The pharmacokinetics of epinephrine/adrenaline autoinjectors

Abstract

Background: For a century, epinephrine has been the drug of choice for acute treatment of systemic allergic reactions/anaphylaxis. For 40 years, autoinjectors have been used for the treatment of anaphylaxis. Over the last 20 years, intramuscular epinephrine injected into the thigh has been recommended for optimal effect.

Objective: To review the literature on pharmacokinetics of epinephrine autoinjectors.

Results: Six studies assessing epinephrine autoinjector pharmacokinetics were identified. The studies, all on healthy volunteers, were completed by Simons, Edwards, Duvauchelle, Worm and Turner over the span of 2 decades. Simons et al. published two small studies that suggested that intramuscular injection was superior to subcutaneous injection. These findings were partially supported by Duvauchelle. Duvauchelle showed a proportional increase in C_max and AUC_0-20 when increasing the dose from 0.3 to 0.5 mg epinephrine intramuscularly. Turner confirmed these findings. Simons, Edwards and Duvauchelle documented the impact of epinephrine on heart rate and blood pressure. Turner confirmed a dose-dependent increase in heart rate, cardiac output and stroke volume. Based on limited data, confirmed intramuscular injections appeared to lead to faster C_max. Two discernable C_max's were identified in most of the studies. We identified similarities and discrepancies in a number of variables in the aforementioned studies.

Conclusions: Intramuscular injection with higher doses of epinephrine appears to lead to a higher C_max. There is a dose dependent increase in plasma concentration and AUC_0-20. Most investigators found two C_max's with T_max 5-10 min and 30-50 min, respectively. There is a need for conclusive trials to evaluate the differences between intramuscular and subcutaneous injections with the epinephrine delivery site confirmed with ultrasound.

Keywords: Area under the curve (AUC); Autoinjector; Cmax; Epinephrine; Intramuscular; Pharmacokinetics; Pre-filled syringe; Subcutaneous; Tmax.

Fig. 1

The group mean epinephrine plasma concentrations after injection of epinephrine: Injection with syringe and 1 inch needle in normal adult men, 0.3 mg green broken line, and 0.5 mg, green line, both with C_max1 at T_max1 5 min. Injection with high pressure epinephrine autoinjector, Anapen^®, in normal adult men, 0.3 mg black line with C_max1 at T_max1 5 min and in obese adult women red line with C_max1 at T_max1 15 min. Ten of 12 women received subcutaneous injection Modified after Duvauchelle et al. [11]