Intranasal Delivery of Antiepileptic Medications for Treatment of Seizures

Abstract

Summary: Acute isolated seizure, repetitive or recurrent seizures, and status epilepticus are all deemed medical emergencies. Mortality and worse neurologic outcome are directly associated with the duration of seizure activity. A number of recent reviews have described consensus statements regarding the pharmacologic treatment protocols for seizures when patients are in pre-hospital, institutional, and home-bound settings. Benzodiazepines, such as lorazepam, diazepam, midazolam, and clonazepam are considered to be medications of first choice. The rapidity by which a medication can be delivered to the systemic circulation and then to the brain plays a significant role in reducing the time needed to treat seizures and reduce opportunity for damage to the CNS. Speed of delivery, particularly outside of the hospital, is enhanced when transmucosal routes of delivery are used in place of an intravenous injection.Intranasal transmucosal delivery of benzodiazepines is useful in reducing time to drug administration and cessation of seizures in the pre-hospital setting, when actively seizing patients arrive in the emergency room, and at home where caregivers treat their dependents. This review summarizes factors to consider when choosing a benzodiazepine for intranasal administration, including formulation and device considerations, pharmacology and pharmacokinetic/pharmacodynamic profiles. A review of the most relevant clinical studies in epilepsy patients will provide context for the relative success of this technique with a number of benzodiazepines and relatively less sophisticated nasal preparations. Neuropeptides delivered intranasally, crossing the blood-brain barrier via the olfactory system, may increase the availability of medications for treatment of epilepsy. Consequently, there remains a significant unmet medical need to serve the pharamcotherapeutic requirements of epilepsy patients through commercial development and marketing of intranasal antiepileptic products.

Treatment of Acute Seizures: Is Intranasal Midazolam a Viable Option?

“…5 The nasal cavity is covered with a thin mucus layer, a monolayer ciliated epithelium, and is innervated by an abundant underlying blood supply. 6 Under ideal conditions, most medication is absorbed from the nasal mucosa and reaches the cerebral cortex within 2 to 5 minutes, thus avoiding first-pass metabolism. 7 Medications suitable for intranasal use must be water-soluble, small enough to permeate nasal mucosa, and potent enough to be effective in small doses.…”

“…It is important, however, to keep in mind that physiologic changes of the nasal passages can occur, for example, during allergic and vasomotor rhinitis, after physical trauma, and during times of increased mucus production. 6 One distinct disadvantage of using intranasal midazolam is the increased nasal mucus production that is sometimes observed during seizure activity. Increases in mucus production and changes in mucociliary clearance rates could affect midazolam's bioavailability.…”

“…Increases in mucus production and changes in mucociliary clearance rates could affect midazolam's bioavailability. 6,8 Midazolam's small molecular weight of 325.8 Da allows for easy permeation of nasal mucosa. 6 Midazolam dissolves in water at a low pH, but at physiologic pH it becomes lipophilic, allowing the medication to cross the blood-brain barrier.…”

“…6,8 Midazolam's small molecular weight of 325.8 Da allows for easy permeation of nasal mucosa. 6 Midazolam dissolves in water at a low pH, but at physiologic pH it becomes lipophilic, allowing the medication to cross the blood-brain barrier. 4,7 Rey and colleagues 9 studied the pharmacokinetics of intranasal midazolam in 6 children (ages 1-5 years) and found the time to maximum concentration to be 12 minutes with a half-life of 2.2 hours when a dose of 0.2 mg/kg was administered.…”

“…6 One method of preventing nasal irritation is to administer intranasal lidocaine 60 seconds before midazolam using a mucosal atomization device. Chiaretti and colleagues 18 found a single 10-mg dose of atomized lidocaine prior to a 0.2 to 0.5 mg/kg dose of intranasal midazolam to be effective at reducing nasal irritation, but the children in this study were given midazolam for conscious sedation rather than for seizures.…”