Is the pharmacology of corticosteroids in the lung modified by age?

Anecdotal clinical observations suggest that older patients with asthma have less beneficial responses to corticosteroids than their younger counterparts. This apparent reduced sensitivity may be because of longer duration of disease, and resultant structural changes, such as remodelling, which reduce steroid responsiveness. Indeed, one study found that patients treated with a β-agonist alone for 2 years appeared to have less response to inhaled corticosteroids than patients who had begun corticosteroid therapy 2 years earlier.1 This suggests that delayed initiation of inhaled corticosteroid treatment — often the case in older patients — decreases corticosteroid responsiveness. If reduced responsiveness to corticosteroids is indeed a function of age, it may be caused by pharmacokinetic or pharmacodynamic mechanisms.

A 1988 study found pharmacokinetic changes in response to prednisolone in 12 older people (aged 65–89 years) compared with 19 younger participants (aged 23–34 years).2 After receiving intravenous and oral prednisolone, older participants had greater total exposure to the drug, because of diminished clearance.2 From this study, it is possible that the systemic clearance of systemically absorbed inhaled corticosteroids may be diminished in older people, although it cannot be assumed that the clearance pathways for all corticosteroids are similarly affected. There are no published studies on the intrapulmonary deposition pharmacokinetics and systemic bioavailability of inhaled corticosteroids in older people.

There is also evidence of age-dependent pharmacodynamic changes in corticosteroid action. Rat studies comparing expression of serotonin-transporter mRNA in the midbrain between young and old rats found that dexamethasone significantly decreased mRNA expression in both age groups, but that its effect was more marked in the older rats.3 Rat studies have also suggested age-dependent loss of hippocampal adrenocorticoid receptors, indicated by an increased basal level of circulating corticosteroids and reduced sensitivity to the dexamethasone suppression test in older rats.4 Similarly, reduced sensitivity of the hypothalamus to corticosteroids has been found in older humans; cortisol infusion caused significantly greater feedback inhibition of adrenocorticotropic hormone in 22 healthy young individuals (aged 20–35 years), compared with 21 older individuals (aged over 65 years).5 While the evidence for diminished responsiveness to corticosteroids at the hypothalamic level with increasing age is consistent in both rats and humans, there are no data on steroid responsiveness of receptors in other parts of the body, such as the lung.

Diminished steroid responsiveness could be due to a number of mechanisms, including a decreased number of steroid receptors, decreased affinity of steroids for their receptors, and downstream effects, such as diminished binding of the steroid-receptor complex to nuclear glucocorticoid response elements. Indeed, a study of the glucocorticoid-receptor binding affinity of peripheral blood mononuclear cells in older people found that it was lower in those with asthma than in those without asthma.6 It was also lower in the patients with asthma who had less response to corticosteroids, compared with those with greater response.

However, it is not known whether the steroid-binding characteristics of peripheral blood mononuclear cells reflect those of target cells in the lungs. In-vitro studies of asthmatic smooth muscle cells have shown that their proliferation is not inhibited by corticosteroids.7 This steroid insensitivity is associated with the absence of a transcription factor, the α-isoform of the cytosine-nucleotide enhancer binding protein (C/α), but it is not known whether this deficiency is related to age.