K.J. Simons

The effect of chronic administration of hydroxyzine on hydroxyzine pharmacokinetics in dogs

Subsensitivity to H1-receptor antagonists has been attributed to autoinduction of enzyme systems and increased clearance rates during chronic drug administration. We studied the changes in serum half-life values and clearance rates in dogs who were administered hydroxyzine, 0.7 mg/kg, intramuscularly, daily, for 150 days. Pharmacokinetic studies were performed on the first day of drug administration, and on days 30, 60, 90, 120, and 150. The mean serum half-life value on day 30, 60, and 120 was significantly longer (p less than 0.05) than that of 2.4 +/- 0.3 hours obtained on day 1. The mean clearance values obtained on days 30, 60, 90, 120, and 150 were significantly slower (p less than 0.05) than the value of 25.12 +/- 4.13 ml/min/kg obtained on day 1 but were not significantly different from each other. Mean serum hydroxyzine concentrations were often significantly higher on the later study days than on day 1. The mean apparent volume of distribution values obtained on days 30, 60, 90, 120, and 150 did not differ significantly from the value of 5.0 +/- 1.5 L/kg obtained on day 1. This study adds to the mounting evidence that subsensitivity to the effects of an H1-receptor antagonist is not due to autoinduction of enzyme systems, more rapid clearance of the drug, and lower concentrations of the drug in serum and tissue.

813 Can epinphrine inhalations by substituted for epinephrine injection in children at risk for systemic anaphylaxis

BACKGROUND For out-of-hospital treatment of anaphylaxis, inhalation of epinephrine from a pressurized metered-dose inhaler is sometimes recommended as a noninvasive, user-friendly alternative to an epinephrine injection. OBJECTIVE To determine the feasibility of administering an adequate epinephrine dose from a metered-dose inhaler in children at risk for anaphylaxis by assessing the rate and extent of epinephrine absorption after inhalation. METHODS We performed a prospective, randomized, observer-blind, placebo-controlled, parallel-group study in 19 asymptomatic children with a history of anaphylaxis. Based on the childs weight, 10, 15, or 20 carefully supervised epinephrine or placebo inhalations were attempted. Before dosing, and at intervals from 5 to 180 minutes after dosing, we monitored plasma epinephrine concentrations, blood glucose, heart rate, blood pressure, and adverse effects. RESULTS Eleven children (mean +/- standard error of the mean: 9 +/- 1 years and 33 +/- 3 kg) in the epinephrine group were able to inhale 11 +/- 2 (range: 3-20) puffs, equivalent to 74% +/- 7% of the precalculated dose or 0.078 +/- 0.009 mg/kg. They achieved a mean peak plasma epinephrine concentration of 1822 +/- 413 (range: 230-4518) pg/mL at 32.7 +/- 6.2 minutes. Eight children (10 +/- 1 years of age and 33 +/- 5 kg) in the placebo group were able to inhale 12 +/- 2 (range: 8-20) puffs, 89% +/- 3% of the precalculated dose, and had a peak endogenous plasma epinephrine concentration of 1316 +/- 247 (range: 522-2687) pg/mL at 44.4 +/- 16.7 minutes. In the children receiving epinephrine compared with those receiving placebo, mean plasma epinephrine concentrations were not significantly higher at any time, mean blood glucose concentrations were significantly higher from 10 to 30 minutes, mean heart rate was not significantly different at any time, and mean systolic and diastolic blood pressures were not significantly increased at most times. After the inhalations of epinephrine or placebo, the children complained of bad taste and many experienced cough or dizziness. After inhaling epinephrine, 1 child developed nausea, pallor, and muscle twitching. CONCLUSIONS Despite expert coaching, because of the number of epinephrine inhalations required and the bad taste of the inhalations, most children were unable to inhale sufficient epinephrine to increase their plasma epinephrine concentrations promptly and significantly. Therefore, we urge caution in recommending epinephrine inhalation as a substitute for epinephrine injection for out-of-hospital treatment of anaphylaxis symptoms in children.