The primary action of beta-adrenergic agonist drugs, including albuterol, is to stimulate adenyl cyclase, the enzyme which catalyzes the formation of cyclic-3',5'- adenosine monophosphate (cyclic AMP) from adenosine triphosphate (ATP) in beta-adrenergic cells. The cyclic AMP thus formed mediates the cellular responses. 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.
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 indicate 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.
In controlled clinical trials, albuterol has been shown 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. Controlled clinical studies and other clinical experience have shown that 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 ECG changes.
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.
Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% 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 are administered concurrently. The clinical significance of these findings is unknown.
Albuterol is rapidly and well absorbed following oral administration.
In studies involving normal volunteers, the mean steady-state peak and trough plasm levels of albuterol were 6.7 ng/mL and 3.8 ng/mL, respectively, following dosing with a 2 mg albuterol tablet every 6 hours and 14.8 ng/mL and 8.6 ng/mL, respectively following dosing with a 4 mg albuterol tablet every 6 hours. Maximum albuterol plasma levels are usually obtained between 2 and 3 hours after dosing, and the elimination half-life is 5 to 6 hours. These data indicate that albuterol administered orally is dose proportional and exhibits dose independent pharmacokinetics.
Albuterol extended-release tablets have been formulated to provide a duration of action of up to 12 hours. In studies conducted in normal volunteers, the mean steady-state peak and trough plasma levels of albuterol were 6.5 ng/mL and 3.0 ng/mL, respectively, following dosing with a 4 mg albuterol extended-release tablet every 12 hours. In addition, it has been shown that administration of a 4 mg albuterol extended-release tablets every 12 hours, and a 2 mg albuterol tablet every 6 hours for 5 days gave comparable peak albuterol levels and similar extent of absorption at steady state.
In other studies, the analysis of urine samples of patients given tritiated albuterol (4 mg to 10 mg) orally showed that 65% to 90% of the dose was excreted over 3 days, with the majority of the dose being excreted within the first 24 hours. Sixty percent of this radioactivity was shown to be the metabolite. Feces collected over this period contained 4% of the administered dose.
In controlled clinical trials in patients with asthma, the onset of improvement in pulmonary function, as measured by maximum midexpiratory flow rate (MMEF), was noted within 30 minutes after a dose of albuterol tablets, with peak improvement occurring between 2 and 3 hours. In controlled clinical trials in which measurements were conducted for 6 hours, significant clinical improvement in pulmonary function (defined as maintaining a 15% or more increase in FEV1 and a 20% or more increase in MMEF over baseline values) was observed in 60% of patients at 4 hours and in 40% at 6 hours. In other single-dose, controlled clinical trials, clinically significant improvement was observed in at least 40% of the patients at 8 hours with the 4 mg albuterol tablet. No decrease in the effectiveness of albuterol tablets has been reported in patients who received long-term treatment with the drug in uncontrolled studies for periods up to 6 months.
In another controlled clinical study in asthmatic patients, it has been demonstrated that the initiation of therapy with either the 4 mg albuterol extended-release tablet dosed every 12 hours, or the 2 mg albuterol tablet dosed every 6 hours, achieve therapeutically comparable effects.
