The phenylephrine concentration-response relationship for blood pressure after nasal delivery in children

Autor: Kenneth E. Johnson, Lisa K. Christensen, Brian J. Anderson, Valerie E. Armstead, David P. Bilyeu, Robert H. Friesen
Rok vydání: 2017
Předmět:
Zdroj: Pediatric Anesthesia. 27:1050-1055
ISSN: 1155-5645
DOI: 10.1111/pan.13221
Popis: SummaryBackground Intranasal phenylephrine is commonly used to vasoconstrict the nasal mucosa, reducing bleeding associated with nasotracheal intubation or endoscopic sinus surgery. There are few data quantifying either absorption pharmacokinetics or phenylephrine concentration effect on blood pressure in children. Methods Published observations of plasma concentration and blood pressure changes after phenylephrine nasal administration (0.1 mL kg−1, 0.25% or 0.5%) in children (n = 52, 2-12 years, 10-40 kg) were pooled with those in adults (23-81 years) given phenylephrine 2.5% (n = 10) and 10% (n = 10) eyedrops. Further pharmacokinetic (PK) data were available from healthy volunteers given oral phenylephrine 10 mg alone, with blood for concentration assay taken at 5, 15, 30, 45 minutes and 1, 2, 3, 6 hours (n = 28). Intravenous time-concentration data were available from four healthy volunteers given phenylephrine 1 mg and who had blood taken for assay on 17 occasions over the subsequent 4 hours. Data were analyzed using an integrated pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed-effects models. Allometry, scaled to a 70-kg person, was used for PK size standardization. Effect was described using an EMAX model. Results A two-compartment model was used to fit PK data while an additional compartment, linked by an equilibration half-time (T1/2keo), was used to describe effect. PK parameter estimates for the nasal formulation were clearance (CL) 160 L h−1, central volume of distribution (V1) 13.3 L, intercompartment clearance (Q) 25.3 L h−1, peripheral volume of distribution (V2) 225 L, absorption half-time (Tabs) 6.2 minutes, absorption lag time (Tlag) 1.5 minutes, and bioavailability (F) 0.183. Bioavailability and absorption of the ophthalmic solution were concentration dependent (F 0.13, Tabs 5.5 minutes for 2.5% solution; F 0.15, Tabs 9.6 minutes for 10% solution). Absorption of the oral formulation was slow (Tabs 48 minutes) with poor bioavailability (F 0.0128). The pediatric PD interrogation revealed a baseline mean arterial pressure of 60 mm Hg, a maximum effect (EMAX) of 25 mm Hg, and an EC50 of 10.3 μg L−1. The effect on vasculature was immediate and T1/2keo was not estimable. Conclusion Absorption of phenylephrine through the nasal mucosa was rapid and similar to the ophthalmic formulation. Bioavailability was also similar to the ophthalmic formulation. The maximum effect (EMAX) in children was half that in adults (EMAX 50 mm Hg).
Databáze: OpenAIRE
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