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CLINICAL PHARMACOLOGY

In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, data indicates that there is a population of beta2-receptors in the human heart existing in a concentration between 10% and 50%. The precise function of these receptors has not been established. (See WARNINGS).

The pharmacologic effects of beta-adrenergic agonist drugs, including albuterol, are at least in part attributable to stimulation through beta-adrenergic receptors on intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3', 5'-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.

Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects.

Albuterol is longer acting than isoproterenol in most patients by any route of administration because it is not a substrate for the cellular uptake processes for catecholamines nor for catechol-O-methyl transferase.

Preclinical:Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5.0% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those in the whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were administered concurrently. The clinical significance of these findings is unknown.

Pharmacokinetics and Disposition: In a single-dose study comparing one 8 mg albuterol extended-release tablet with two 4 mg immediate-release albuterol tablets, USP in 17 normal adult volunteers, the extent of availability of albuterol extended-release tablets was shown to be about 80% of albuterol tablets, USP with or without food. In addition, lower mean peak plasma concentration and longer time to reach the peak level were observed with albuterol extended-release tablets as compared with albuterol tablets, USP. The single-dose study results also showed that food decreases the rate of absorption of albuterol from albuterol extended-release tablets without altering the extent of bioavailability. In addition, the study indicated that food causes a more gradual increase in the fraction of the available dose absorbed from the extended-release formulation as compared with the fasting condition.

In another single-dose study in adults, 8 mg and 4 mg albuterol extended-release tablets were shown to deliver dose-proportional plasma concentrations in the fasting state. Definitive studies for the effect of food on 4 mg albuterol extended-release tablets have not been conducted. However, since food lowers the rate of absorption of 8 mg albuterol extended-release tablets, it is expected that food reduces the rate of absorption of 4 mg albuterol extended-release tablets also.

Albuterol extended-release tablets have been formulated to provide duration of action of up to 12 hours. In an 8-day, multiple-dose, crossover study, 15 normal adult male volunteers were given 8 mg albuterol extended-release tablets every 12 hours or 4 mg albuterol tablets, USP every 6 hours. Each dose of albuterol extended-release tablets and the corresponding doses of albuterol tablets, USP were administered in the postprandial state. Steady-state plasma concentrations were reached within 2 days for both formulations. Fluctuations (Cmax-Cmin/Caverage) in plasma concentrations were similar for albuterol extended-release tablets administered at 12-hour intervals and albuterol tablets, USP administered every 6 hours. In addition, the relative bioavailability of albuterol extended-release tablets was approximately 100% of the immediate-release tablet at steady state. A summary of these results is shown in the following table:

Mean Values at Steady State

  Cmax
(ng/mL)
Cmin
(ng/mL)
Tmax
(h)
T1/2
(h)
AUC
(ng·h/mL)
Albuterol Extended-Release Tablets 13.7 8.1 6.0 9.3 134
Albuterol Tablets, USP 13.9 8.1 2.6 7.2 132

The mean plasma albuterol concentration versus time data at steady state after the administration of albuterol extended-release tablets 8 mg every 12 hours are displayed in the following graph:

Mean Plasma Albuterol Concentration at Day 8

Mean Plasma Albuterol Concentration at Day 8 - Illustration

Pharmacokinetic studies of 4- and 8-mg albuterol extended-release tablets have not been conducted in pediatric patients. Bioavailability of 4- and 8-mg albuterol extended-release tablets in pediatric patients relative to 2- and 4-mg immediate release albuterol has been extrapolated from adult studies showing comparability at steady-state dosing and reduced bioavailability after single dose administration.

Last reviewed on RxList: 8/8/2008
This monograph has been modified to include the generic and brand name in many instances.

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