In vitro studies and in vivo pharmacologic studies have demonstrated that Alupent® (metaproterenol sulfate USP) has a preferential effect on beta-2 adrenergic receptors compared with isoproterenol. While it is recognized that beta-2 adrenergic receptors are the predominant receptors in bronchial smooth muscle, recent data indicate that there is a population of beta-2 receptors in the human heart existing in a concentration between 10-50%. The precise function of these, however, is not yet established (See WARNINGS section).
The pharmacologic effects of beta adrenergic agonist drugs, including Alupent, are at least in part attributable to stimulation through beta adrenergic receptors of intracellular adenyl cyclase, the enzyme which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (c-AMP). Increased c-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.
Absorption, biotransformation and excretion studies in humans following administration by inhalation have shown that approximately 3 percent of the actuated dose is absorbed intact through the lungs. The major metabolite, metaproterenol-3-0-sulfate, is produced in the gastrointestinal tract. Alupent is not metabolized by catechol-0-methyltransferase nor have glucuronide conjugates been isolated to date.
Pulmonary function tests performed concomitantly usually show improvement following aerosol Alupent administration, e.g. an increase in the one-second forced expiratory volume (FEV1) maximum expiratory flow rate, forced vital capacity, and/or a decrease in airway resistance. The resultant decrease in airway obstruction may relieve the dyspnea associated with bronchospasm.
Controlled single- and multiple-dose studies have been performed with pulmonary function monitoring. The duration of effect of a single dose of two to three inhalations of Alupent (that is, the period of time during which there is a 20 percent or greater increase in FEV1) has varied from 1 to 5 hours.
In repetitive-dosing studies (up to q.i.d.) the duration of effect for a similar dose of Alupent has ranged from about 1 to 2.5 hours. Present studies are inadequate to explain the divergence in duration of the FEV1 effect between single- and repetitive-dosing studies, respectively.
Recent studies in laboratory animals (minipigs, rodents and dogs) recorded the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta agonists and methylxanthines were administered concurrently. The significance of these findings when applied to humans is currently unknown.