Antiinflammatory Drugs

Published on 29/05/2015 by admin

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Last modified 29/05/2015

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Chapter 16 Antiinflammatory Drugs

Asthma and chronic obstructive pulmonary disease (COPD) are both inflammatory diseases. The nature of the inflammatory cascade is complex but different in each disease, asthma involving eosinophils and COPD and severe asthma involving neutrophils, among other inflammatory cell types. Therefore, asthma and COPD should be treated differently. Corticosteroids (also known as glucocorticoids or simply steroids), and particularly inhaled corticosteroids, constitute the most effective treatment for persistent asthma and are recommended as first-line agents in both adults and children. This group of drugs improves quality of life and lung function, by relieving symptoms, combating airway hyperresponsiveness, reducing inflammation, and limiting exacerbations. They are less effective at reducing COPD-specific inflammation and are not recommended until the disease has progressed to more advanced stages. Oral and systemic steroids are of benefit in treating COPD exacerbations, although their use is limited by side effects.

Bronchodilators, alone or in combination with an inhaled steroid, are the mainstay of COPD therapy, although a significant number of patients continue to suffer exacerbations while using these drugs. Only recently has a new class of antiinflammatory drug, the phosphodiesterase-4 (PDE4) inhibitors, been proved effective for the treatment of COPD, and at present only one drug in this class, roflumilast, has been approved for clinical use.

This chapter reviews these two classes of antiinflammatory drugs, highlighting their mode of action, clinical efficacy, and possible side effects. Some of the most commonly used systemic and inhaled corticosteroids are compared, with particular attention to dosing equivalence.

Corticosteroids

Corticosteroids have been the cornerstone of treatment for various inflammatory diseases affecting any and all body systems and structures for more than 60 years. They were first applied to the treatment of inflammatory diseases of the lungs in 1949. The development of inhaled corticosteroids has revolutionized the treatment of asthma, providing local antiinflammatory properties while minimizing the side effects that limit the use of oral and systemic steroids.

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).

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.

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).

Pharmacokinetics