xation.
Albuterol relaxes the smooth muscle of all airways, from the trachea to the terminal bronchioles. Albuterol acts as afunctional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against allbronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release ofmediators from mast cells in the airway. While it is recognized that beta2-adrenergic receptors are the predominant
receptors on bronchial smooth muscle, data indicate that there are beta-receptors in the human heart, 10% to 50% ofwhich are cardiac beta2-adrenergic receptors. The precise function of these receptors has not been established [seeWarnings and Precautions (5.4)].
Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form ofbronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects.
However, inhaled albuterol, like other beta-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients, as measured by pulse rate, blood pressure, symptoms, and/or electrocardiographic changes [see Warnings
and Precautions (5.4)].
12.2 Pharmacodynamics
In a pharmacodynamic (PD) trial conducted in 47 patients, the PD and safety profiles were similar for albuterol sulfateMDPI and ProAir HFA. Comparable changes from baseline in the PD measures (serum glucose and potassiumconcentrations, QTcB, QTcF, heart rate, systolic blood pressure, and diastolic blood pressure) were observed followingcumulative dose administration up to 1440 mcg of both albuterol sulfate MDPI and ProAir HFA. The overall safety,efficacy and PD profile of albuterol sulfate MDPI and ProAir HFA were comparable.
Following 90 or 180 mcg single-dose inhalation, the bronchodilatory effect of albuterol sulfate MDPI was significantlygreater than placebo and comparable to that of ProAir HFA in patients 12 years of age and older (N=71) and pediatricpatients 4 to 11 years of age (N=61) with persistent asthma.
Cardiac Electrophysiology
As with other beta2-adrenergic agonists, albuterol sulfate MDPI prolonged QT intervals following a 1440 mcg cumulativedose. The prolongation was comparable to that of ProAir HFA.
12.3 Pharmacokinetics
Absorption
Albuterol was rapidly absorbed into the systemic circulation with peak plasma concentrations occurring at half an hourfollowing single- or multiple-dose oral inhalation(s) of albuterol sulfate MDPI. In a cumulative dose study, the AUC0-twas comparable between albuterol sulfate MDPI group and ProAir HFA group; Cmax value was approximately one-thirdhigher in albuterol sulfate MDPI group than ProAir HFA group.
DistributionThe volume of distribution has not been determined for albuterol sulfate MDPI. Published literature suggests thatalbuterol exhibits low in vitro plasma protein binding (10%).
Elimination
The accumulation ratio (~1.6 fold) was observed following one week QID dosing. The corresponding effective half-lifewas approximately 5 hours, which was consistent with the elimination half-life following both single- or multiple-doseadministration.
Metabolism
Information available in the published literature suggests that the primary enzyme responsible for the metabolism ofalbuterol in humans is SULTIA3 (sulfotransferase). When racemic albuterol was administered either intravenously or viai |
