Drugs Used in Asthma
The word asthma is derived from a Greek word meaning difficulty in breathing. The clinical expression of asthma varies from a mild intermittent wheeze or cough to severe chronic obstruction that can restrict normal activity. Acute asthma attacks are triggered by a variety of stimuli, including exposure to allergens or cold air, exercise, and upper respiratory tract infections. Recently, a number of genetic polymorphisms have been associated with an increased risk of developing asthma. Thus, genetic factors probably contribute to the exaggerated response of the asthmatic airway to various environmental challenges. The most severe exacerba-tion of asthma, status asthmaticus, is a life-threatening condition that requires hospitalization and must be treated aggressively. Unlike most exacerbations of the disease, status asthmaticus is by definition unresponsive to standard therapy.
The most important outcomes for successful therapy of asthma are as follows:
· Prevent chronic and troublesome symptoms
· Maintain (near) normal pulmonary function
· Maintain normal activity levels
· Prevent recurrent exacerbations of asthma and minimize the need for emergency department visits or hospitalizations
· Provide optimal pharmacotherapy with mini-mal or no adverse effects
Asthma symptoms are produced by reversible narrow-ing of the airway, which increases resistance to airflow and consequently reduces the efficiency of movement of air to and from the alveoli. In addition to airway ob-struction, cardinal features of asthma include inflamma-tion and hyperreactivity of the airway. In contrast to chronic obstructive pulmonary disease (emphysema and chronic bronchitis), the airway obstruction associated with asthma is generally reversible. However, severe long-standing asthma changes the architecture of the airway. These changes, including smooth muscle hyper-trophy and bronchofibrosis, can lead to an irreversible decrement in pulmonary function. These structural changes are limited to the airways. The lung parenchyma is generally spared.
An aberrant immune response associated with al-lergy appears to underlie asthma in most children over age 3 years and in most young adults; allergy-induced asthma is also known as extrinsic asthma. In contrast, a large number of patients, especially those who acquire asthma as older adults, have no discernible immunolog-ical basis for their condition, although airway inflamma-tion remains a characteristic of the disease; this type of asthma is termed intrinsic asthma. Other patients may have both allergic and nonallergic forms of asthma.
Three factors contribute to airway obstruction in asthma: (1) contraction of the smooth muscle that sur-rounds the airways; (2) excessive secretion of mucus and in some, secretion of thick, tenacious mucus that ad-heres to the walls of the airways; and (3) edema of the respiratory mucosa. Spasm of the bronchial smooth muscle can occur rapidly in response to a provocative stimulus and likewise can be reversed rapidly by drug therapy. In contrast, respiratory mucus accumulation and edema formation are likely to require more time to develop and are only slowly reversible.
The recognition that asthma is a disease of airway in-flammation (Fig. 39.1) has fundamentally changed the manner in which the disease is treated.
Thus, it is useful to discuss the involvement of various mediators and in-flammatory cells in antigen-induced asthma, an exten-sively studied, albeit simplistic, model of the disease. In this model, antigens, such as ragweed pollen or house mite dust, sensitize individuals by eliciting the produc-tion of antibodies of the immunoglobulin (Ig) E type. These antibodies attach themselves to the surface of mast cells and basophils. If the individual is reexposed to the same antigen days to months later, the resulting antigen–antibody reaction on lung mast cells will trigger the release of histamine and the cysteinyl leukotrienes, agents that produce bronchoconstriction, mucus secre-tion, and pulmonary edema. Mast cells also release a va-riety of chemotactic mediators, such as leukotriene B4 and cytokines. These agents recruit and activate addi-tional inflammatory cells, particularly eosinophils and alveolar macrophages, both of which are also rich sources of leukotrienes and cytokines. Ultimately, re-peated exposure to antigen establishes a chronic inflam-matory state in the asthmatic airway.