In the second part of our study, we used a single high dose of each of three commonly prescribed inhaled corticosteroids in the United Kingdom to evaluate differences between the drugs in their effects on the HPA axis. Although a number of authors have suggested that fluticasone may have less effect than budesonide on morning cortisol levels when given at therapeutic equivalent doses, these studies were undertaken to study the comparative efficacy of the drugs; cortisol studies were a secondary end point and were not always com-plete.’ Furthermore, these studies involved spacer devices in an unspecified proportion of cases, which makes direct comparison of the drugs more difficult website natural asthma treatment. A further problem with such studies is that most of the patients were already taking medium to high doses of inhaled steroids prior to inclusion in the studies and the mean baseline cortisol level was < 300 nmol/L, whereas all 32 baseline (placebo) measurements in the present study were > 300 nmol/L, confirming that the patients of Barnes et al and Ayres et al already had mild suppression of their cortisol level before entering the studies. In contrast, most studies that were designed to compare the systemic potency of fluticasone, budesonide, and beclomethasone (in normal volunteers and asthmatic subjects) have found that fluticasone is more potent when given at microgram equivalent doses. Clark and Lipworth showed that twice-daily dosing of fluticasone in asthmatic subjects for 4 days produced suppression of both overnight urinary free cortisol and 8:00 am cortisol. This was evident for dosages ranging from 250 to 1,000 ^g bid. Fluticasone was more than twice as potent as budesonide at all dose levels in these asthmatic subjects, a finding that was replicated in the present study using normal volunteers. Kellerman et al showed the systemic effects of fluticasone (1,000 ^g bid when given to 118 asthmatic patients for 29 days) was only slightly less than that of 10 mg of prednisolone qd. The high degree of systemic bioavailability of fluticasone would be predicted from its known high affinity for the steroid receptor. In addition, the drug/receptor complex has a longer half-life than that of the other steroids. Our study suggests that fluticasone has at least 2:1 potency with reference to systemic side effects, a ratio similar to its known 2:1 therapeutic potency compared with beclomethasone and budes-onide. These findings suggest a similar therapeutic index for fluticasone and budesonide (similar clinical benefit and similar systemic effects at equi-potent doses). It is likely that beclomethasone has a lower therapeutic index (due to greater oral bioavailability and active metabolites), and it is recommended that budesonide or fluticasone should be used if very high doses of inhaled steroid are required.
In conclusion, the present study shows that ultra-high doses of inhaled corticosteroids produce a substantial fall in serum cortisol level, allowing useful comparisons to be made between the effects of different inhaler devices and different drugs. We found that the choice of inhaler device can influence the degree of systemic bioavailability of inhaled steroids, and we found that the systemic potency ratio of fluticasone propionate to budesonide is at least 2:1 in normal human volunteers, a level similar to that reported in asthmatic subjects for therapeutic and systemic effects.
Category: Inhaled Corticosteroids
Tags: adrenal suppression, beclomethasone dipropionate, bioavailability, budesonide, fluticasone propionate, inhaled corticosteroids