The medical and scientific communities have recog-nized that asthma is not simply a disease marked by acute bronchospasm but rather a complex chronic in-flammatory disorder of the airways. On the basis of this knowledge, antiinflammatory agents, particularly corti-costeroids, are now included in the treatment regimens of an ever-increasing proportion of asthmatic patients.
A major breakthrough in asthma therapy was the intro-duction in the 1970s of aerosol corticosteroids. These agents (Table 39.3) maintain much of the impressive therapeutic efficacy of parenteral and oral cortico-steroids, but by virtue of their local administration and markedly reduced systemic absorption, they are associ-ated with a greatly reduced incidence and severity of side effects. The success of inhaled steroids has led to a substantial reduction in the use of systemic cortico-steroids. Inhaled corticosteroids, along with β2-adreno-ceptor agonists, are front-line therapy of chronic asthma.
All corticosteroids have the same general mechanism of action; they traverse cell membranes and bind to a spe-cific cytoplasmic receptor. The steroid-receptor complex translocates to the cell nucleus, where it attaches to nu-clear binding sites and initiates synthesis of messenger ri-bonucleic acid (mRNA). The novel proteins that are formed may exert a variety of effects on cellular func-tions. The precise mechanisms whereby the cortico-steroids exert their therapeutic benefit in asthma remain unclear, although the benefit is likely to be due to several actions rather than one specific action and is related to their ability to inhibit inflammatory processes.At the mo-lecular level, corticosteroids regulate the transcription of a number of genes, including those for several cytokines.
The corticosteroids have an array of actions in sev-eral systems that may be relevant to their effectiveness in asthma. These include inhibition of cytokine and mediator release, attenuation of mucus secretion, up-regulation of β-adrenoceptor numbers, inhibition of IgE synthesis, attenuation of eicosanoid generation, de-creased microvascular permeability, and suppression of inflammatory cell influx and inflammatory processes. The effects of the steroids take several hours to days to develop, so they cannot be used for quick relief of acute episodes of bronchospasm.
The corticosteroids are effective in most children and adults with asthma. They are beneficial for the treat-ment of both acute and chronic aspects of the disease. Inhaled corticosteroids, including triamcinolone ace-tonide (Azmacort), beclomethasone dipropionate (Beclo-vent, Vanceril), flunisolide (AeroBid), and fluticasone (Flovent), are indicated for maintenance treatment of asthma as prophylactic therapy. Inhaled corticosteroids are not effective for relief of acute episodes of severe bronchospasm. Systemic corticosteroids, including pred-nisone and prednisolone, are used for the short-term treatment of asthma exacerbations that do not respond to β2-adrenoceptor agonists and aerosol corticosteroids. Systemic corticosteroids, along with other treatments, are also used to control status asthmaticus. Because of the side effects produced by systemically administered corticosteroids, they should not be used for maintenance therapy unless all other treatment options have been exhausted.
A fixed combination of inhaled fluticasone and sal-meterol (Advair) is available for maintenance antiin-flammatory and bronchodilator treatment of asthma.
The side effects of corticosteroids range from minor to severe and life threatening. The nature and severity of
side effects depend on the route, dose, and frequency of administration, as well as the specific agent used. Side effects are much more prevalent with systemic adminis-tration than with inhalant administration. The potential consequences of systemic administration of the corti-costeroids include adrenal suppression, cushingoid changes, growth retardation, cataracts, osteoporosis, CNS effects and behavioral disturbances, and increased susceptibility to infection. The severity of all of these side effects can be reduced markedly by alternate-day therapy.
Inhaled corticosteroids are generally well tolerated. In contrast to systemically administered corticosteroids, inhaled agents are either poorly absorbed or rapidly metabolized and inactivated and thus have greatly di-minished systemic effects relative to oral agents. The most frequent side effects are local; they include oral candidiasis, dysphonia, sore throat and throat irritation, and coughing. Special delivery systems (e.g., devices with spacers) can minimize these side effects. Some studies have associated slowing of growth in children with the use of high-dose inhaled corticosteroids, al-though the results are controversial. Regardless, the purported effect is small and is likely outweighed by the benefit of control of the symptoms of asthma.
Care should be taken in transferring patients from systemic to aerosol corticosteroids, as deaths due to ad-renal insufficiency have been reported. In addition, al-lergic conditions, such as rhinitis, conjunctivitis, and eczema, previously controlled by systemic corticos-teroids, may be unmasked when asthmatic patients are switched from systemic to inhaled corticosteroids. Caution should be exercised when taking cortico-steroids during pregnancy, as glucocorticoids are terato-genic. Systemic corticosteroids are contraindicated in patients with systemic fungal infections.