Adrenal suppression inhaled glucocorticoids

The first inhaled glucocorticoid, beclomethasone dipropionate, revolutionized asthma therapy, when it was found that topical delivery to the lung resulted in reduced systemic side-effects (adrenal suppression, oseteoporosis and growth inhibition) typically seen with oral steroid treatments. Interestingly, a further reduction in systemic exposure was achieved with the introduction of fluticasone propionate (1). The evolution of this drug stemmed from observations with the steroid 17-carboxylates that showed that these esters were active topically when esterified, while the parent acids were inactive. Thus it was realized that enzymatic hydrolysis of the ester would lead to systemic deactivation. SAR studies led to a series of carbothioates, which were very active in vivo when topically applied to rodents, but were inactive after oral administration. It was shown that fluticasone propionate (1) underwent first pass metabolism in the liver to the corresponding inactive 173-carboxylic acid (la) (Scheme 1). This observation was... 

Hypothalamic-pituitary-adrenal axis function provides one of the most sensitive markers of the systemic activity of inhaled glucocorticoids (35), and suppression can be used as a surrogate marker for adverse effects of inhaled glucocorticoids in other tissues. 

In addition to these case reports, there has been a survey of symptomatic adrenal suppression associated with inhaled glucocorticoids in the UK (45). Only 24% of the questionnaires were returned (709 responses), and there were 28 cases of symptomatic adrenal suppression... 

In a double-blind, randomized pilot study of the efficacy and adverse effects of inhaled fluticasone in 25 newborn preterm infants who required mechanical ventilation for treatment of respiratory distress syndrome, the infants were randomized to receive inhaled fluticasone 1000 micrograms/day or placebo (47). The hypothalamic-pituitary-adrenal axis was assessed by the response to corticotropin-releasing factor. AU basal and post-stimulation plasma corticotropin and serum cortisol concentrations were significantly less with inhaled fluticasone than placebo. Cumulative high-dose inhaled glucocorticoids caused moderately severe suppression of both the pituitary and the adrenal glands. This systemic activity is probably associated with pulmonary vascular absorption that avoids hepatic first-pass metabolism. 

Different inhaled glucocorticoids have been compared for their suppressing effects on the hypothalamic-pituitary-adrenal axis (18). In a large meta-analysis, budesonide or beclomethasone dipropionate in doses of over 1500 micrograms/day was associated with adrenal... 

Horses appear to be more sensitive to the adrenosuppressive effects of aerosolized corticosteroids than human patients. Documentation of systemic absorption (adrenal suppression) of inhaled beclometasone and fluticasone raises concerns that other systemic glucocorticoid effects may occur following aerosol administration of corticosteroids. The administration of adrenosuppressive doses (>1600 p,g/day) of beclometasone dipropionate to asthmatic human patients does not produce the other systemic side-effects of glucocorticoid administration, including a roimd face (Cushingoid facies), polyuria, polydipsia, hyperglycemia, obesity, altered carbohydrate metabolism, osteoporosis, abortion, posterior subcapsular cataract and aseptic necrosis of the... 

Endocrine The effects of inhaled glucocorticoids on the hypothalamic-pituitary-adrenal axis in adults and children were reviewed in SEDA-31 (p. 305). In summary, at low doses inhaled glucocorticoids have little effect, but at high doses (2000 micrograms beclometasone equivalents) adrenal suppression can occur. In a French survey of 11 783 hospital specialists combined with a pharmacovigilance database, there were 46 cases of adrenal insufficiency attributable to inhaled corticosteroids at doses of over 500 micrograms beclometasone equivalents in children and over 1000 micrograms beclometasone equivalents in adults 12 cases were associated with concomitant use of enzyme inhibitors [10 ]. 

In contrast, in a randomized controlled trial in 645 patients with moderate asthma uncontrolled by regular inhaled glucocorticoids compared with combined beclometasone diproprionate and formoterol, there was no evidence of adrenal suppression [12. This may suggest that the doses of glucocorticoids were too low. 

---