Table 2.

Non-IV modes of administration of rescue therapies

Routes of Administration	Advantages	Disadvantages	Special Considerations
Intrapulmonary	The large surface area of alveoli in the lungs allows for efficient absorption of small molecules The lungs have very high perfusion rate with very thin alveolar-capillary membrane Rapid onset of action	Determination of the dose is difficult as it depends on the amount of material deposited in specific regions of the respiratory tract The size, shape, and flow characteristics of the aerosolized drug need to be tightly controlled for adequate deposition lung tissue is sensitive, and poorly soluble drug particles at high exposure concentrations can impair lung clearance Breathing abnormalities during a seizure can impair drug deposition; delivery device size may need to be different in adult and pediatric patients	Alprazolam Staccato System(thermal vaporization aerosol Device) uses normal inhalation to heat up a stainless steel plate in which a thin film of alprazolam is coated. Sublimation and condensation of the drug into small particles occur for delivery. However, as alprazolam does not have an indication for seizures, one or more phase III clinical trials will likely to be needed for FDA approval.
Intramuscular	Easy access and administration	A relatively slow rate of drug absorption The risk of improper injection The requirement of the longer needles Different needle size dependent on the body adipose tissue	Autoinjectors of DZP and MDZ can be valuable to be used by paramedics
Subcutaneous	Easy access and administration	Volume restriction Risk of induration, sloughing, and abscess Requires training and manual dexterity for injection If frequently administered, may require injection site rotation	A DZP production is currently in preclinical development and has orphan drug designation.
Intranasal	Faster drug administration and absorption Requires minimal training Easily administered Carries little risk of injury Faster onset of action	Mucociliary clearance can remove the drug from the nasal cavity before the entire dose is absorbed into the nasal mucosa Lower bioavailability in larger dose volumes as nasal cavity accommodates only up to 200 μL of the solution and excess volume tends to drain into the nasopharynx or out of the anterior nares High concentration MDZ contains solubilizers that can irritate the mucosa and result in significant discomfort Nasal secretions and nasal blood flow variability may lead to variations in absorption rates and bioavailability	Commercial products of IN MDZ and DZP recently received FDA approval for seizure clusters
Rectal	Better absorption rate than the buccal route as rectal epithelium(160–190 μm) thinner than buccal epithelium(500–800 μm) Relatively large volumes can be administered compared to IN route	Socially inappropriate, Difficulty in administration Takes more extended time for positioning and removal of clothes Variable absorption Expensive	Although rectal diazepam is the oldest FDA–approved product for acute repetitive seizures, future use may be diminished with the recent availability of other products