Beta Adrenergic Agonists

Beta adrenergic agonists and theophylline are the principal bronchodilators employed in the treatment of bronchial asthma. During the last decade, the clinical usefulness of theophylline has been enhanced by the availability of serum theophylline determinations and sustained release formulations. Beta adrenergic bronchodilators were initially somewhat eclipsed in the United States by these improvements in theophylline therapy. Now, however, with the introduction of selective and long lasting adrenergic agents, appreciation of their role in the treatment of bronchial asthma is increasing. Selection of the appropriate adrenergic bronchodilators is more complex than the use of theophylline because of the greater variety of available agents and routes of administration, because of the special problems related to proper techniques of aerosol therapy, and because of the development of beta adrenergic tolerance or subsensitivity.

Recognition of receptors with differing sensitivity to the naturally-occurring catecholamines began with Alquist in 1948. He identified alpha receptors which mediate predominantly excitatory responses and beta receptors which mediate primarily inhibitory responses. Lands in 1967 further separated the beta receptors on the basis of their relative responsiveness to epinephrine and norepinephrine into betax, modulating excitatory responses of the heart and adipose tissue, and betas mediating the inhibitory responses which include not only relaxation of bronchial, vascular and uterine smooth muscle, but also inhibition of secretory activity of a variety of cells including histamine release from mast cells, antibody production by lymphocytes and enzyme release by polymorphonuclear leukocytes.


The response to beta adrenergic stimulation is mediated by three distinct structural units in the cell membrane. First is a receptor with specificity of either the beta! or betas type. Upon occupation of this receptor by an agonist, interaction with a quanine nucleotide-sensitive regulator protein occurs. This combination then activates the third component, adenylate cyclase, which converts ATP to cyclic 3’5’adenosine monophosphate (cAMP) which in turn modulates most of the beta adrenergic responses.

Epinephrine was first used as a bronchodilator in 1910, followed in 1924 by the introduction of ephedrine into Western medicine (other popular bronchodilators). In 1941, with the introduction of isoproterenol, a drug free of alpha-adrenergic stimulating properties, began the systematic development of adrenergic bronchodilators with selective and long lasting effects (Fig 1). Changes in the isoproterenol structure involved one of two approaches. First was modification in the catechol nucleus which consists of a phenolic ring with hydroxyl groups in the 3 and 4 position. By either changing the position of the hydroxyl groups to the third and fifth carbons or by substituting another chemical group for the hydroxyl on the third carbon, the compound is no longer a catecholamine and, therefore, no longer susceptible to degradation by the enzyme catechol-O-methyl-transferase (COMT). Increased selectivity for the betas receptor can be achieved by increasing the size of the side chain adjacent to the nitrogen atom. Increasing the bulk in this position also makes the drug resistant to degradation by monoamine-oxidase (MAO) and further prolongs its action.

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Figure 1. The structural relationships of the adrenergic bron-chodilators.