Pharmacodynamics

Cellular, Tissue, and Systemic Effects

The primary therapeutic effect of corticosteroids in respiratory disease results from reducing the number of inflammatory cells in the airways, such as eosinophils, T lymphocytes, mast cells, and dendritic cells. Corticosteroids inhibit the recruitment of inflammatory cells by reducing chemotaxis and adhesion, phagocytosis, and respiratory burst activity, as well as the production of inflammatory mediators such as cytokines and eicosanoids. Corticosteroids also have lytic effects on circulating lymphocytes and induce neutrophilia through decreased adhesion and demargination of polymorphonuclear cells. In particular, airway endothelia are thought to be a major target for the antiinflammatory properties of inhaled steroids in asthma.

In COPD, however, even high-dose inhaled corticosteroids have little effect on airway inflammation, although they are effective when combined with a long-acting β₂-agonist (LABA) (Figure 16-1).

Figure 16-1 Inhaled corticosteroids and long-acting β-agonists reduce airway inflammation in chronic obstructive pulmonary disease (COPD). This figure demonstrates the reduction in inflammatory cells and cytokines in endobronchial biopsy specimens after 12 weeks of treatment with combination therapy, compared with placebo. IFN-γ, interferon-γ; SALM/FPP, salmeterol/fluticasone propionate; TFN-α, transforming growth factor-α.

(From Barnes NC, Qiu Y, Pavord ID, et al: Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease, Am J Respir Crit Care Med 173:736–743, 2006.)

Molecular Mechanisms

The primary effect of corticosteroids appears to be at the genetic level, activating transcription of antiinflammatory genes and repressing proinflammatory genes. They act primarily by binding to intracellular glucocorticoid receptors, which in turn regulate gene expression through glucocorticoid response elements (GREs) (Figure 16-2). Once inside the nucleus, glucocorticoid receptors dimerize and bind to GREs in the promoter regions of steroid-responsive genes, altering gene transcription and initiating a cascade of antiinflammatory effects downstream. Mediators affected by corticosteroids include cytokines, adhesion molecules, and chemokines. Nuclear glucocorticoid receptor monomers also interact with transcription factors such as nuclear factor (NF)-κB, to suppress expression of a number of proinflammatory genes. Corticosteroids can also decrease protein synthesis by decreasing messenger RNA (mRNA) stability.

Figure 16-2 Molecular mechanisms of corticosteroid action. Corticosteroids diffuse readily across the cell membrane, where they bind glucocorticoid receptors. Corticosteroid binding causes dissociation of chaperone proteins (such as heat shock protein 90), thereby allowing translocation of the glucocorticoid receptor to the nucleus. Once in the nucleus, the glucocorticoid receptor can dimerize and bind to glucocorticoid response elements (GREs), or it can bind to other transcription factors (such as activator protein 1 and nuclear factor-κB) as a monomer.

(From McGhan RM: Corticosteroids. In Albert RK, Spiro SG, Jett JR, editors: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008, p 484.)

Recent work has focused on the role of corticosteroids in regulating gene expression through effects on histone acetylation and chromatin compaction. Inflammatory signals cause chromatin unwinding by histone acetyltransferase activity. Corticosteroids can directly inhibit histone acetyltransferases and recruit histone deacetylases (HDACs) to their site of action, seemingly independent of glucocorticoid receptor binding to GREs. Corticosteroids interact with specific HDACs (such as HDAC2) that target specific histone proteins (e.g., histone H₄), regulating expression of particular regions of the genome. The net effect is to decrease histone acetylation, promoting chromatin compaction and downregulation of inflammatory gene expression (Figure 16-3).

Figure 16-3 Effects of inflammation and corticosteroids on chromatin compaction. Inflammation promotes acetylation of histones by increasing histone acetyltransferase (HAT) activity; in addition, histone deacetylase (HDAC) activity is decreased in inflammatory lung diseases including asthma and chronic obstructive pulmonary disease (COPD). Corticosteroids promote chromatin compaction and silencing of gene transcription by inhibiting HAT activity and by increasing HDAC activity. ACh, acetylcholine.

(From McGhan RM: Corticosteroids. In Albert RK, Spiro SG, Jett JR, editors: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008, p 485.)

Synergy with Bronchodilators

Inhaled corticosteroids and β₂-agonists appear to work in synergy: The steroids upregulate β₂-adrenoreceptors and prevent tachyphylaxis in response to β₂-agonists, while β₂-agonists increase translocation of glucocorticoid receptors from the cytoplasm to their site of action in the nucleus. As might be expected, then, these two important drug classes have an additive effect when given in combination, which may explain the greater efficacy of fixed-dose combinations in COPD compared with that achieved with inhaled steroid monotherapy.

Steroid Resistance

Resistance to corticosteroids is problematic, because high doses are associated with side effects. Several mechanisms of steroid resistance have been described. Inactivating mutations in the glucocorticoid receptor occur in rare cases; these patients typically suffer no side effects of corticosteroid treatment. More commonly, steroid resistance is acquired during the course of inflammatory diseases and may, in fact, be induced selectively in inflamed tissues through the action of inflammatory cytokines. Alternative splicing of the glucocorticoid receptor may result in accumulation of β-glucocorticoid receptors that do not bind steroids, and may decrease the activity of steroid-bound α-glucocorticoid receptors through formation of heterodimers and through competitive binding to GREs. Additional mechanisms may include phosphorylation of glucocorticoid receptors that alters their pharmacologic activity and acquired HDAC deficiency, resulting in decreased steroid-induced chromatin compaction.

Pharmacokinetics

Side Effects

Generally, side effects are more common with systemic steroids than with inhaled agents (Table 16-3). Tolerability can be improved further by reducing dosage or treatment duration where possible, and with improvements in formulation as described above. Long-term use of systemic steroids can be associated with weight gain, increased susceptibility to infection secondary to immunosuppression, growth retardation in children, and osteoporosis. All forms of corticosteroids can hinder growth in children, although growth retardation associated with inhaled steroids is transient and of no long-term significance. The Childhood Asthma Management Program study monitored growth in 1041 children treated with budesonide, nedocromil, or placebo for 4 to 6 years and found a 1.1-cm lag in height gained in patients taking budesonide compared with placebo. This lag was experienced primarily during the first year of the study.

Corticosteroids adversely affect bone health, with osteoporosis, osteoporotic fractures, and avascular osteonecrosis being relatively common and severe toxicities resulting from systemic administration. The incidence of osteoporosis seems to be related to daily use, prolonged duration of use, and significant cumulative lifetime dose, and this complication has been seen with doses as low as 5 to 7.5 mg/day of prednisone.

Adrenal insufficiency is a well-described consequence of systemic corticosteroid use. The risk seems minimal with inhaled steroidal agents. Although suppression of morning cortisol levels does occur in response to these agents, the risk of clinically apparent adrenal insufficiency is small (although supported by published case reports).

Systemic corticosteroids are potent immunosuppressors, particularly when prescribed in higher doses and for prolonged periods of time. Courses of 2 to 8 weeks of systemic steroids used to treat acute exacerbations of COPD do not seem to be associated with increased rates of infection. Chronic corticosteroid use is recognized to carry a risk for Pseudomonas and Pneumocystis infections, tuberculosis, and herpes zoster.

Side effects of inhaled steroidal agents are mostly associated with deposition of the drug in the oropharynx, such as oral candidiasis (thrush) and dysphonia, although the incidence of these events can be reduced by rinsing the mouth after taking the drug. Inhaled formulations have been associated with decreased bone mineral density in at least one randomized controlled trial. Inhaled steroids initially were not thought to increase the risk of lung infections, but more recently, the TORCH (Towards a Revolution in COPD Health) trial found an increased frequency of pneumonia among patients receiving inhaled steroids (fluticasone propionate, with or without salmeterol), possibly a result of localized immunosuppression in the lungs.

Prevention and Management of Corticosteroid Toxicity

To reduce side effects associated with inhaled corticosteroid use, patients should be educated on proper inhaler technique and on washing out the mouth after use, and those who use MDIs should be given a spacer to add to their device. Symptoms associated with use of an MDI sometimes may be reduced or eliminated by a switch to a dry powder inhaler. Children who use a nebulizer for steroid delivery should wash the face after using the medication.

In patients on pharmacologic doses of systemic steroids, periodic ophthalmologic examination can detect the development of cataracts and glaucoma, which may respond to reduction in dose or, if the steroid dose cannot be reduced, other treatments. The role of ophthalmologic assessment in patients on inhaled steroidal agents is less clear, but these patients should certainly be referred for evaluation of any ophthalmologic symptoms and for routine, age-appropriate care.

Screening for and management of cardiovascular risk factors, including hypertension, hyperglycemia, and hyperlipidemia, also are warranted in patients receiving chronic systemic steroids.

Patients receiving chronic systemic or inhaled steroid therapy should have routine bone mineral density measurements (particularly in high-risk groups), and they should be encouraged to perform weight-bearing exercise and to take calcium and vitamin D supplements (in the absence of any contraindications). Hormone replacement, bisphosphonates, calcitonin, and hydrochlorothiazide (HCTZ) can be considered in patients with established osteoporosis.

Avoidance of nonsteroidal antiinflammatory drugs (NSAIDs) is appropriate in patients receiving systemic steroids. Vigilance for psychiatric symptoms is prudent; if such symptoms are present, the patient can be managed by reducing the dose of steroid and/or by pharmacotherapy targeting the psychiatric symptoms.

Patients receiving chronic steroid therapy should be alerted to the increased risk of infection and should be encouraged to seek prompt evaluation at the earliest sign of infection. If possible, any vaccinations that are appropriate should be administered before therapy starts. If long-term administration of moderate to high doses of systemic corticosteroids is anticipated, prophylaxis for Pneumocystis pneumonia may be appropriate.

Patients receiving chronic systemic steroid therapy should be alerted to the symptoms of adrenal insufficiency and should be encouraged not to skip doses.

Pharmacodynamics

Molecular Mechanisms

Roflumilast and other PDE4 inhibitors bind directly to PDE4 to block its activity, thereby reducing inflammation (Figure 16-4). PDE4 is expressed in many cells involved in the inflammatory response that underlies COPD.

Figure 16-4 Molecular pathways affected by inhibition of phosphodiesterase 4 (PDE4). PDE4 inhibitors block the activity of PDE4, causing accumulation of cyclic adenosine monophosphate (cAMP) and downstream increase in protein kinase A (PKA) activation. This in turn leads to protein phosphorylation (P), resulting in an overall antiinflammatory effect. Although increased cAMP levels generally are associated with smooth muscle relaxation, this is not a characteristic of roflumilast. ADP, adenosine diphosphate; ATP, adenosine triphosphate.

(Modified from Rabe KF: Roflumilast for the treatment of chronic obstructive pulmonary disease, Expert Rev Respir Med 4:543–555, 2010.)

Pharmacokinetics

In humans, roflumilast is rapidly converted to roflumilast N-oxide, which is responsible for most therapeutic effects. It has a long half-life, which allows once-daily dosing, and is taken orally at the optimal dose of 500 µg. In clinical studies, the main benefit of this drug in patients with COPD was found to be reduction in the frequency of moderate to severe COPD exacerbations.

Phase III clinical testing has shown that roflumilast is most effective in a subpopulation of patients with COPD who are at increased risk for COPD exacerbations. The target subgroup includes patients with severe COPD (i.e., with a postbronchodilator forced expiratory volume in 1 second [FEV₁] less than 50%), symptoms of chronic bronchitis (which is linked to an increased risk of exacerbations), and a history of more than one exacerbation in the past year. These patients are most likely to suffer from repeated exacerbations (the “frequent exacerbator” phenotype) and therefore benefit the most from the clinical effects of roflumilast—that is, in reducing exacerbation frequency. Clinical studies have shown that roflumilast significantly improves lung function and reduces exacerbations when added to most COPD maintenance therapy regimens—including a LABA, a long-acting muscarinic antagonist (LAMA), or inhaled steroid—in this patient subgroup as described (Figure 16-5).

Figure 16-5 Clinical effects of roflumilast on lung function (A) and exacerbation rate (B). Both 12- and 6-month studies were performed in patients with chronic obstructive pulmonary disease (COPD), chronic bronchitis (not required in the salmeterol study), and at least one exacerbation in the past year. Patients were allowed to take long-acting β₂-agonists (LABAs) or short-acting muscarinic antagonists (SAMAs) as concomitant medications in the 12-month studies; all patients were taking salmeterol or tiotropium in the 6-month studies. Effects of roflumilast were observed on top of effects of concomitant medications. The 6-month studies were not powered to detect differences in exacerbation rate. *Indicates post hoc analyses. CI, confidence interval; FEV₁, forced expiratory volume in 1 second.

(Modified from Rabe KF: Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease, Br J Pharmacol 163:53–67, 2011.)

Side Effects

All PDE4 inhibitors have been associated with gastrointestinal side effects such as nausea and diarrhea. Roflumilast is clinically effective at a relatively low dose (compared with other PDE4 inhibitors), thereby minimizing the risk of side effects. In 1-year phase III clinical studies, the incidence of side effects was 67% with roflumilast and 62% with placebo, although study discontinuations were more often associated with roflumilast (14%) than with placebo (11%). Diarrhea, headache, and weight loss appear to be the most limiting side effects associated with roflumilast, although in most cases, these appear to resolve with continued use of the drug. Further investigation has shown that the weight reduction associated with roflumilast was due mostly to loss of fat mass rather than fat-free body mass, and additional metabolic effects of this systemic drug are the subject of ongoing investigations.