider parameters of Fick's law such as absorptive surface area, blood flow, membrane thickness, and lipid solubility, because these factors affect both rate and extend of absorption. For example, the lung has a 50 000-fold greater absorptive surface area than that associated with a subcutaneous injection. Lipid solubility is a physicochemical property that influences the absorption rate of small molecule drugs. Among drugs currently used or under development for rescue therapy, allopregnanolone has the greatest lipid solubility at physiologic pH, followed by propofol, midazolam, diazepam, lorazepam, alprazolam, and brivaracetam. However, greater lipid solubility correlates with lower water solubility, complicating formulation of rescue therapies. One approach to overcoming poor aqueous solubility involves the use of a water-soluble prodrug coadministered with a converting enzyme, which is being explored for the intranasal delivery of diazepam. With advances in seizure prediction technology and the development of drug delivery systems that provide rapid onset of effect, rescue therapies may prevent the occurrence of seizures, thus greatly improving the management of epilepsy.