0
Editorials |

The Dull-Edged Sword of Inhaled Corticosteroids FREE TO VIEW

Susan M. Harding, MD, FCCP
Author and Funding Information

Affiliations: Birmingham, AL 
 ,  Associate Professor of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham.

Correspondence to: Susan M. Harding, MD, FCCP, Associate Professor of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, 1900 University Blvd, THT-Rm 215, Birmingham, AL 35294; e-mail: sharding@uab.edu



Chest. 1999;116(4):854-856. doi:10.1378/chest.116.4.854
Text Size: A A A
Published online

The pathobiology of asthma includes an inflammatory process, and asthma management with inhaled corticosteroids improves asthma control, pulmonary function, and quality of life, and decreases the number of asthma-related emergency room visits and hospitalizations.1 The administration of inhaled corticosteroids also reduces airway responsiveness with respect to methacholine challenge; prevents allergen-induced bronchoconstriction in atopic patients; and, when directly compared to leukotriene modifiers in patients with mild to moderate persistent asthma, results in a higher magnitude of improvement in FEV1.,12 At the cellular level, inhaled corticosteroids decrease the number and state of activation of eosinophils and lymphocytes, as evidenced in BAL and endobronchial biopsy specimens, and may alter epithelial basement membrane morphology in asthma patients. Inhaled corticosteroids have been used successfully for > 20 years, and their side-effect profile is favorable, especially when compared to the profile associated with oral corticosteroids.34 Inhaled corticosteroids are currently considered to be the foundation of asthma management.5The advent of higher-dose inhaled corticosteroids has “freed” many asthma patients from oral corticosteroids; however, inhaled corticosteroids, especially in higher doses, can be partially absorbed and can cause systemic consequences.6 These potential systemic consequences are the dull-edged sword of inhaled corticosteroids.

One potential systemic effect of inhaled corticosteroid therapy is the suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Normal cortisol secretion is diurnal in nature, and it occurs in approximately 10 bursts a day, subject to circadian and individual variations and to the sleep-wake cycle. In general, peak cortisol secretion occurs between 4:00 am and 8:00 am, with a nadir of secretion between 8:00 pm and 12:00 am.7

As presented in this issue of CHEST (see page 931), Weiner et al examined 28 patients with mild to moderate asthma who did not receive treatment with oral or inhaled corticosteroids for at least 3 months. The researchers measured the nocturnal cortisol secretion following the inhalation of a placebo (night 1), or a single 500-μg dose of fluticasone propionate by diskhaler (night 2) at 8:00 pm. When compared to the placebo, the inhalation of fluticasone propionate decreased the early morning rise in cortisol secretion, and nocturnal cortisol production was reduced by 29%. There was also a significant correlation between FEV1 values and cortisol production (R2 = 0.865), with subjects with a higher FEV1 having lower levels of nocturnal cortisol production. Dry powder inhalers, as used in the study by Weiner et al, utilize an inhalation technique that differs from conventional metered-dose inhalers. This drug delivery system could alter pulmonary drug deposition and systemic absorption.

Although the clinical significance of this observation is unclear (especially with the study design weakness of discontinuing cortisol measurements at 6:00 am), this study shows that even a single dose of inhaled fluticasone propionate, especially in patients with higher FEV1 values, disrupts the normal nocturnal cortisol secretion. Likewise, a study of 19 children with asthma found a dose-dependent suppression of the HPA axis caused by inhaled beclomethasone when examining nocturnal adrenal suppression.8The fluticasone propionate inhalation package insert states that dosages of 500 μg bid for 1 year resulted in abnormal responses to a 6-h cosyntropin infusion in 4% of subjects.9 Although further studies are needed to further clarify this issue, there are some interesting take-home points. (1) Patients with asthma should receive the lowest possible dose necessary of inhaled corticosteroids to control their asthma. The clinician should examine the possibility of tapering the inhaled corticosteroid dose or “stepping down” asthma therapy at every clinic visit, especially in patients with excellent pulmonary function. (2) Even the “new” generation of inhaled and dry powder inhaled corticosteroids have the potential for systemic absorption and side effects. Asthma patients, especially those with normal pulmonary function, may be more prone to the systemic absorption of the active drug. (3) Patients need to be educated about the potential for adrenal suppression when using inhaled corticosteroids, especially at higher doses, over a prolonged period of time. An estimation of the HPA axis suppression can be done using multiple methods, and each method has its own limitations. For instance, the measurement of plasma cortisol levels during insulin-induced hypoglycemia is the best test to evaluate the cortisol response to stress. However, this test is difficult to perform, and it carries a risk if not performed correctly, so this test is not commonly used in clinical practice. The corticotropin-releasing hormone (CRH) test measures plasma adrenocorticotropic hormone (ACTH) and cortisol responses to CRH by measuring the HPA axis function. However, this test is expensive and is not widely used. The metyrapone stimulation test measures the entire HPA axis, but may not give a good assessment of adrenal function during stress. Plasma or urinary-free cortisol does not measure HPA reserve and is not a good test to measure adrenal responsiveness to stress. The response of synthetic ACTH (cosyntropin) is generally the method preferred to assess adrenocortical function in asthma patients on corticosteroids; however, it may be normal in a patient with hypothalamic or pituitary insufficiency.,6 Previous studies10 in asthma patients have shown that even dosages of 1,000 μg/d of inhaled corticosteroids may alter circadian secretion when measuring serum cortisols over a 24-h period. (4) The combined use of leukotriene modifiers with inhaled corticosteroids may allow a reduction of the inhaled corticosteroid dose without precipitating asthma exacerbations. This combined approach may lessen the potential side effects of inhaled corticosteroids and may have an additive effect on asthma control. Future approaches to asthma therapy may include agents that modulate other cytokines, including interleukin-4 (IL-4) and IL-5.

Meanwhile, studies examining the effect of fluticasone propionate on the HPA axis should include a 24-h monitoring of cortisol production. Another important principle to consider in designing experiments involving chronotherapeutics and circadian rhythm effects of cortisol secretion is to examine the administration-time-dependent differences to the effects of the medication.11 Experiments using alternate dosing schedules, similar to the studies performed on oral corticosteroids, may improve asthma management, thus averting the “dull-edged sword.”

Dr. Harding currently does not receive grant funding or consulting fees from Glaxo Wellcome, Inc, manufacturer of Flovent Rotadisk (fluticasone propionate). She has previously received grant funding from Glaxo Wellcome, Inc, to examine the association between asthma and gastroesophageal reflux. She owns no stock in Glaxo Wellcome, Inc.

References

Juniper, E, Kline, P, Vanzieleghem, M, et al (1990) Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics.Am Rev Respir Dis142,832-836. [PubMed]
 
Drazen, JM, Israel, E, O’Byrne, PM Treatment of asthma with drugs modifying the leukotriene pathway.N Engl J Med1999;340,197-206. [PubMed] [CrossRef]
 
Djukanović, R, Wilson, JW, Britten, KM, et al Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma.Am Rev Respir Dis1992;145,669-674. [PubMed]
 
Jeffery, PK, Godfrey, RW, Ädelroth, E, et al Effects of treatment on airway inflammation and thickening basement membrane reticular collagen in asthma: a quantitative light and electron microscopy study.Am Rev Respir Dis1992;145,890-899. [PubMed]
 
National Asthma Education and Prevention Program.. Expert panel report 2: guidelines for the diagnosis and management of asthma. NIH Publication No. 97–405. 1997; National Institutes of Health. Bethesda, MD:.
 
Kamada, AK, Szefler, SJ, Martin, RJ, et al Issues in the use of inhaled glucorticoids.Am J Respir Crit Care Med1996;153,1739-1748. [PubMed]
 
Liddle, GW Analysis of circadian rhythms in human adrenocortical secretory activity.Arch Intern Med1966;117,739-743. [PubMed]
 
Law, CM, Honor, JW, Marchant, JL, et al Nocturnal adrenal suppression in asthmatic children taking inhaled beclomethasone dipropionate.Lancet1986;1,942-944. [PubMed]
 
Glaxo Wellcome, Inc. Package insert for Flovent Rotadisk, 50 μg, Flovent Rotadisk, 100 μg, and Flovent Rotadisk, 250 μg. Publication RL-666. Research Triangle Park, NC: Glaxo Wellcome, 1998.
 
Tamaoki, J, Kondo, M, Sakai, N, et al Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid.Am J Respir Crit Care Med1997;155,1235-1240. [PubMed]
 
Pincus, DJ, Szefler, SJ, Ackerson, LM, et al Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy.J Allergy Clin Immunol1995;95,1172-1178. [PubMed]
 

Figures

Tables

References

Juniper, E, Kline, P, Vanzieleghem, M, et al (1990) Effect of long-term treatment with an inhaled corticosteroid (budesonide) on airway hyperresponsiveness and clinical asthma in nonsteroid-dependent asthmatics.Am Rev Respir Dis142,832-836. [PubMed]
 
Drazen, JM, Israel, E, O’Byrne, PM Treatment of asthma with drugs modifying the leukotriene pathway.N Engl J Med1999;340,197-206. [PubMed] [CrossRef]
 
Djukanović, R, Wilson, JW, Britten, KM, et al Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma.Am Rev Respir Dis1992;145,669-674. [PubMed]
 
Jeffery, PK, Godfrey, RW, Ädelroth, E, et al Effects of treatment on airway inflammation and thickening basement membrane reticular collagen in asthma: a quantitative light and electron microscopy study.Am Rev Respir Dis1992;145,890-899. [PubMed]
 
National Asthma Education and Prevention Program.. Expert panel report 2: guidelines for the diagnosis and management of asthma. NIH Publication No. 97–405. 1997; National Institutes of Health. Bethesda, MD:.
 
Kamada, AK, Szefler, SJ, Martin, RJ, et al Issues in the use of inhaled glucorticoids.Am J Respir Crit Care Med1996;153,1739-1748. [PubMed]
 
Liddle, GW Analysis of circadian rhythms in human adrenocortical secretory activity.Arch Intern Med1966;117,739-743. [PubMed]
 
Law, CM, Honor, JW, Marchant, JL, et al Nocturnal adrenal suppression in asthmatic children taking inhaled beclomethasone dipropionate.Lancet1986;1,942-944. [PubMed]
 
Glaxo Wellcome, Inc. Package insert for Flovent Rotadisk, 50 μg, Flovent Rotadisk, 100 μg, and Flovent Rotadisk, 250 μg. Publication RL-666. Research Triangle Park, NC: Glaxo Wellcome, 1998.
 
Tamaoki, J, Kondo, M, Sakai, N, et al Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid.Am J Respir Crit Care Med1997;155,1235-1240. [PubMed]
 
Pincus, DJ, Szefler, SJ, Ackerson, LM, et al Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy.J Allergy Clin Immunol1995;95,1172-1178. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543