P2Adrenoceptor Agonists

Asthma Free Forever

Asthma Free Forever By Jerry Ericson

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Drugs acting at ^-adrenoceptors are the most common group of agents used in the treatment of asthma and other related respiratory diseases. Although several drugs in this group, such as isoproterenol and salbutamol, have been used for many years in the symptomatic treatment of bronchospasms, recent research has focused on the use of b2-adrenergic stimulants as prophylactic drugs because of their ability to inhibit the release of spasmogens and inflammagens from human mast cells; in fact, short-acting b2-agonists represent an important treatment for the relief of asthma symptoms [33]. Furthermore, asthmatics patients are known to have greater response to bronchodilators than do patients of chronic obstructive pulmonary disease [34].

Early structure-activity studies designed to provide selective b2-receptor drug-binding clearly established the value of N-substitution for enhancing the b2 selectivity of norepinephrine analogues [35], and subsequent work also highlighted the importance of uptake mechanisms and biotransformation by catechol-o-methyltransferase (COMT) in the metabolic inactivation of both natural and synthetic catecholamines [36]. These advances have led to the development of potent, b2 selective bronchodilators, which, when administered by inhalation aerosols, are practically devoid of any major side effects. However, it is generally accepted that aerosol administration of such drugs generally leads to deposition at sites other than the target receptors. In addition, it may be appropriate, for example, in the case of an acute asthmatic attack to attain a rapid, prolonged, and effective concentration of the drug at the desired receptor site. Unfortunately, in this respect, relatively little progress has been made in establishing the regional distribution of b2-receptors in the lung. Autoradiographic studies in human lung [37] indicated that b2-receptors are located in smooth muscle from the large and small airways, with a greater population in bronchioli than in bronchi. High densities of receptors were also observed in airway epithelial cells and in bronchial submucosal glands, from the large bronchi to the terminal bronchioli. b2-receptors appear to be most highly concentrated in the alveolar wall; however, the physiological role of such receptors is not clear.

Recent examples of drugs that exhibit improved affinity for exoreceptor binding in the lung have been reported. The drug salmeterol (6) was developed from molecular modification of salbutamol (4) [38], and represents a b2-receptor stimulant with high exoreceptor affinity in order to persist in the vicinity of the b2-receptors in the respiratory tract. Salmeterol given by inhalation has a markedly prolonged bronchodilatory effect compared to salbutamol, exhibiting sustained bronchodilation over a 12-hour period, with no tachyphylaxis after nine days of treatment [39].

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