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Albuterol (Albuterol Sulfate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Albuterol tablets contain albuterol sulfate, USP, the racemic form of albuterol and a relatively selective beta2-adrenergic bronchodilator. Albuterol sulfate has the chemical name α1-[(tert-Butylamino)methyl]-4-hydroxy-m-xylene-α,α'-diol sulfate (2:1) (salt) and the following structural formula:

Albuterol sulfate has a molecular weight of 576.71, and the molecular formula is (C13H21NO3)2•H2SO4. Albuterol sulfate is a white or practically white powder, freely soluble in water and slightly soluble in ethanol.

The World Health Organization recommended name for albuterol base is salbutamol.

Each albuterol tablet for oral administration contains 2 or 4 mg of albuterol as 2.4 or 4.8 mg of albuterol sulfate, respectively. Each tablet also contains the following inactive ingredients: lactose (hydrous), magnesium stearate, pregelatinized (corn) starch and sodium lauryl sulfate.

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 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 (see WARNINGS).

The pharmacologic effects of beta-adrenergic agonist drugs, including albuterol, are at least in part attributable to stimulation through beta-adrenergic receptors of 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% of the plasma concentrations. In structures outside the 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.

Pharmacokinetics

Albuterol is rapidly absorbed after oral administration of one 4 mg albuterol tablet in normal volunteers. Maximum plasma concentrations of about 18 ng/mL of albuterol are achieved within 2 hours, and the drug is eliminated with a half-life of about 5 hours.

In other studies, the analysis of urine samples of patients given 8 mg of tritiated albuterol orally showed that 76% 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.

Clinical Trials

In controlled clinical trials in patients with asthma, the onset of improvement in pulmonary function, as measured by maximum midexpiratory flow rate (MMEF), was 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, clinically significant improvement (defined as maintaining a 15% or more increase in forced expiratory volume in 1 second [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. No decrease in the effectiveness of albuterol tablets was reported in patients who received long-term treatment with the drug in uncontrolled studies for periods up to 6 months.

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