Combivent - Clinical Pharmacology

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Ventilation/ perfusion studies have shown no clinically significant effects on pulmonary gas exchange or arterial oxygen tension. At recommended doses, ipratropium bromide does not produce clinically significant changes in pulse rate or blood pressure.

Albuterol Sulfate:

Mechanism of Action

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 beta 2 -adrenergic receptors are the predominant receptors on bronchial smooth muscle, recent data indicate that there is a population of beta 2 -receptors in the human heart which comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors, however, is not yet established (See WARNINGS).

Activation of beta 2 -adrenergic receptors on airway smooth muscle leads to the activation of adenylyl cyclase and to an increase in the intracellular concentration of cyclic-3', 5'-adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation.

Albuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway.

Albuterol has been shown in most clinical trials to have more bronchial smooth muscle relaxation effect than isoproterenol at comparable doses while producing fewer cardiovascular effects. However, all beta-adrenergic drugs, including albuterol sulfate, can produce a significant cardiovascular effect in some patients (See PRECAUTIONS).

Pharmacokinetics

Albuterol is longer acting than isoproterenol in most patients because it is not a substrate for the cellular uptake processes for catecholamines nor for metabolism by catechol-0-methyl transferase. Instead, the drug is conjugatively metabolized to albuterol 4'-0-sulfate. In a pharmacokinetic study in 12 healthy male volunteers of two inhalations of albuterol sulfate, 103 mcg dose/ inhalation through the mouthpiece, peak plasma albuterol concentrations ranging from 419 to 802 pg/ mL (mean 599 ± 122 pg/ mL) were obtained within three hours post-administration.