Pharmacologic management of asthma

Abstract

Therapy for asthma has largely been focused on the end-organ effect of bronchoconstriction on airway smooth muscle. Xanthine derivatives such as theophylline were the initial oral bronchodilators used to manage asthma. Recent therapies directed at airway smooth muscle relaxation promote bronchodilation through stimulation of the b-adrenoreceptor. 1 The pharmacologic evolution of b-adrenergic agonists has led to the development of airway smooth muscle receptor‐specific agents, agents that can be administered topically through aerosol inhalation, and agents that are long lasting. Epidemiologic studies have validated the safety of the long-acting b-adrenoreceptor drugs and established that tachyphylaxis, as measured by the direct bronchodilating effect of these agents after repeated use, is inconsequential. More recently, the focus of asthma therapy development has been on modification of the inflammatory component of this disorder. 2 Oral corticosteroids cause substantial improvement in objective measures of lung function, but these agents are associated with considerable toxicity. 3, 4 The development of potent, highly lipidsoluble agents permits twice-daily dosage and may lead to a reduction in oral corticosteroid use in patients with corticosteroid-dependent asthma. Furthermore, inhaled corticosteroids provide an effective means of managing the pathology of inflammation with minimal adverse effects. With the enhanced understanding of asthma pathophysiology, drugs now are being designed to act against different steps in the inflammatory process. Newer agents include those directed at antagonizing the effects of leukotrienes that are secreted from inflammatory cells. These include two classes: 5-lipoxygenase inhibitors and leukotriene receptor antagonists. A number of other therapies are currently in development. Some of these interventions (e.g., monoclonal antibodies) prevent adhesion of inflammatory cells to vascular endothelium in conducting airways. Other mechanisms of action of investigational agents include modification of Thelper (TH2) cell interactions that trigger inflammatory activation, suppression of eosinophil development, and induction of eosinophil apoptosis in the bone marrow. PATHOPHYSIOLOGY