Antiinflammatory Drugs

Chapter 16 Antiinflammatory Drugs



Klaus F. Rabe


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).


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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.


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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).


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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



Systemic


The route of administration for systemic steroids depends, to some degree, on the indication. Very high doses of corticosteroids given for acute conditions generally require parenteral administration. When the prescribed steroid dose can be achieved by oral administration (e.g., prednisone, 1 mg/kg daily), there is no clear benefit to parenteral therapy. The pharmacologic activity of systemic steroids depends on both the pharmacokinetic and pharmacodynamic properties of the drug. Dosing equivalence is based on the biologic activity of a given dose, as measured by antiinflammatory activity and sodium-retaining activity.


Oral steroids are readily absorbed by the gastrointestinal tract. The degree of first-pass hepatic elimination varies, with oral bioavailability ranging from 60% to 90%. Cortisone and prednisone are prodrugs and require hydroxylation in the liver for activation. After absorption, steroids are bound to proteins such as albumin and circulate systemically. The rate-limiting step in the elimination of a steroid drug is reduction and conjugation in the liver, although the final fate of these water-soluble metabolic end products is excretion in the urine. The metabolism of parenteral steroids is similar, except without first-pass elimination.



Inhaled


Between 10% and 60% of a dose of inhaled corticosteroid (ICS) is deposited in the lung, where it is absorbed into the systemic circulation and cleared through the liver. The remainder of the dose is deposited in the oropharynx, which can lead to local side effects. Any of the dose that is swallowed undergoes absorption into the portal circulation and undergoes first-pass elimination, as for oral steroids.


A number of methods have been developed for delivering inhaled steroids, including use of metered dose inhalers (MDIs), dry powder inhalers, and, less commonly, nebulizers. Historically, the propellants used in MDIs were chlorofluorocarbons, but recognition of the environmental impact of these agents led to the development of hydrofluoroalkanes as the propellant. All of these methods of delivery vary with respect to the particle size generated and velocity of delivered drug, resulting in small differences in equivalent dosing but similar efficiency of drug delivery.

Related posts:

  1. Nonbacterial Infectious Pneumonia
  2. Idiopathic Pulmonary Fibrosis and Other Interstitial Lung Diseases
  3. Lung Cancer: Clinical Evaluation and Staging
  4. Air Pollution

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Jun 12, 2016 | Posted by in RESPIRATORY | Comments Off on Antiinflammatory Drugs

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