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Jun.30.2012

Inhaled Respiratory Corticosteroids

Summary

  • Inhaled respiratory corticosteroids are an integral part of asthma management and act as anti-inflammatory agents in the airways of the lung.
  • Inhaled respiratory corticosteroids have similar efficacy with regard to lung function in adults with persistent asthma.
  • At low to moderate doses, inhaled respiratory corticosteroidsare well tolerated; however, at high doses and with longer duration of use, systemic absorption increases and leads to an increase in the risk of adverse effects.
  • Ciclesonide favors maximum therapeutic effect in the lung while minimizing the risk of systemic adverse events.

Pharmacology/Mechanism of Action

Corticosteroids readily cross cell membranes and bind with high affinity to the glucocorticoid cytoplasmic receptor. The activated receptor binds to glucocorticoid-responsive genes and leads to induction or repression of transcription of potent anti-inflammatory or proinflammatory mediators, respectively. This mechanism takes place over a period of hours to days. For instance, corticosteroids increase the synthesis of secretory leukocyte protease inhibitor in human airway epithelial cells, important in reducing airway inflammation.[50600] Moreover, glucocorticoids indirectly inhibit the transcription of several inflammatory cytokines (eg, interleukin-1, tumor necrosis factor-alpha) and chemokines (eg, interleukin-8, monocyte chemotactic protein-1). The latter are chemotactic for leukocytes at the site of inflammation. Down regulation of cytokines leads to a reduction of expression of adhesion molecules on endothelial cells, preventing the adhesion and transmigration of leukocytes to the site of inflammation. The net effect of these processes is a reduction in edema.[50600]

 

Asthma is a chronic bronchial inflammatory disorder associated with increased mucus secretions and peribronchial edema composed of cell infiltrates.[50599] Acute symptoms of asthma usually arise from bronchoconstriction; chronic asthma can lead to permanent airway remodeling.[50599] The anti-inflammatory actions of inhaled respiratory corticosteroids reduce the bronchial inflammation, thereby treating respiratory symptoms associated with asthma. Asthma is associated with immunoglobulin E (IgE) hypersensitivity; therefore, it is exacerbated in the presence of aeroallergens.[50599] The allergens bridge the IgE antibodies on the surface of mast cells and other leukocytes and trigger release of chemotactic substances, which initiate an inflammatory response. This leads to mucus deposition in the lung. Corticosteroids decrease IgE synthesis, thereby reducing the bronchial hyper-responsiveness to allergens.[50599]

Therapeutic Use

  • Inhaled respiratory corticosteroids are the most effective prophylactic agents for mild to moderate asthma and persistent symptoms in both adults and children.[50599][50600]
  • Regular treatment with inhaled respiratory corticosteroids reduces exacerbations, improves control of symptoms and lung function (eg, peak expiratory flow [PEF]), reduces airway hyper-responsiveness, and reduces hospital admissions and deaths from asthma.[50599][50600][50603]
  • Regular treatment with inhaled respiratory corticosteroids in patients with chronic obstructive pulmonary disease improves symptoms, lung function, and quality of life.[63765]
  • Inhaled respiratory corticosteroids are a long-term treatment, and therefore not effective for acute exacerbations of asthma or immediate symptom relief.
  • For patients of any age unable to coordinate inhalation and actuation, a spacer or valved holding chamber (VHC) should be used with amenable inhaler types. In general, children less than 4 years old require administration with a tight-fitting face mask and spacer/VHC device to achieve optimal delivery.

 

Dose Ranges and Potency of Inhaled Respiratory Corticosteroids

Drug

Usual Dosea

Glucocorticoid Potency

Age group (years)

1 to 4

5  to 11

12 and older

12 and older

12 and older

Previous therapy

Any

Bronchodilator

Inhaled Steroid

Systemic Steriodb

BeclomethasoneNA40 - 80 mcg 2x/day40 - 80 mcg 2x/day40 - 160 mcg 2x/day40 - 160 mcg 2x/dayHigh

Budesonide

Inhalation powder (e.g., Pulmicort Flexhaler)

NA180 - 360 mcg 2x/day360 mcg 2x/day360 mcg 2x/day360 mcg 2x/dayHigh; low systemic activity; weak mineralocorticoid activity
Nebulizer suspension (e.g., Pulmicort respules)250 - 500 mcg/day 1 to 2x/day500 mcg/day 1 to 2x/dayNANANA
CiclesonideNANA80 mcg 2x/day80 mcg 2x/day320 mcg 2x/dayHighC

Fluticasone

Inhalation suspension (e.g., Flovent HFA)

NA88 mcg 2x/day88 mcg 2x/day88 - 220 mcg 2x/day440 mcg 2x/dayMedium
Inhalation powder (e.g., Flovent Diskus)NA50 mcg 2x/day100 mcg 2x/day100 - 250 mcg 2x/day500-1000 mcg 2x/day
MometasoneNA110 mcg/day220 mcg/day220 mcg/day440 mcg 2x/dayMedium

Abbreviation: NA, not approved

aUsual dose recommended by manufacturer. bAfter 1 week of inhaled corticosteroid treatment, begin slow rate of oral steroid withdrawal, not exceeding decrements of 2.5 mg/day of prednisone or equivalent; close patient monitoring is warranted. cMetabolized to an active metabolite that has high potentcy

Comparative Efficacy

Inhaled respiratory corticosteroids are similar chemically and structurally but have different pharmacodynamic properties that may result in different clinical effects.[50601] For instance, the active metabolite of ciclesonide, des-CIC, undergoes rapid hepatic metabolism into inactive metabolites upon leaving the lung [32882], therefore favoring maximum therapeutic effect in the lung while minimizing the risk of systemic adverse events.[50602]

With regard to dosing, in patients with mild or moderate persistent asthma, low doses of inhaled respiratory corticosteroids are equally efficacious for improving symptoms compared with high doses, and the dose-response relationship appears to flatten for most clinical parameters and lung function.[50599] Dose adjustments can take place depending on the progression of the asthma severity, with high doses used in patients with severe asthma. Corticosteroid responsiveness is decreased in smokers and in patients with predominantly neutrophilic inflammatory asthma.[50599]

 

Key Findings

  • Ciclesonide, fluticasone, budesonide, and beclomethasone have similar effectiveness and efficacy with regard to lung function in adults with persistent asthma.[50605][50606]
  • Fluticasone leads to increased hoarseness when given at the same dose as budesonide and beclomethasone.[50605]
  • Mometasone is more effective than other inhaled steroids for oral corticosteroid-sparing effect.[50607]

 

Inhaled Respiratory Corticosteroid Comparative Efficacy Trials

Citation/Study NameDesign/RegimenResultsConclusion
Adams NP, et al. Cochrane Database Syst Rev. 2007;4:CD002310 [50605]Meta-analysis of RCTs comparing fluticasone with either BDP or BUD in the treatment of chronic asthma. 71 studies with 14,602 participants were included. Numbers of studies and subjects varied across analyses: studies, 4-17; subjects, 646-4179

All fluticasone vs BDP or BUD

 

FEV1, and FVC; 1:1 and 1:2 dose ratios:

No significant differences between the groups

 

PEF rates

1:1 dose ratio

am:

Change from baseline: MD, 6.13 L/min; 95% CI, 1.49-10.77

pm:

Change from baseline: MD, 8.57 L/min; 95% CI, 0.00-17.13

 

1:2 dose ratio

am:

Change from baseline: MD, 7.42 L/min; 95% CI, 4.97-9.87

pm: No significant differences between groups

 

Safety measures

1:1 dose ratio

Hoarseness, sore throat/pharyngitis and other AEs: No significant differences between groups

 

1:2 dose ratio

Sore throat/pharyngitis: Peto OR, 1.45; 95% CI, 1.10-1.92

 

Any AEs or hoarseness: No significant difference

Fluticasone given at half the equivalent daily dose of BDP or BUD leads to small improvements in measures of airway caliber, but it has a higher risk of causing sore throat.

 

Manning P, et al. Cochrane Database Syst Rev. 2008;2:CD007031[50606]

 

Meta-analysis of RCTs comparing ciclesonide with other steroids. 21 trials with 7243 participants were included. Numbers of studies and subjects varied across analyses: studies, 2-5; subjects, 758-2607

1:1 dose ratio

FEV1, FVC, and PEF rates

No significant differences between the groups;

 

Candidiasis was less frequent with ciclesonide compared with fluticasone. Other adverse events occurred with similar frequency between ciclesonide and BDP/BUD

Ciclesonide is equivalent to BDP/BUD in terms of peak flow, FEV1, and peak flow at dose ratios of 1:1.
Abdullah AK, et al. Ann Allergy Asthma Immunol. 2008;101:74-81 [50607]Meta-analysis of 18 placebo-controlled randomized trials of 7 inhaled steroids for their OCS-sparing effect

OCS-sparing effect compared with placebo

 

Benefit ratio (BR) for complete elimination of OCS: mometasone, 17.2; BUD, 8.2; BDP and fluticasone, 5.4; triamcinolone, 4.6; ciclesonide, 2.8; and flunisolide, 2.2 (all p<0.05 vs. placebo)

 

BR

Mometasone > triamcinolone (p=0.02)

Mometasone > ciclesonide (p=0.01)

Mometasone > flunisolide (p=0.01)

BUD > ciclesonide (p=0.02)

BUD > flunisolide (p=0.03)

 

OCS dose change

BDP < fluticasone (p<0.001)

BDP< flunisolide (p<0.001)

 

All other comparisons were statistically nonsignificant or did not have data available.

All inhaled steroids studied were significantly more effective than placebo for OCS sparing, but mometasone may be slightly  more effective than others

Abbreviations: AE, adverse events; BDP, beclomethasone; BUD, budesonide; FEV1, forced expired volume in 1 second; FVC, forced vital capacity; MD, mean difference; OCS, oral corticosteroid; OR, odds ratio; PEF, peak expiratory flow.

Adverse Reactions/Toxicities

Oral candidiasis (thrush)

Positive throat cultures of Candida can be identified in 45-58% of patients treated with inhaled respiratory corticosteroids; however, clinical thrush is diagnosed in < one-third of patients. Thrush is more frequent in adults and with higher doses of inhaled respiratory corticosteroids. In order to reduce potential of thrush, a spacer or VHC can be used with inhalers and patients are advised to rinse their mouths after inhalation. Topical antifungal agents are used to treat active infections.[50599][50608][50609]

Dysphonia

Dysphonia is reported in up to half of patients who use an inhaled respiratory corticosteroid and is associated with vocal stress and increasing doses of inhaled respiratory corticosteroids.[50608][50609] Spacer or valved holding chamber use, temporary reduction of inhaled respiratory corticosteroid dose, or rest from vocal stress can reduce and treat dysphonia.[50599]

Delay in growth

Although low or medium doses of inhaled respiratory corticosteroids may potentially decrease or delay growth velocity in children or adolescents, the effects are small, nonprogressive, and may be reversible. Physicians should monitor the growth of children and adolescents taking inhaled respiratory corticosteroids and should weigh the benefit–risk profile of inhaled respiratory corticosteroid therapy if growth appears slowed.[50599]

Reduction in bone mineral density (BMD)

In adults, use of inhaled respiratory corticosteroids is associated with a small dose-dependent reduction in bone mineral density (BMD) scores, as calcium absorption is reduced.[50604] It is recommended that in patients with a low BMD or risk factors for osteoporosis, BMD be measured every 1 to 2 years and concomitant bone-protecting therapies used, eg, bisphosphonates, if necessary.[50599] In perimenopausal women taking inhaled respiratory corticosteroids, supplements of calcium and vitamin D are recommended.[50599]

Skin thinning

Corticosteroids can produce skin changes such as loss of subcutaneous tissue, making skin fragile, transparent, and less resistant to trauma, and increasing skin bruising.[50610] These effects are dose and duration dependent and are more common in older patients after prolonged inhaled respiratory corticosteroids use.[50604]

Ocular adverse reactions

High cumulative lifetime exposure to inhaled respiratory corticosteroids may increase the prevalence of cataracts or the risk for glaucoma in patients with family history of glaucoma. Thus, periodic assessments for increased intraocular pressure in patients who use high doses of hnhaled respiratory corticosteroids and have a family history of glaucoma are warranted.[50599]

Hypothalamus-pituitary-adrenal (HPA) axis suppression

Although the risk is very low with low or medium dose inhaled corticosteroids, suppression of the hypothalamus-pituitary-adrenal (HPA) axis is possible, depending on the individual’s susceptibility to the effect, dose, frequency, and duration of therapy.[50599]

Drug Interactions

Drugs that inhibit or induce CYP3A4 isoenzymes

Corticosteroids are substrates of the cytochrome P450 3A4 (CYP3A4) isoenzyme and therefore inhibitors (eg, ketoconazole) or inducers (eg, barbiturates) of CYP3A4 may increase or reduce serum concentrations of inhaled respiratory corticosteroids and their metabolites, respectively.

Vaccines

Patients taking inhaled respiratory corticosteroids are immunocompromised; therefore, their immune response to vaccines may be low compared with healthy subjects. Higher doses or more frequent boosters of vaccines may be required. In general, patients with severe immunosuppression due to large doses of corticosteroids should not receive vaccination with live-virus vaccines.

Metyrapone

Corticosteroids should be discontinued prior to and during testing with metyrapone (for the diagnosis of adrenal insufficiency), as they can interfere with the test results.

Safety Issues

Acute asthma

Inhaled respiratory corticosteroids are controller medications for asthma; they should not be used to treat an acute attack as they will not help acute bronchospasm. Inhaled respiratory corticosteroids can cause acute bronchospasm during inhalation of therapy; if bronchospasm occurs, treat the acute attach with a short-acting bronchodilator.

Active infection

Corticosteroid therapy can mask the symptoms of viral, fungal, or bacterial infection and should be initiated or continued in patients with an active infection only if the appropriate anti-infective treatment is instituted.

Pediatrics

Because of the risks associated with higher doses of inhaled respiratory corticosteroids if patients older than 12 years require more than low-dose inhaled corticosteroids alone to control asthma, it is recommended to add long-acting beta2-agonists rather than increasing the dose of the steroid. The safety and efficacy of inhaled respiratory corticosteroids have not been studied adequately in children younger than 5 years. However, the National Asthma Education and Prevention Program Expert Panel recommends low-dose inhaled respiratory corticosteroids for the daily long-term therapy in children 0-4 years of age, along with close monitoring of the response to therapy.[50599]

[32882]Rohatagi S, Arya V, Zech K, et al. Population pharmacokinetics and pharmacodynamics of ciclesonide. J Clin Pharmacol 2003;43:365-78.

[50599]Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007;120(5 Suppl):S94-138.

[50600]Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond). 1998;94(6):557-572.

[50601]Adams N, Bestall JM, Lasserson TJ, Jones PW. Inhaled fluticasone versus inhaled beclomethasone or inhaled budesonide for chronic asthma. Cochrane Database Syst Rev. 2004(2):CD002310.

[50602]Nave R, Bethke TD, van Marle SP, Zech K. Pharmacokinetics of [14C]ciclesonide after oral and intravenous administration to healthy subjects. Clin Pharmacokinet. 2004;43(7):479-486.

[50603]Tattersfield AE, Knox AJ, Britton JR, Hall IP. Asthma. Lancet. 2002;360(9342):1313-1322.

[50604]Global strategy for diagnosis, management, and prevention of COPD. From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) Update 2013. http://www.goldcopd.org/. Accessed Sept 18, 2013.

[50605]Adams N, Lasserson TJ, Cates CJ, Jones PW. Fluticasone versus beclomethasone or budesonide for chronic asthma in adults and children. Cochrane Database Syst Rev. 2007(4):CD002310.

[50606]Manning P, Gibson PG, Lasserson TJ. Ciclesonide versus other inhaled steroids for chronic asthma in children and adults. Cochrane Database Syst Rev. 2008(2):CD007031.

[50607]Abdullah AK, Khan S. Relative oral corticosteroid-sparing effect of 7 inhaled corticosteroids in chronic asthma: a meta-analysis. Ann Allergy Asthma Immunol. 2008;101(1):74-81.

[50608]British guideline on the management of asthma. Thorax. 2003;58 Suppl 1:i1-94.

[50609]Jackson LD, Polygenis D, McIvor RA, Worthington I. Comparative efficacy and safety of inhaled corticosteroids in asthma. Can J Clin Pharmacol. 1999;6(1):26-37.

[50610]Capewell S, Reynolds S, Shuttleworth D, Edwards C, Finlay AY. Purpura and dermal thinning associated with high dose inhaled corticosteroids. BMJ. 1990;300(6739):1548-1551.

[63765]Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2021. Retrieved 3/8/2021. Available on the World Wide Web at https://goldcopd.org/wp-content/uploads/2020/11/GOLD-REPORT-2021-v1.1-25Nov20_WMV.pdf

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