Intranasal epinephrine effects on epinephrine pharmacokinetics and heart rate in a nasal congestion canine model

Abstract

Background: Histamine release and vasodilation during an allergic reaction can alter the pharmacokinetics of drugs administered via the intranasal (IN) route. The current study evaluated the effects of histamine-induced nasal congestion on epinephrine pharmacokinetics and heart rate changes after IN epinephrine. Methods: Dogs received 5% histamine or saline IN followed by 4 mg epinephrine IN. Nasal restriction pressure, epinephrine concentration, and heart rate were assessed. Maximum concentration (C max), area under plasma concentration-time curve from 1 to 90 min (AUC 1-90), and time to reach C max (T max) were measured. Clinical observations were documented. Results: In the 12 dogs in this study, nasal congestion occurred at 5-10 min after IN histamine administration versus no nasal congestion after IN saline. After administration of IN epinephrine, IN histamine-mediated nasal congestion was significantly reduced to baseline levels at 60, 80, and 100 min. There were no significant differences in C max and AUC 1-90 between histamine and saline groups after IN epinephrine delivery (3.5 vs 1.7 ng/mL, p = 0.06, and 117 vs 59 ng/ mL*minutes, p = 0.09, respectively). After receiving IN epinephrine, the histamine group had a significantly lower T max versus the saline group (6 vs 70 min, respectively; p = 0.02). Following IN epinephrine administration, the histamine group showed rapidly increased heart rate at 5 min, while there was a delayed increase in heart rate (occurring 30-60 min after administration) in the saline group. Clinical observations included salivation and emesis. Conclusion: IN histamine led to more rapid epinephrine absorption and immediately increased heart rate compared with IN saline. IN epinephrine decreased histamine-induced nasal congestion.

Development of neffy, an Epinephrine Nasal Spray, for Severe Allergic Reactions

“…Administration of a single dose of neffy following NAC-induced allergic rhinitis resulted in an increase in the rate of epinephrine absorption. It is assumed that this increased absorption is due to the increased permeability in the nasal mucosa, as this phenomenon was observed in the anaphylaxis dog model and has been reported in the literature [ 49 , 50 ]. At the same time, neffy 2 mg with rhinitis also resulted in more rapid clearance compared with normal nasal conditions ( Figure 10 ).…”

“…Although epinephrine is considered the only safe and effective first-line treatment of anaphylaxis [ 46 ], there have been reports of safety issues due to overdosing, both following manual IM administration and EAI administration [ 29 , 47 , 48 ]. For IN products, it has been reported that epinephrine absorption during an allergic reaction may be increased due to changes in vascular permeability [ 49 , 50 ]. A high dose of epinephrine in the presence of increased permeability in the nasal mucosa, due to an allergic reaction or population variability, could potentially result in excessive absorption and increase the risk of overdose [ 51 ].…”

“…This may be because vasoactive mediators such as histamine released during anaphylaxis increase vascular permeability [ 72 , 73 ]. Increased epinephrine absorption has also been reported under histamine-induced nasal congestion in dogs [ 50 ]. These data suggest that IN absorption of epinephrine may be enhanced during the increased permeability associated with a more severe anaphylaxis event.…”

Pharmacokinetics of intravenous, oral transmucosal, and intranasal buprenorphine in healthy male dogs

“…In addition, drugs administered by the nasal route can directly reach the central nervous system (CNS) via the trigeminal and olfactory nerves (Erdo et al, 2018). The IN route of administration in dogs has been investigated for midazolam, dexmedetomidine, epinephrine, naloxone, and ketamine (Bleske et al, 1992; Charalambous et al, 2017; Charalambous et al, 2019; Dretchen et al, 2020; Santangelo et al, 2019; Tuttle et al, 2020; Vlerick et al, 2020; Wahler et al, 2019). These studies reported the intranasal route of administration to be clinically effective and/or results in adequate plasma concentrations of the investigated drug.…”