ADVERSE EFFECTS OF INHALED GLUCOCORTICOIDS

Abstract

Inhaled glucocorticoid (IGC) therapy offers the potential of controlling asthma without the side effects consistently associated with systemic glucocorticoids (GCs) by delivering an efficacious topical dose with minimal systemic absorption. There is no evidence that the GC cytosol receptor differs in the various cells of the body. Therefore, any absorption of IGC has the potential to adversely affect other tissues. The determinants of systemic effects depend on the dose and potency of the respective IGC, first-pass clearance by the liver of the absorbed swallowed component, local lung metabolism, GC-receptor affinity, lipid solubility, and tissue half-life. The delivery system must also be considered, because systemic absorption will vary when the same dose of a given IGC is delivered by nebulizer, powered metered dose inhaler (pMDI) with hydrofluorocarbon propellant, pMDI with hydrofluoroalkane propellant, and pMDI with spacer or dry-powder inhaler. Comparisons of side effects among the various IGCs cannot be separated from comparisons of efficacy, because side effects will probably occur with any IGC if the dose is sufficiently large (Fig. 1). Controlled studies comparing IGCs dosed at equivalent clinical efficacy are an ideal that, for the most part, has not been realized. Thus, data for accurate comparisons are lacking. Most published studies provide data for beclomethasone dipropionate (BDP), budesonide (BUD), and fluticasone (FLU), with limited information for flunisolide and triamcinolone. 67 In addition to the variability among the IGCs, assessment of IGC adverse effects is confounded by the difficulty of designing and performing side-effect studies. The adverse effects of IGCs are time-dependent, which makes prospective studies longer, more expensive, and complex. Noncontroversial means of measuring the potential side effects are generally either not available or not acceptable. Very sensitive assays identify more side effects, but these observations may not be clinically relevant. Previous or intermittent systemic GC therapy may confound observations. Asthma, as a primary disease process, influences some of the physiologic functions attributed to IGCs, so studies must include groups of patients matched for severity and chronicity of asthma. Finally, the sensitivity for IGC side effects varies among different populations and among different members of the populations. Thus, although mean data may not demonstrate risk, individual patients may nevertheless experience side effects. Possible reasons for the variability within and among populations include pharmacokinetic factors, such as absorption and clearance differences, variable GC–steroid receptor affinities, and differing tissue susceptibilities caused by pre-existing risk factors for a given side effect. Factors influencing the occurrence of systemic side effects with IGCs include •Properties of the IGC •Dose, duration and frequency of administration •Delivery system and technique •Pharmacokinetic factors Absorption from lung and gastrointestinal tract Clearance rate Cytosol steroid receptor affinity •Patient factors Age Gender Severity of asthma Topical side effects of IGCs include hoarseness, taste perversion, dysphonia, and oropharyngeal candidiasis. These are not discussed in this artic le. These side effects tend to be relatively mild and are generally improved by the use of a spacer, mouth rinsing, or reduction of dosing frequency. Occasionally, patients find these problems to be sufficiently severe to discontinue the use of IGC. There is no convincing evidence that IGCs increase infections other than pharyngeal candidiasis. One cross-sectional study in a population with a relatively high prevalence of pulmonary tuberculosis showed an increase in active disease among users of IGCs. 79 This finding has not been confirmed. Severe varicella infection has been reported, but it is rare in patients receiving nasal IGCs. 1 Although advisory bodies have recommended caution if varicella occurs in a patient using IGCs and suggest discontinuation of therapy or use of gamma globulin, 22 adverse outcomes from IGC use have not been reported in these patients. 65 The side effects of IGCs discussed in this article are hypothalamic-pituitary-adrenal (HPA) axis suppression, growth suppression, osteoporosis, ocular complications, and dermal thinning and bruising.