Inhaled corticosteroid therapy for asthma: therapeutic and toxic potentials

Corticosteroids are an effective but potentially hazardous treatment for asthma. When only parenteral and oral forms, such as hydrocortisone, methylprednisolone, and prednisone, were available, the hazards were considered too great, except for patients with severe, unremitting asthma. Some of the hazards are immediately apparent, such as fluid retention, weight gain, mood alteration, insomnia, hypertension, and hyperglycemia. Others, such as cataracts, glaucoma, osteoporosis, and avascular necrosis of bone, take longer to appear but may not reverse when therapy is stopped. In pharmacological terms, the therapeutic ratio—the ratio of efficacy to toxicity— of systemic treatment with any of the available corticosteroids is unfavorable. The ratio changed in the early 1970s with the introduction of topically active corticosteroids that could be delivered by aerosol. By delivering a corticosteroid with high receptor affinity directly into the airways, the local activities responsible for clinical efficacy are preserved, and the systemic activities responsible for toxicity and side effects are greatly reduced. Proof of the profound reduction in systemic delivery of inhaled corticosteroids was provided by case reports of Addisonian crisis in patients in whom oral corticosteroids had been tapered too rapidly after inhaled beclomethasone was started. Evidence of the efficacy of inhaled corticosteroid therapy in asthma is now persuasive. Many double-blind, controlled trials have shown that it improves maximum expiratory flow and reduces symptoms, use of inhaled b-agonists, and the risk of hospitalization (1). Recent studies suggest that delay in initiating treatment with an inhaled corticosteroid may reduce the amount of potential improvement (2– 4). Early introduction of inhaled corticosteroids may prevent the development of tissue hyperplasia and fibrosis, or “remodeling,” of the airway wall that is now believed to lead to irreversible losses in pulmonary function in patients with asthma of many years’ duration (5,6). This evidence was considered so compelling that the 1997 revision of the National Asthma Education and Prevention Program’s Guidelines for the Diagnosis and Management of Asthma recommends regular therapy with an inhaled corticosteroid, even for patients with mild but persistent asthma (7). As described in the Guidelines, “mild persistent asthma” is mild indeed. Its features include any of the following: use of an inhaled b-agonist for relief of symptoms more than twice a week, exacerbations that interfere with activity, or waking from sleep more than twice a month. Most patients with asthma have a mild form of the disease, so broad implementation of this recommendation would greatly increase the number of patients regularly taking an inhaled corticosteroid. This heightens the importance of certainty that the treatment is safe. Until recently, this safety seemed assured. When given in standard doses, inhaled corticosteroids rarely, if ever, cause the acute toxicities commonly noted with oral therapy. Studies of morning plasma cortisol levels showed little evidence of adrenal suppression with doses of beclomethasone under 800 mg/day (8), and surveys of women who had taken inhaled corticosteroids for many years showed no loss in bone mineral density (9). But certainty over the safety of inhaled corticosteroid therapy has lately been shaken by reports of a weak but statistically significant association with cataracts and glaucoma in the elderly (10,11), and more impressively, with a reduction in the rate of growth of preadolescent children (12). The reduction in the rate of growth is small, however, and it is not clear whether the reduction in rate affects final height. Furthermore, all of the studies showing a reduction in growth rate examined inhaled beclomethasone dipropionate, which has lower first-pass hepatic metabolism than the newer agents, budesonide or fluticasone, and whose first metabolite— beclomethasone monopropionate—also has corticosteroid activity. A similar study of fluticasone failed to find a significant effect on growth (13). The reduction in the growth rate proves that there is a systemic effect from inhaled doses of beclomethasone that were previously thought to be entirely safe. Thus, inhaled corticosteroids in usual doses have the potential for both efficacy and toxicity. The key to their use, as for any drug, is choosing the dose that optimizes the therapeutic ratio. Calculating the therapeutic ratio is difficult when both efficacy and toxicity can only be measured over long peAm J Med 2000;108:338 –340. From the Cardiovascular Research Institute, Department of Medicine, University of California at San Francisco, San Francisco, California. Requests for reprints should be addressed to Homer A. Boushey, MD, University of California at San Francisco, 505 Parnassus Avenue, San Francisco, California 94143-0130.