Beta-Adrenergic Agonists

All the important sympathomimetic bronchodilators are either catecholamines or related compounds. Epinephrine, a natural adrenal gland hormone and neurotransmitter, is the prototype drug. Sympathomimetic drugs have been used since antiquity. For more than 5000 years the Chinese used Ma Huang, which was derived from the plant Ephedra equisetina. In 1926, Chen and Schmidt described the active constituent, ephedrine. Epinephrine entered the picture in 1900 when SolisCohen wrote "The Use of Adrenal Substance in the Treatment of Asthma. " The adrenal substance was available initially only as tablets of the desiccated gland, until Takamine isolated a benzoyl derivative from purified adrenal extract. This "adrenaline" was found to be identical to the compound "epinephrine. " The naturally occurring catecholamines—epinephrine, nonepinephrine, and dopamine—are synthesized by decarboxylation and hydroxlation of tyrosine in the neuroendocrine cells. After synthesis, catecholamines are stored in vesicles in the synaptic end of the neurons of adrenergic nerves or in the adrenal medulla. Extensive investigations have elucidated the physiologic properties and led to the development of highly efficacious synthetic analogues that have great therapeutic value. These synthetic compounds differ in chemical structure, absorption, and metabolism, but their fundamental action is the same. When administered in sufficient quantity by the appropriate route, they relieve smooth muscle constriction, facilitate mucociliary transport, activate ion pumps within the airways, and downregulate the release of mast cell contents. After release, catecholamines can react with the adrenergic receptor on target cells, can reenter the storage vesicles, or can enter cells and be metabolized by catecholamine O-methyl transferase (COMT) to an inactive compound. Most catecholamines are cleared rapidly by reentering the storage vesicles of the nerve ending. This accounts for their short duration of action. After methylation at the 3-hydroxy position by sulfatase in the gut, catecholamines become inactive. Smooth muscle extends from the trachea to the alveolar ducts and is under the control of the autonomic nervous system. Vagal innervation (parasympathetic) down to the terminal bronchiole is well proved, but evidence is lacking for direct sympathetic innervation of bronchial smooth muscle in man. However, there is excellent evidence for the presence of adrenoreceptors in bronchial smooth muscle. In 1948, Ahlquist proposed that adrenoreceptors be classified as alpha-receptors and beta-receptors. By studying the order of potency of a series of agonist drugs, he demonstrated that for tissue responses, which he termed "alpha," order of potency was epinephrine > norepinephrine > isoproterenol. For "beta" responses, the order of potency was isoproterenol > epinephrine > norepinephrine. Beta-receptors predominate in bronchial smooth muscle. The presence of alphareceptors has been demonstrated, but only following beta-blockade. Beta-adrenoreceptors were further subdivided into beta1and beta2-receptors by Lands and associates. The concept of beta1and beta2-receptors has been supported by the development of specific beta1 and beta2-adrenoreceptor antagonists and selective beta2-agonist agents with minimal beta1-mediated side effects. The major effects of stimulating the alphaand beta-receptor groups in man are summarized in Table 1. When used in treatment of asthma, the therapeutic effect of epinephrine-related compounds is due to principally three factors: bronchodilation effect, facilitation of mucociliary clearance, and anti-inflammatory effect via inhibition of mediator release. Patients claim that bronchodilators, administered either by aerosol or oral route, facilitate