Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis.Reports dealing systemic adverse effects of inhaled corticosteroid therapy the systemic effects of inhaled corticosteroids on adrenal gland, growth, bone, skin, and eye, and reports on pharmacology and pharmacokinetics were reviewed where appropriate. Corticosteroidd were included that contained evaluable data on systemic effects monounsaturated fat boost testosterone healthy volunteers as well as in asthmatic children and adults. A statistical meta-analysis using regression was performed for parameters of adrenal suppression in 27 studies. Marked adrenal suppression occurs with high doses of inhaled corticosteroid above 1. Meta-analysis showed significantly greater potency for dose-related adrenal suppression with fluticasone compared with beclomethasone dipropionate, budesonide, or triamcinolone acetonide, whereas prednisolone and fluticasone corticksteroid were approximately equivalent on a Inhaled corticosteroids in doses above 1.
Meta-analysis of 21 studies that evaluated effects on hour or overnight urinary cortisol levels. The data were analyzed using multiple regression analysis of slopes, depicting the line of best fit for each drug. There were no significant differences among beclomethasone, triamcinolone, and budesonide.
Meta-analysis of 13 studies that evaluated effects on 8 AM plasma and serum cortisol levels. Copyright American Medical Association. Reports dealing with the systemic effects of inhaled corticosteroids on adrenal gland, growth, bone, skin, and eye, and reports on pharmacology and pharmacokinetics were reviewed where appropriate.
Studies were included that contained evaluable data on systemic effects in healthy volunteers as well as in asthmatic children and adults. A statistical meta-analysis using regression was performed for parameters of adrenal suppression in 27 studies. Meta-analysis showed significantly greater potency for dose-related adrenal suppression with fluticasone compared with beclomethasone dipropionate, budesonide, or triamcinolone acetonide, whereas prednisolone and fluticasone propionate were approximately equivalent on a Inhaled corticosteroids in doses above 1.
Long-term, high-dose inhaled corticosteroid exposure increases the risk for posterior subcapsular cataracts, and, to a much lesser degree, the risk for ocular hypertension and glaucoma. Skin bruising is most likely to occur with high-dose exposure, which correlates with the degree of adrenal suppression. Meta-analysis shows that fluticasone propionate exhibits greater dose-related systemic bioactivity compared with other available inhaled corticosteroids, particularly at doses above 0.
The long-term systemic burden will be minimized by always trying to achieve the lowest possible maintenance dose that is associated with optimal asthmatic control and quality of life. THE LAST decade has led to a greater understanding of the mechanisms causing asthma and particularly the underlying role of the inflammatory process in this condition. Corticosteroids are generally accepted to be the first-line choice of anti-inflammatory therapy for the treatment of asthma.
As a consequence, it is now relatively uncommon to see the unpleasant systemic adverse effects that are associated with oral corticosteroid maintenance therapy.
Present asthma management guidelines emphasize the importance of early intervention with inhaled corticosteroids as first-line anti-inflammatory therapy.
This in turn has resulted in debate regarding the relative risks and benefits of newer vs older inhaled corticosteroids. The purpose of this article is to provide an objective and systematic review of the systemic adverse effects of inhaled corticosteroid therapy and the clinical relevance of inhaled corticosteroids in the treatment of asthmatic patients.
In particular, the article will focus on the effects on adrenal gland, growth, bone, eye, and skin. In addition, the bibliographies of eligible articles and reviews were used along with scientific session abstracts in key respiratory- and allergy-based journals. Eligible studies for review provided sufficient information on patient demographics, study design, randomization and control procedures, route of drug administration, measurement of end points, and data analysis.
The main results of this review were qualitative, as it was not possible to perform an overall statistical meta-analysis due to the wide variation in selected end points for a given tissue-specific effect.
However, where appropriate, a given end point was analyzed to produce a comparable response across different studies. This was only possible for end points of adrenal suppression, where there were sufficient evaluable data, namely, for effects on 8 AM plasma or serum cortisol levels and on urinary cortisol or cortisol-creatinine excretion hour or overnight.
There were 21 eligible studies for urinary cortisol levels and 13 eligible studies for 8 AM cortisol levels, constituting a total of 27 different studies for both end points. For these data, model fitting was applied using multiple regression analysis of slopes to ascertain whether there were significant differences in slope gradients between drugs.
The different studies were weighted according to their sample size when performing the regression analysis. The format for this article is first to provide a general overview of factors that determine the systemic bioactivity profile of inhaled corticosteroids, followed by a detailed appraisal of tissue-specific adverse effects, including the results of the meta-analysis for adrenal suppression.
It is not within the scope of this article to discuss the antiasthmatic efficacy of inhaled corticosteroids in any detail, as this has been reviewed elsewhere with respect to dose-response relationships and risk-benefit ratio. Lipophilic substitutions of the basic glucocorticosteroid nucleus result in compounds that exhibit a high level of receptor potency and affinity, a high degree of local tissue uptake and retention with topical application, and a high degree of first-pass biotransformation in the liver.
Corticosteroids administered by inhalation exhibit a high degree of topical potency at the glucocorticoid receptor, and so delivery of low doses may achieve a high local concentration within the airway. The degree of topical potency is assessed conventionally using the skin vasoconstrictor assay. Using this method, an approximate rank-order potency ratio can be calculated for the different inhaled corticosteroids in the following order from greatest to least potency: The degree of topical activity is also related to the affinity for glucocorticoid receptor binding.
In other words, enhanced potency and affinity may cause a commensurate increase in systemic and airway bioactivity profiles. The ratio of airway to systemic activity will also depend on the relative dose-response relationships for airway efficacy and systemic adverse effects. Thus, increasing the dose of inhaled corticosteroid on the flat part of the efficacy curve will confer little further benefit, but at the same time may coincide with the steep part of the systemic curve, resulting in a worse therapeutic index.
Evidence also suggests that the degree of lipophilicity will determine the dwell time at the local tissue site after topical administration. Thus, enhanced lipophilicity may represent a 2-edged sword in terms of greater airway and systemic retention. The specific purpose of inhaled corticosteroid therapy is to target drug delivery directly to the site of airway inflammation.
Although there is a small degree of direct absorption from the buccal cavity, most of the oropharyngeal dose is swallowed and subsequently absorbed from the gastrointestinal tract. Thus, most of the respirable dose delivered to the lung will be bioavailable in the systemic circulation as unchanged active drug. It is also pertinent to consider the pharmacokinetic profile and in particular the elimination half-life, as this will determine the degree of accumulation after steady state dosing.
Fluticasone propionate has an elimination half-life of When comparing different drugs, it is important to consider their respective delivery devices, as the respirable fraction will determine clinical efficacy and lung absorption. The effects of mouth rinsing or using a spacer will be determined by the degree of first-pass inactivation for the swallowed fraction as well as the increase in respirable dose with a spacer.
The relative systemic potency ratio can be calculated by comparing 2 drugs on the steep part of their respective dose-response curves using a sufficiently sensitive end point. Ideally, the relative potency ratio would be calculated for efficacy and systemic activity in the same study, to assess a comparative therapeutic index for both drugs.
In practice, this is extremely difficult to achieve, because the steep part of the dose-response curve for clinical efficacy does not usually coincide with the steep part of the curve for systemic activity.
The type of subject used for evaluation may also be an important factor. A reduction in peripheral airway caliber in asthmatic patients may significantly reduce the degree of lung absorption and hence influence the systemic bioactivity.
However, when comparing 2 drugs, the relative difference in systemic activity will probably be the same in healthy subjects as in asthmatics, providing that the identical end point is used. Another important factor when studying patients is that there may be effects of previous corticosteroid exposure, eg, as in considering the legacy of previous prednisone treatment. The sensitivity of the measured end points for the study will also have a major bearing on the results.
For example, in studies looking at adrenal suppression, the timing of spot measurements of early morning cortisol concentration is critical, in that peak levels usually occur no later than 8 AM as a consequence of the normal circadian rhythm. This explains the results of studies where there has been only a small detectable effect on early morning cortisol concentration measured at a variable time between 8 and 10 AM in patients receiving fluticasone.
The use of knemometry an electronic method for measuring lower-leg growth to measure small differences in lower-leg length is a good example of a test that is highly sensitive as a short-term marker of systemic bioactivity in children but does not predict effects of inhaled corticosteroids on long-term growth.
The administration of exogenous inhaled corticosteroids results in a negative feedback effect on glucocorticoid receptors in the anterior pituitary gland and hypothalamus, which in turn suppresses levels of corticotropin-releasing hormone and corticotropin, respectively, and a consequent reduction in cortisol secretion from the adrenal cortex. Prolonged suppression of corticotropin levels eventually results in atrophy of the adrenal cortex.
The presence of low endogenous cortisol levels is not clinically relevant, providing there is additional glucocorticoid activity due to the presence of exogenous corticosteroid in the systemic circulation.
The presence of adrenal cortical atrophy becomes clinically relevant if exogenous corticosteroid therapy is abruptly stopped, or if there is an intercurrent stressful stimulus eg, surgery, trauma, infection, myocardial infarction , whereby the adrenal cortex is incapable of mounting a sufficient endogenous cortisol response, resulting in an acute adrenal insufficiency crisis.
In general terms, there are 2 types of tests of adrenocortical function, namely, screening tests of basal adrenocortical activity and dynamic stimulation tests to assess adrenocortical reserve. The most sensitive way to evaluate basal adrenocortical activity is to perform a hour integrated measurement of plasma cortisol levels or urinary free cortisol excretion. Proper compliance with hour urine collection is also difficult to achieve in an outpatient setting, and hence fractionated overnight and early morning urinary cortisol collections may be used to overcome this problem.
This technique can be further refined by correcting the urinary free cortisol excretion for creatinine excretion, being expressed as a urinary cortisol-creatinine ratio. Indeed, the measurement of overnight or early morning urinary cortisol-creatinine excretion has been shown to be as sensitive as an integrated hour urinary free cortisol collection and is more sensitive than a spot measurement of 9 AM plasma cortisol levels.
THE PURPOSE of a dynamic stimulation test with corticotropin or corticotropin-releasing hormone is to assess whether there is any impairment of adrenal cortical reserve that might occur in response to physiological stressful stimuli. When using a synthetic corticotropin ie, cosyntropin stimulation test, it is important to use the correct dose that mimics a physiological stress response.
In this respect, the conventional g dose of cosyntropin is times the dose required for a stimulated cortisol response, and as such represents a supraphysiological dose of corticotropin. Comparative dose-response studies in healthy volunteers for fluticasone and budesonide given by metered-dose inhaler have shown relative potency ratios fluticasone-budesonide of 2.
When comparing both drugs given via the metered-dose inhaler device, assuming half the dose of fluticasone is therapeutically equivalent to 1 dose of budesonide, this would result in fluticasone exhibiting approximately 1.
The budesonide Turbuhaler and fluticasone Diskhaler are therapeutically equivalent on a milligram-for-milligram basis, whereas the fluticasone Diskhaler exhibits 1.
The greater degree of systemic bioactivity with fluticasone probably represents a complex interplay of factors, including accumulation in blood, retention in systemic tissue, and prolonged receptor occupancy. These studies do not provide information on the relative therapeutic index of each drug, as there is no commensurate evaluation of antiasthmatic clinical efficacy.
The effects of inhaled corticosteroids have also been compared with those of oral corticosteroids in dose-response studies. In a dose-ranging study in asthmatic patients, fluticasone propionate 0. Toogood et al 66 compared oral prednisone and inhaled budesonide via large-volume spacer in terms of their relative efficacy and cortisol suppression. In patients who were not dependent on prednisone, the relative potency ratio budesonide vs prednisone for efficacy was In patients who were dependent on prednisone, the ratios for efficacy and cortisol suppression were With all inhaled corticosteroids given at high dosage, there is likely to be a dual effect due to topical bioactivity from the airway dose as well as prednisonelike activity from the systemic bioavailable dose.
The component of systemic bioactivity is therefore likely to be greater with fluticasone, which along with its topical potency may contribute to its antiasthmatic effects when given at high doses.
This may partially explain why it is possible to wean patients from oral prednisone maintenance therapy by using high-dose inhaled fluticasone. In other words, systemic prednisone is being substituted with systemic fluticasone.
This suggests that patients who are weaned from oral prednisone therapy with high-dose inhaled corticosteroids should be closely monitored for evidence of persistent impaired adrenal function, and particularly when using high-potency drugs such as fluticasone.
Most studies in asthmatic children have shown that with doses of inhaled corticosteroid of 0. First, Agertoft and Pedersen 68 showed that dry-powder formulations of fluticasone propionate and budesonide, in doses of 0. Second, Nicolaizik et al 75 showed that budesonide and beclomethasone dipropionate given via metered-dose inhaler at 0. Studies of doses greater than 0.
It is probably more clinically relevant to look at individual data for abnormally low cortisol values rather than to evaluate the statistical significance of mean responses. For the reasons discussed previously, it is pertinent to evaluate absolute cortisol values in studies of asthmatic patients but not in healthy volunteers. In a study by Clark et al 49 of asthmatic children, 18 of 30 patients had low cortisol values when given fluticasone propionate compared with 6 of 30 when given budesonide, in terms of overnight urinary cortisol excretion, when both drugs were given via a large-volume spacer with a dose range of 0.
In adult asthmatics, 21 of 36 had low overnight urinary cortisol measurements when given fluticasone propionate vs 3 of 36 when given budesonide, when both drugs were given with a dose range of 0.
The likelihood of impaired adrenal reserve and insufficient cortisol response to stress can be evaluated using a dynamic stimulation test. Smith and Hodson 86 studied 54 asthmatic adults receiving long-term beclomethasone dipropionate therapy via metered-dose inhaler in doses ranging from 0.
Brown et al 87 studied a group of 78 adults with asthma who had been receiving long-term inhaled corticosteroid therapy, with evidence of adrenal suppression being identified at results of screening in 16 of the patients who were taking high-dose beclomethasone dipropionate 1.
In a multicenter parallel group study of adults with asthma given 6-month treatment with 0. A meta-analysis of 21 studies of urinary cortisol levels Figure 1 and 13 studies of suppression of 8 AM plasma cortisol levels Figure 2 revealed fluticasone to exhibit significantly steeper dose-related systemic bioactivity than beclomethasone, budesonide, or triamcinolone.