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