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.

Keywords: Allergy; Anaphylaxis; Epinephrine; Histamine; Intranasal; Nasal congestion; Severe allergy; Vasodilation.

Fig. 1

Intranasal Aerosol Delivery and Pressure Measurement System. Schematic of the system used for measurements of changes in nasal congestion restriction

Fig. 2

Study Design. Timing of nasal pressure measurements and pharmacokinetic measurements after histamine or saline IN administration, following epinephrine IN administration

Fig. 3

Effect of IN Epinephrine on Histamine-Induced Nasal Congestion. IN histamine led to increased nasal pressure at 10 min after administration, as compared to IN saline. IN epinephrine reduced histamine-induced nasal pressure increase at all time points measured. Data represent mean ± SEM. IN, intranasal, P, pressure

Fig. 4

Effect of IN Epinephrine on Epinephrine Plasma Concentrations After IN Histamine or Saline. Group average epinephrine concentration-time profiles are plotted for the histamine and saline groups. Immediately after IN epinephrine, the average epinephrine plasma concentration was greater in the histamine group versus the saline group. Data represent mean ± SD. IN, intranasal

Fig. 5

Effect of IN Epinephrine on Epinephrine Pharmacokinetics After IN Histamine or Saline. While there were no statistically significant differences in Cmax and AUC_1–90 between groups, there was a significantly shorter T_max with the histamine versus saline group. The reported C_max and T_max, values were calculated using post-dose baseline-subtracted epinephrine concentrations for each dog, and the AUC_1–90 was calculated using the trapezoid rule. Plasma concentration vs time data were first analyzed for each individual dog, and then PK parameters were averaged from individual dogs within each group. Data represent mean ± SD. *p < 0.05. AUC_1–90, area under plasma concentration-time curve from 1 to 90 min; C_max, maximum concentration; IN, intranasal; PK, pharmacokinetics; T_max, time to reach maximum concentration

Fig. 6

Effect of IN Epinephrine on Heart Rate After IN Histamine or Saline. Mean heart rate immediately increased after IN histamine versus IN saline administration. At 5 min after IN epinephrine delivery, mean heart rate increased in the histamine group, and remained near baseline levels in the saline group. Elevations in heart rate were maintained in the histamine group, and occurred in the saline group at 60 min, and then maintained for the duration of the study. Data represent mean ± SD. bpm, beats per minute, IN, intranasal