Dose Response to Inhaled Corticosteroids: Benefits and Risks

 

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Abstract

The therapeutic ratio for inhaled corticosteroid therapy is determined by the relative dose-response relationships for anti-asthmatic clinical efficacy and systemic adverse effects. In patients with mild to moderate asthma the steep part of the curve for clinical efficacy occurs at doses less than 0.8mg/day, with their being minimal evidence of systemic bioactivity at such doses. There may be sometimes further benefit in more severe asthmatics at doses above 0.8mg/day, although this is usually associated with the steep part of the curve for systemic adverse effects. The threshold dose above which the therapeutic ratio begins to decline will depend on the severity of asthma and individual glucocorticoid receptor sensitivity, and the particular pharmacological and pharmacokinetic properties of the drug. Each patient will therefore exhibit their own individual curve for the benefit to risk ratio with a given inhaled corticosteroid. The same relationships apply to children albeit at lower doses, with a watershed in the benefit to risk occurring above 0.4mg/day in the majority of cases. When comparing different inhaled corticosteroids, it is important to consider the unique interaction between the drug and the inhaler device, as the lung dose will determine both clinical efficacy and systemic bioactivity. Higher potency compounds such as fluticasone propionate may result in improved clinical efficacy, although this may be accompanied by a commensurate increase in systemic activity. Doseresponse data from meta-analysis shows that even when allowing for differences in potency, there is an excess of systemic activity with fluticasone propionate compared with other inhaled corticosteroids in terms of comparing therapeutically equivalent doses. Dose-response studies to simultaneously evaluate anti-asthmatic efficacy and systemic activity are required in order to properly evaluate the relative therapeutic ratios of the different available inhaled corticosteroids. There are also dose-related effects on bone metabolism using surrogate biochemical markers. Bone density measurements suggest an increased risk of osteoporosis and bone fracture related to cumulative exposure in susceptible patients receiving high-dose inhaled corticosteroid therapy. There is also evidence of a long-term accumulative effect for the development of posterior subcapsular cataracts. Bruising in the skin is a visible sign of increased collagen turnover that should prompt screening for other tissue-specific adverse effects. Growth should always be measured in any asthmatic child because it may be influenced by the disease process itself as well as by the exogenous corticosteroid therapy. Most of the available evidence, however, suggests that the catch-up phase after the pubertal growth spurt usually results in normal or near normal adult height. In underprivileged groups the combination of suboptimal asthma control and poor nutritional status are probably more important determinants of impaired growth than any putative effects of inhaled corticosteroid therapy. There is good evidence to show that inhaled corticosteroids, even at high dosage, exhibit a better therapeutic ratio than that of maintenance oral corticosteroid therapy. For patients who require persistently high doses of inhaled corticosteroid, however, regular annual or biennial checks should be made for effects on skin, eye, adrenal gland, bone, and growth. Alternative nonsteroidal treatment modalities such as long-acting β₂-agonists, theophyllines, cromones, or antileukotrienes should be considered as a way of facilitating the use of lower doses of inhaled corticosteroid. The physician should always be aware of the potential for dose-related systemic effects and therefore strive to identify the lowest possible maintenance dose of inhaled corticosteroid because this will result in the smallest risk for long-term systemic effects.