Beta adrenergic drugs are the most potent bronchodilators currently approved for clinical use in asthma and obstructive lung disease. Among the beta agonists, the individual agents vary in their rapidity of onset and duration of action. Inhaled, short-acting, selective beta-2 adrenergic agonists are the mainstay of acute asthma therapy, while inhaled, long-acting, selective beta-2 adrenergic agonists (in combination with inhaled glucocorticoids) play a role in long-term control of moderate to severe asthma.
The mechanism of action of beta adrenergic medications and their clinical use in the management of asthma will be reviewed here. The general approach to asthma management, the treatment of acute exacerbations of asthma, and an overview of the delivery of inhaled medications are discussed separately. (See "An overview of asthma management" and "Treatment of acute exacerbations of asthma in adults", section on 'Inhaled beta agonists' and "Delivery of inhaled medication in adults".)
MECHANISM OF ACTION
Beta agonists were developed through modifications of the epinephrine molecule to allow selective interaction with the beta-1 and beta-2 receptors (eg, isoproterenol), rather than the combined alpha and beta effects of epinephrine. Further modification allows selectivity for beta-2 receptors on bronchial smooth muscle to achieve bronchodilation without the tachycardia associated with activation of beta-1 receptors on cardiac muscle. Agents available by inhalation that are selective for the beta-2 adrenergic receptor (eg, albuterol, levalbuterol, salmeterol, formoterol) are preferred for asthma therapy compared with nonbeta-2 selective agents (eg, metaproterenol), because they provide equivalent bronchodilation with less cardiac stimulation . Isoproterenol, a nonselective beta agonist, is no longer used to treat asthma exacerbations, due to the better safety and duration of action profiles of other available medications.
The beta-2 receptor is a G protein-coupled transmembrane receptor that activates the enzyme adenylyl cyclase . Activation of adenylyl cyclase produces cyclic adenosine monophosphate (cAMP). The exact mechanism by which cAMP causes smooth muscle relaxation is not fully understood, but likely involves activation of protein kinase A and changes in intracellular calcium concentrations. Activation of the beta-2 receptor also affects potassium channels through a separate mechanism. The function of the beta-2 adrenergic receptor and the role of polymorphisms of the receptor in individual responses to beta agonists are discussed separately. (See "Beta-2 adrenergic receptor dysfunction and polymorphism in asthma".)
Variations in the molecular structure of beta agonists affect the onset and duration of bronchodilation. As an example, prolongation of the bronchodilator effect (relative to isoproterenol) is achieved by modifications that reduce susceptibility to degradation by catechol O-methyl transferase (COMT) and monoamine oxidase . In addition, the long, lipophilic side chains of formoterol and salmeterol attach to the plasma membrane and increase the duration of binding of the drugs to the adrenergic receptor. The lipophilic side chain of salmeterol leads to incorporation of the drug into the cell membrane and activation of the beta adrenergic receptor through an alternate binding site, rather than the usual site in the aqueous surface of the cell membrane . It is thought that accessing the alternate binding site deeper in the cell membrane slows the onset of action of salmeterol. In contrast, formoterol has a different lipophilic side chain and its onset of action is comparable to that of albuterol (also known as salbutamol).