Chemistry. The adrenal cortex secretes cortisol (hydrocortisone) and, by modification of its structure, it was possible to develop derivatives, such as prednisone, prednisolone, and dexamethasone, with enhanced corticosteroid effects but with reduced mineralocorticoid activity (Chapter 42). These derivatives with potent glucocorticoid actions were effective in asthma when given systemically but had no anti-asthmatic activity when given by inhalation. Further substitution in the 17α ester position resulted in steroids with high topical activity, such as beclomethasone dipropionate, triamcinolone, flunisolide, budesonide, and fluticasone propionate, which are potent in the skin (dermal blanching test) and were later found to have significant anti-asthma effects when given by inhalation (Figure 36–8).
Mechanism of Action. Corticosteroids enter target cells and bind to glucocorticoid receptors (GR) in the cytoplasm (Chapter 42). There is only one type of GR that binds corticosteroids and no evidence for the existence of subtypes that might mediate different aspects of corticosteroid action (Barnes, 2006a). The steroid-GR complex moves into the nucleus, where it binds to specific sequences on the upstream regulatory elements of certain target genes, resulting in increased (or rarely, decreased) transcription of the gene, with subsequent increased (or decreased) synthesis of the gene products. GR may also interact with protein transcription factors and coactivator molecules in the nucleus and thereby influence the synthesis of certain proteins independently of any direct interaction with DNA. The repression of transcription factors, such as activator protein-1 (AP-1) and NF-κB, is likely to account for many of the anti-inflammatory effects of steroids in asthma. In particular, corticosteroids reverse the activating effect of these pro-inflammatory transcription factors on histone acetylation by recruiting HDAC2 to inflammatory genes that have been activated through acetylation of associated histones (Figure 36–9). GRs are acetylated when corticosteroids are bound and bind to DNA in this acetylated state as dimers, whereas the acetylated GR has to be deacetylated by HDAC2 in order to interact with inflammatory genes and NF-κB (Ito et al., 2006).
There may be additional mechanisms that are also important in the anti-inflammatory actions of corticosteroids. Corticosteroids have potent inhibitory effects on MAP kinase signaling pathways through the induction of MKP-1, which may inhibit the expression of multiple inflammatory genes (Clark, 2003).
Anti-Inflammatory Effects in Asthma. The mechanisms of action of corticosteroids in asthma are still poorly understood, but their efficacy is most likely related to their anti-inflammatory properties. Corticosteroids have widespread effects on gene transcription, increasing the transcription of several anti-inflammatory genes and suppressing transcription of many inflammatory genes. Steroids have inhibitory effects on many inflammatory and structural cells that are activated in asthma and prevent the recruitment of inflammatory cells into the airways (Figure 36–10). Studies of bronchial biopsies in asthma have demonstrated a reduction in the number and activation of inflammatory cells in the epithelium and submucosa after regular ICS, together with a healing of the damaged epithelium. Indeed, in patients with mild asthma the inflammation may be completely resolved after inhaled steroids.
Steroids potently inhibit the formation of cytokines (e.g., IL-1, IL-3, IL-4, IL-5, IL-9, IL-13, TNF-α, and granulocyte-macrophage colony-stimulating factor, GM-CSF) that are secreted in asthma by T-lymphocytes, macrophages, and mast cells. Corticosteroids also decrease eosinophil survival by inducing apoptosis. Corticosteroids inhibit the expression of multiple inflammatory genes in airway epithelial cells, probably the most important action of ICS in suppressing asthmatic inflammation. Corticosteroids also prevent and reverse the increase in vascular permeability due to inflammatory mediators in animal studies and may therefore lead to resolution of airway edema. Steroids have a direct inhibitory effect on mucus glycoprotein secretion from airway submucosal glands, as well as indirect inhibitory effects by down-regulation of inflammatory stimuli that stimulate mucus secretion.
Corticosteroids have no direct effect on contractile responses of airway smooth muscle; improvement in lung function after ICS is presumably due to an effect on the chronic airway inflammation and airway hyperresponsiveness. A single dose of ICS has no effect on the early response to allergen (reflecting their lack of effect on mast cell mediator release) but inhibits the late response (which may be due to an effect on macrophages, eosinophils, and airway wall edema) and also inhibits the increase in airway hyperresponsiveness.
ICS have rapid anti-inflammatory effects, reducing airway hyperresponsiveness and inflammatory mediator concentrations in sputum within a few hours (Erin et al., 2008). However, it may take several weeks or months to achieve maximal effects on airway hyperresponsiveness, presumably reflecting the slow healing of the damaged inflamed airway. It is important to recognize that corticosteroids suppress inflammation in the airways but do not cure the underlying disease. When steroids are withdrawn there is a recurrence of the same degree of airway hyperresponsiveness, although in patients with mild asthma it may take several months to return.
Effect on β2 Adrenergic Responsiveness. Corticosteroids increase β adrenergic responsiveness, but whether this is relevant to their effect in asthma is uncertain. Steroids potentiate the effects of β agonists on bronchial smooth muscle and prevent and reverse β receptor desensitization in airways in vitro and in vivo (Barnes, 2002; Giembycz et al., 2008). At a molecular level, corticosteroids increase the transcription of the β2 receptor gene in human lung in vitro and in the respiratory mucosa in vivo and also increase the stability of its messenger RNA. They also prevent or reverse uncoupling of β2 receptors to Gs. In animal systems, corticosteroids prevent down-regulation of β2 receptors.
β2 Agonists also enhance the action of GR, resulting in increased nuclear translocation of liganded GR receptors and enhancing the binding of GR to DNA. This effect has been demonstrated in sputum macrophages of asthmatic patients after an ICS and inhaled LABA (Usmani et al., 2005). This suggests that β2 agonists and corticosteroids enhance each other's beneficial effects in asthma therapy.
Pharmacokinetics. The pharmacokinetics of oral corticosteroids are described in Chapter 42. The pharmacokinetics of inhaled corticosteroids are important in relation to systemic effects (Barnes et al., 1998b). The fraction of steroid that is inhaled into the lungs acts locally on the airway mucosa but may be absorbed from the airway and alveolar surface. Thus, a portion of an inhaled dose reaches the systemic circulation. Furthermore, the fraction of inhaled steroid that is deposited in the oropharynx is swallowed and absorbed from the gut. The absorbed fraction may be metabolized in the liver (first-pass metabolism) before reaching the systemic circulation (Figure 36–3). The use of a spacer chamber reduces oropharyngeal deposition and therefore reduces systemic absorption of ICS, although this effect is minimal in corticosteroids with a high first-pass metabolism. Mouth rinsing and discarding the rinse have a similar effect, and this procedure should be used with high-dose dry powder steroid inhalers with which spacer chambers cannot be used.
Beclomethasone dipropionate and ciclesonide are prodrugs that release the active corticosteroid after the ester group is cleaved by esterases in the lung. Ciclesonide is available as a MDI (alvesco) for asthma and as a nasal spray for allergic rhinitis (omnaris). Budesonide and fluticasone propionate have a greater first-pass metabolism than beclomethasone dipropionate and are therefore less likely to produce systemic effects at high inhaled doses.
Routes of Administration and Dosing
Inhaled Corticosteroids in Asthma. Inhaled corticosteroids are recommended as first-line therapy for all patients with persistent asthma. They should be started in any patient who needs to use a β2 agonist inhaler for symptom control more than twice weekly. They are effective in mild, moderate, and severe asthma and in children as well as adults (Barnes et al., 1998b). Although it was recommended that ICS be initiated at a relatively high dose and then the dose reduced once control was achieved, there is no evidence that this is more effective than starting with the maintenance dose. Dose-response studies for ICS are relatively flat, with most of the benefit derived from doses <400 μg beclomethasone dipropionate or equivalent (Adams et al., 2008). However, some patients (with relative corticosteroid resistance) may benefit from higher doses (up to 2000 μg/day).
For most patients, ICS should be used twice daily, a regimen that improves compliance once control of asthma has been achieved (which may require four-times daily dosing initially or a course of oral steroids if symptoms are severe). Administration once daily of some steroids (e.g., budesonide, mometasone, and ciclesonide) is effective when doses ≤400 μg are needed. If a dose 800 μg daily via pMDI is used, a spacer device should be employed to reduce the risk of oropharyngeal side effects. ICS may be used in children in the same way as in adults; at doses ≤400 μg/day there is no evidence of significant growth suppression (Pedersen, 2001). The dose of ICS should be the minimal dose that controls asthma; once control is achieved, the dose should be slowly reduced (Hawkins et al., 2003). Nebulized corticosteroids (e.g., budesonide) are useful in the treatment of small children who are not able to use other inhaler devices.
Inhaled Corticosteroids in Chronic Obstructive Pulmonary Disease. Patients with COPD occasionally respond to steroids, and these patients are likely to have concomitant asthma. Corticosteroids have no objective short-term benefit on airway function in patients with true COPD, although these agents often produce subjective benefit because of their euphoric effect. Corticosteroids do not appear to have any significant anti-inflammatory effect in COPD; there appears to be an active resistance mechanism, which may be explained by impaired activity of HDAC2 as a result of oxidative stress (Barnes, 2009). ICS have no effect on the progression of COPD, even when given to patients with presymptomatic disease; additionally, ICS have no effect on mortality (Calverley et al., 2007; Yang et al., 2007). ICS reduce the number of exacerbations in patients with severe COPD (FEV1 <50% predicted) who have frequent exacerbations and are recommended in these patients, although there is debate about whether these effects are due to inappropriate analysis of the data (Suissa et al., 2008). Oral corticosteroids are used to treat acute exacerbations of COPD, but the effect is very small (Niewoehner et al., 1999).
Patients with cystic fibrosis, which involves inflammation of the airways, are also resistant to high doses of ICS.
Systemic Steroids. Intravenous steroids are indicated in acute asthma if lung function is <30% predicted and in patients who show no significant improvement with nebulized β2 agonist. Hydrocortisone is the steroid of choice because it has the most rapid onset (5-6 hours after administration), compared with 8 hours with prednisolone. The required dose is uncertain; it is common to give hydrocortisone 4 mg/kg initially, followed by a maintenance dose of 3 mg/kg every 6 hours. Methylprednisolone is also available for intravenous use, but there is no evidence that the high doses previously used (1 g) are more effective. Intravenous therapy is usually given until a satisfactory response is obtained, and then oral prednisolone may be substituted. Oral prednisolone (40-60 mg) has a similar effect to intravenous hydrocortisone and is easier to administer. A high dose of inhaled fluticasone propionate (2000 μg daily) is as effective as a course of oral prednisolone in controlling acute exacerbations of asthma in a family practice setting and in children in an emergency department setting, although this route of delivery is more expensive (Levy et al., 1996; Manjra et al., 2000).
Prednisolone and prednisone are the most commonly used oral steroids. Clinical improvement with oral steroids may take several days; the maximal beneficial effect is usually achieved with 30-40 mg prednisone daily, although a few patients may need 60-80 mg daily to achieve control of symptoms. The usual maintenance dose is ∼10-15 mg/day. Short courses of oral steroids (30-40 mg prednisolone daily for 1-2 weeks) are indicated for exacerbations of asthma; the dose may be tapered over 1 week after the exacerbation is resolved (the taper is not strictly necessary after a short course of therapy, but patients find it reassuring). Oral steroids are usually given as a single dose in the morning because this coincides with the normal diurnal increase in plasma cortisol and produces less adrenal suppression than if given in divided doses or at night. Alternate-day treatment has the advantage of less adrenal suppression, although in many patients control of asthma is not optimal on this regimen.
Adverse Effects. Corticosteroids inhibit ACTH and cortisol secretion by a negative feedback effect on the pituitary gland (Chapter 42). Hypothalamic-pituitary-adrenal (HPA) axis suppression depends on dose and usually only occurs with doses of prednisone >7.5-10 mg/day. Significant suppression after short courses of corticosteroid therapy is not usually a problem, but prolonged suppression may occur after several months or years. Steroid doses after prolonged oral therapy must be reduced slowly. Symptoms of "steroid withdrawal syndrome" include lassitude, musculoskeletal pains, and, occasionally, fever. HPA suppression with inhaled steroids is usually seen only when the daily inhaled dose exceeds 2000 μg beclomethasone dipropionate or its equivalent daily.
Side effects of long-term oral corticosteroid therapy include fluid retention, increased appetite, weight gain, osteoporosis, capillary fragility, hypertension, peptic ulceration, diabetes, cataracts, and psychosis. Their frequency tends to increase with age. Very occasionally adverse reactions (such as anaphylaxis) to intravenous hydrocortisone have been described, particularly in aspirin-sensitive asthmatic patients.
The incidence of systemic side effects after ICS is an important consideration, particularly in children (Barnes et al., 1998b) (Table 36–4). Initial studies suggested that adrenal suppression occurred only with inhaled doses >1500-2000 μg/day. More sensitive measurements of systemic effects include indices of bone metabolism, such as serum osteocalcin and urinary pyridinium cross-links, and in children, knemometry, which may be increased with inhaled doses as low as 400 μg/day beclomethasone dipropionate in some patients. The clinical relevance of these measurements is not yet clear, however. Nevertheless, it is important to reduce the likelihood of systemic effects by using the lowest dose of inhaled steroid needed to control the asthma, and by use of a large-volume spacer to reduce oropharyngeal deposition.
Several systemic effects of inhaled steroids have been described and include dermal thinning and skin capillary fragility (relatively common in elderly patients after high-dose inhaled steroids). Other side effects, such as cataract formation and osteoporosis, are reported but often in patients who are also receiving courses of oral steroids. There has been particular concern about the use of inhaled steroids in children because of growth suppression (Pedersen, 2001). Most studies have been reassuring that doses ≤400 μg/day have not been associated with impaired growth; on the contrary, there may even be a growth spurt as asthma is better controlled. There is some evidence that use of high-dose ICS is associated with cataract and glaucoma, but it is difficult to dissociate the effects of ICS from the effects of courses of oral steroids that these patients usually require.
ICS may have local side effects due to the deposition of inhaled steroid in the oropharynx. The most common problem is hoarseness and weakness of the voice (dysphonia) due to atrophy of the vocal cords following laryngeal deposition of steroid; it may occur in up to 40% of patients and is noticed particularly by patients who need to use their voices during their work (lecturers, teachers, and singers). Throat irritation and coughing after inhalation are common with MDI and appear to be due to additives because these problems are not usually seen if the patient switches to a DPI. There is no evidence for atrophy of the lining of the airway. Oropharyngeal candidiasis occurs in ∼5% of patients. There is no evidence for increased lung infections, including tuberculosis, in patients with asthma. Growing evidence suggests that high doses of ICS increase the risk of pneumonia in patients with COPD (Singh et al., 2009); although this is reported with high doses of fluticasone propionate, a similar increase in pneumonia has not been found with budesonide, which may be explained by its lower systemic effects (Sin et al., 2009).
It may be difficult to extrapolate systemic side effects of corticosteroids using data from normal subjects. In asthmatic patients, systemic absorption form the lung is reduced, presumably because of reduced and more central deposition of the inhaled drug in more severe patients (Brutsche et al., 2000; Harrison et al., 2001); most of the inhaled drug deposits in larger airways, thereby limiting effects in the smaller airways where inflammation is also found, especially in patients with severe asthma. Corticosteroid MDIs with HFA propellants produce smaller aerosol particles and may have a more peripheral deposition, making them useful in treating patients with more severe asthma.