26 Pharmacology 4: Anti-Inflammatory Drugs

Question 1

Asthma

• General
• Characterized by…
• Pathogenesis
• Chemical mediators
• IMPORTANT CONCEPT 1: Asthma and effective treatments

Answer 1

• General
  
  • Chronic disorder of the airways
• Characterized by…
  
  • Reversible airflow obstruction and airway inflammation
  • Persistent airway hyper-reactivity (AHR)
  • Airway remodeling
• Pathogenesis
  
  • Chronic inflammation of the bronchial mucosa is prominent with iinfiltration of activated T-lymphocytes and eosinophils
  • This results in subepithelial fibrosis and the release of chemical mediators that can damage the epithelial lining of the airway
• Chemical mediators
  
  • Many of these mediators are released following activation and degranulation of mast cells in the bronchial tree
  • Some of these mediators act as chemotactic agents for other inflammatory cells
  • They also produce mucosal edema, which narrows the airway and stimulates smooth muscle contraction, leading to bronchoconstriction
  • Excessive production of mucus can cause further airway obstruction by plugging the bronchiolar lumen
• IMPORTANT CONCEPT 1: Asthma and effective treatments
  
  • Asthma is an inflammatory disease
  • Effective treatments for the chronic management of asthma should be directed to reduce the inflammatory response

Question 2

Inflammatory mediators in asthma

Answer 2

• Activation of mast cells results in secretion of several mediators that contribute to the pathogenesis of asthma
• These mediators produce bronchconstriction and initiate both the acute inflammatory response and attract cells responsible for maintaining chronic inflammation
• IL, interleukin
• GM-CSF, granulocyte and macrophage colony-stimulating factor
• PG, prostaglandin
• TNF, tissue necrosis factor
• IFN interferon

Question 3

The available agents for treating asthma can be divided into two general categories

Answer 3

• Drugs that inhibit smooth muscle contraction
  
  • I.e., the so-called “quick relief medications” or bronchodilators (beta-adrenergic agonists, methylxanthines, and anticholinergics)
• Agents that prevent and/or reverse inflammation
  
  • I.e., the “long-term control medications” (glucocorticoids, leukotriene inhibitors and receptor antagonists, and mast cell-stabilizing agents, or cromones)

Question 4

Glucocorticoid physiology

• Synthesis
• Secretion
• Physiological effects

Answer 4

• Synthesis
  
  • Synthesized in the adrenal cortex at a daily rate of 10 mg/day and
• Secretion
  
  • Exhibit a diurnal pattern of secretion (i.e. 16μg/dL in blood @ 8 a.m. and 4 μg/dL @ 4 p.m.)
  • Have access to all tissues in the body and exert wide-ranging effects on many organ systems
  • Under conditions of severe stress, glucocorticoid levels can rise at least 10-fold
• Physiological effects
  
  • Regulation of carbohydrate, protein and lipid metabolism
  • Maintenance of fluid and electrolyte balance
  • Preservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system and the nervous system
  • Preservation of organismal homeostasis

Question 5

Glucocorticoid physiology

• The impact of glucocorticoids
• Glucocorticoids and mineralocorticoids
• Important side effects of glucocorticoid therapy
• IMPORTANT CONCEPT 2: The anti-inflammatory and immunosuppressive actions of glucocorticoids…

Answer 5

• The impact of glucocorticoids
  
  • Potent antiinflammatory and immunosuppressive actions
  • Affect various tissues
  • Systemic treatment with pharmacological doses of glucocorticoids generates many adverse side effects
• Glucocorticoids and mineralocorticoids
  
  • Physiological glucocorticoids (i.e. cortisol) bind with reasonably high affinity to the mineralocorticoid receptor
• Important side effects of glucocorticoid therapy
  
  • Alterations in fluid and electrolyte handling (mediated physiologically by the mineralocorticoid receptor)
  • Ensuing hypertension
• IMPORTANT CONCEPT 2: The anti-inflammatory and immunosuppressive actions of glucocorticoids…
  
  • Play an important role in preventing potential damaging effects of an unopposed inflammatory response and can be exploited therapeutically

Question 6

Effects of glucocorticoids on components of inflammatory / immune responses

• Macrophages and monocytes
• Endothelial cells
• Basophils
• Fibroblasts
• Lymphocytes

Answer 6

• Macrophages and monocytes + endothelial cells + fibroblasts
  
  • Arachidonic acid and its metabolites (prostaglandins and leukotrienes)
    
    • Mediated by glucocorticoid inhibition of cyclooxygenase–2 and phospholipase A2
    • Fibroblasts: glucocorticoids also suppress growth factor–induced DNA synthesis and fibroblast proliferation
• Macrophages and monocytes + endothelial cells + lymphocytes
  
  • Cytokines, including: interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha (TNF-alpha)
    
    • Production and release are blocked. The cytokines exert multiple effects on inflammation (e.g., activation of T cells, stimulation of fibroblast proliferation)
• Macrophages and monocytes + endothelial cells
  
  • Acute phase reactants
    
    • These include the third component of complement
• Endothelial cells
  
  • Endothelial leukocyte adhesion molecule-1 (ELAM-1) and inracellular adhesion molecule-1 (ICAM-1)
    
    • ELAM-1 and ICAM-1 are intracellular adhesion molecules that are critical for leukocyte localization
• Basophils
  
  • Histamine, leukotriene C4
    
    • IgE-dependent release inhibited by glucocorticoids
• Fibroblasts
  
  • Arachidonic acid metabolites
    
    • Mediated by glucocorticoid inhibition of cyclooxygenase–2 and phospholipase A2
    • Glucocorticoids also suppress growth factor–induced DNA synthesis and fibroblast proliferation
• Lymphocytes

Question 7

Potential adverse effects associated with inhaled glucocorticoids

• Adverse effects + risks
• IMPORTANT CONCEPT 3: The beneficial effects of systemic glucocorticoids to limit inflammation…
  
  • Is counter-balanced by its many adverse side effects

Answer 7

• Hypothalamic–pituitary– adrenal axis suppression
  
  • No significant risk until dosages of budesonide or beclomethasone increased to >1500 g/day in adults or >400 g/day in children
• Bone resorption
  
  • Modest but significant effects at doses possibly as low as 500 g/day
• Carbohydrate and lipid metabolism
  
  • Minor, clinically insignificant changes occur with dosages of beclomethasone >1000 g/day
• Cataracts
  
  • Anecdotal reports, risk unproven
• Skin thinning
  
  • Dosage-related effect with beclomethasone dipropionate over a range of 400 to 2000 g/day
• Purpura
  
  • Dosage-related increase in occurrence with beclomethasone over a range of 400 to 2000 g/day
• Dysphonia
  
  • Usually of little consequence
• Candidiasis
  
  • Incidence <5%, reduced by use of spacer device
• Growth retardation
  
  • Difficult to separate effect of disease from effect of treatment, but no discernible effects on growth when all studies are considered
• IMPORTANT CONCEPT 3: The beneficial effects of systemic glucocorticoids to limit inflammation is counter-balanced by its many adverse side effects

Question 8

Mechanism of action of glucocorticoids

• The glucocorticoid receptor (GR)
  
  • Glucocorticoid effects in target tissues are mediated by…
  • The GR, like all NRs
  • Thus, many of the changes in cellular physiology that result from glucocorticoid exposure…
• Glucocorticoid regulation of gene expression
  
  • Each tissue and cell type contains…
  • Specific sequences within genes that are regulated by glucocorticoids are recognized by…
  • The binding of the GR to target gene sequences can lead…

Answer 8

• The glucocorticoid receptor (GR)
  
  • Glucocorticoid effects in target tissues are mediated by…
    
    • A single receptor protein, the GR, which is a member of the nuclear receptor (NR) superfamily
  • The GR, like all NRs
    
    • A transcription factor that exerts most of its physiological effects through the positive or negative regulation of specific target genes
  • Thus, many of the changes in cellular physiology that result from glucocorticoid exposure…
    
    • Are not acute and require hours or even days to develop
• Glucocorticoid regulation of gene expression
  
  • Each tissue and cell type contains…
    
    • A distinct set of target genes that are regulated by glucocorticoids
  • Specific sequences within genes that are regulated by glucocorticoids are recognized by…
    
    • Hormone-bound GR
  • The binding of the GR to target gene sequences can lead…
    
    • Either to increased or decreased transcription of that gene.

Question 9

Mechanism of action of glucocorticoids

• Glucocorticoid repression of inflammatory modulator gene expression
  
  • Transcription factors, Nuclear Factor-kappa B (NF-kB) and AP-1
  • When bound to hormone, the GR…
  • These effects of glucocorticoids are observed…
• IMPORTANT CONCEPT 4: The broad anti-inflammatory actions of glucocorticoids are due primarily but not exclusively to…

Answer 9

• Glucocorticoid repression of inflammatory modulator gene expression
  
  • Transcription factors, Nuclear Factor-kappa B (NF-kB) and AP-1
    
    • Regulate a number of genes of the immune system
    • Are subject to activation by many external stimuli
  • When bound to hormone, the GR…
    
    • Can inhibit the action of NF-kB and AP-1 on many genes
    • Leads to repression of transcription of genes that are activated in an immune or inflammatory response
  • These effects of glucocorticoids are observed…
    
    • In many cells of the immune system
• IMPORTANT CONCEPT 4: The broad anti-inflammatory actions of glucocorticoids are due primarily but not exclusively to…
  
  • Transcriptional repression of pro-inflammatory genes in multiple cell types by the GR

Question 10

Mechanism of action of glucocorticoids:
Modulation of chromatin structure of target genes by GRs

• DNA within the nucleus is packaged into…
• In general, the extent of transcription from a given gene is influenced by…
• Chromatin associated with actively vs. inactively transcribed genes
• When associated with its target genes, the GR also recruits…
• Thus, when activating gene transcription, GR recruits…
• Increased histone acetylation by HATs…
• When repressing gene transcription, GR recruits…
• Decreased histone acetylation by HDACs…

Answer 10

• DNA within the nucleus is packaged into…
  
  • Chromatin due to its association with basic proteins known as histones
• In general, the extent of transcription from a given gene is influenced by…
  
  • The strength of its binding to histones
• Chromatin associated with actively vs. inactively transcribed genes
  
  • Actively transcribed genes are generally associated with less condensed chromatin
  • Inactive genes are associated with more condensed chromatin
• When associated with its target genes, the GR also recruits…
  
  • Large protein complexes that function to modify the chromatin structure of target genes
• Thus, when activating gene transcription, GR recruits…
  
  • Enzymes such as Histone Acetyltransferases (HATs) to the gene
• Increased histone acetylation by HATs…
  
  • Neutralizes some histone basic character and “loosens” their grip on DNA
• When repressing gene transcription, GR recruits…
  
  • Enzymes such as Histone Deacetylases (HDAC) to the gene
• Decreased histone acetylation by HDACs…
  
  • Restores histone basic character and “tightens” their grip on DNA

Question 11

Mechanism of action of glucocorticoids:
Modulation of chromatin structure of target genes by GRs

• The balance between gene specific histone acetylation and deacetylation will ultimately impact…
• It is therefore rather surprising that a global decrease in HDAC activity was detected in patients with…
• Importantly, decreased HDAC activity in this case was associated with…
• IMPORTANT CONCEPT 5: The GR regulates…

Answer 11

• The balance between gene specific histone acetylation and deacetylation will ultimately impact…
  
  • The efficiency of transcription of that given gene
• It is therefore rather surprising that a global decrease in HDAC activity was detected in patients with…
  
  • Chronic obstructive pulmonary disease (COPD)
• Importantly, decreased HDAC activity in this case was associated with…
  
  • Enhanced transcription of some pro-inflammatory genes
• IMPORTANT CONCEPT 5: The GR regulates…
  
  • Gene transcription (either positively or negatively) through the gene-selective recruitment of histone modifying enzymes

Question 12

Pharmacology of glucocorticoids for the treatment of asthma:
Structure / activity relationships

• Chemical modification of cortisol can dramatically influence…
• Prednisolone
• The fluorinated glucocorticoids dexamethasone and betamethasone
• Cortisone
• IMPORTANT CONCEPT 6: Structural modifications of the natural glucocorticoid cortisol generate…

Answer 12

• Chemical modification of cortisol can dramatically influence…
  
  • Its half-life and efficacy
• Prednisolone
  
  • Has enhanced glucocorticoid activity with reduced mineralocorticoid activity
  • Is metabolized much more slowly than cortisol
• The fluorinated glucocorticoids dexamethasone and betamethasone
  
  • Have very long half-lives
  • Are potent glucocorticoids
  • Have no detectable mineralocorticoid action
• Cortisone
  
  • Must be enzymatically reduced by 11ß-hydroxysteroid dehydrogenase (typically in liver) in order to be active
• IMPORTANT CONCEPT 6: Structural modifications of the natural glucocorticoid cortisol generate…
  
  • Hormones with enhanced half-life and more potent and efficacious glucocorticoid activity

Question 13

Pharmacology of glucocorticoids for the treatment of asthma:
Delivery of glucocorticoids

• Systemic glucocorticoids
• However, the development of aerosol delivery systems for glucocorticoids has led to…
• Various glucocorticoid formulations are available for aerosol delivery that differ in their…
• Various factors influence the choice and dose of the drug used including…
• However, maximal improvement of lung function may not occur until…

Answer 13

• Systemic glucocorticoids
  
  • Not routinely used for asthma treatment given the potential for side effects
  • Still used for chronic, severe asthma
• However, the development of aerosol delivery systems for glucocorticoids has led to…
  
  • Dramatic increases in the therapeutic index of glucocorticoid treatment for less severe, chronic asthma
  • Thus, this allows for the generalized anti-inflammatory actions of this hormone to be exploited
• Various glucocorticoid formulations are available for aerosol delivery that differ in their…
  
  • Affinity for the GR
• Various factors influence the choice and dose of the drug used including…
  
  • The severity of the disease
  • The devise used for drug delivery
• However, maximal improvement of lung function may not occur until…
  
  • Several weeks after treatment

Question 14

Pharmacology of glucocorticoids for the treatment of asthma:
Delivery of glucocorticoids

• Several systemic effects of inhaled steroids have been described and include…
• Inhaled steroids may have local side effects due to…
• The most common problems

Answer 14

• Several systemic effects of inhaled steroids have been described and include…
  
  • Dermal thinning
  • Skin capillary fragility
• Inhaled steroids may have local side effects due to…
  
  • Tthe deposition of inhaled steroid in the oropharynx
• The most common problems
  
  • Hoarseness
  • Dysphonia
  • Oropharyngeal candidiasis occurs in 5% of patients

Question 15

Pharmacology of glucocorticoids for the treatment of asthma:
Delivery of glucocorticoids

• Even with proper use of aerosol devices,…
• Thus, even inhaled glucocorticoids have some oral bioavailability
• In addition, pulmonary retention of ICS…
• Furthermore, reversible lipid conjugation (i.e. fatty acid esterification) of some ICS…
• Differential lipid conjugation can influence…
• IMPORTANT CONCEPT 7: The aerosol delivery of glucocorticoids to the lungs limits…

Answer 15

• Even with proper use of aerosol devices,…
  
  • Typically 2-10% of inhaled glucocorticoids are deposited in lung with the remainder swallowed and absorbed in the gut
• Thus, even inhaled glucocorticoids have some oral bioavailability
  
  • Fraction of oral dose the reaches the systemic circulation
  • Reflective of both the fraction absorbed and fraction escaping first pass metabolism
• In addition, pulmonary retention of ICS…
  
  • Limits their absorption into the systemic circulation
  • Is positively correlated with their lipophilicity
• Furthermore, reversible lipid conjugation (i.e. fatty acid esterification) of some ICS…
  
  • Occurs in pulmonary cells
  • Leads to prolonged pulmonary retention
• Differential lipid conjugation can influence…
  
  • The dosing regimen of an ICS
• IMPORTANT CONCEPT 7: The aerosol delivery of glucocorticoids to the lungs limits…
  
  • Systemic exposure to the hormone and greatly reduces side effects

Question 16

Pharmacology of glucocorticoids for the treatment of asthma:
New approaches for glucocorticoid treatment of asthma

• Fluticasone propionate
• 17ß-carboxylic acid derivative
• Thus, the bioavailability of these drugs…
• The risk of systemic effects

Answer 16

• Fluticasone propionate
  
  • New analog of potent glucocorticoids
  • The active component of FLOVENT
  • Are subjected to rapid inactivation in liver
• 17ß-carboxylic acid derivative
  
  • The only circulating metabolite of fluticasone propionate detected
  • Formed through the cytochrome P450 3A4 pathway
  • Inactive metabolite
  • Has lower affinity (approximately 1/2,000) than the parent drug for GR in human lung cytosol and negligible pharmacological activity in animal studies
• Thus, the bioavailability of these drugs…
  
  • Is negligible outside of the airways
• The risk of systemic effects
  
  • Due to improper inhalation and swallowing of the drug
  • Dramatically reduced

Question 17

Pharmacology of glucocorticoids for the treatment of asthma:
New approaches for glucocorticoid treatment of asthma

• Novel GR agonists (e.g. ciclesonide [ALVESCO®])
• Typical local side effects of inhaled soft steroids
• Current preparations of inhaled soft steroids such as ciclesonide
• Esterases that act on these soft steroids are present…
• The oral bioavailability for inhaled fluticasone propionate and ciclesonide
• IMPORTANT CONCEPT 8: New generation synthetic glucocorticoids

Answer 17

• Novel GR agonists (e.g. ciclesonide [ALVESCO®])
  
  • Preferentially activated in lung relative to the oropharynx (i.e. “soft steroids”)
  • Typically are esterified at the C21-hydroxyl (a group required for interactions with the GR) and therefore inactive
  • Activated by an esterase that exists in lung but that is not present in the oropharynx
• Typical local side effects of inhaled soft steroids
  
  • Minimal
• Current preparations of inhaled soft steroids such as ciclesonide
  
  • Have a much higher pulmonary deposition (i.e. ~50%) relative to fluticasone propionate (i.e. ~15%)
• Esterases that act on these soft steroids are present…
  
  • In other tissues in the body
  • Systemic adverse effects of these compounds can occur if they enter the systemic circulation
• The oral bioavailability for inhaled fluticasone propionate and ciclesonide
  
  • Comparable (i.e. < 1%)
• IMPORTANT CONCEPT 8: New generation synthetic glucocorticoids
  
  • More rapid metabolism in the liver
  • Overcome potential side effects due to ingested hormone upon aerosol delivery

Question 18

Pharmacology of glucocorticoids for the treatment of asthma:
New approaches for glucocorticoid treatment of asthma:
Glucocorticoids can also be combined with long-acting ß2-adrenergic receptor agonists (LABA) in a single inhaler devise

• Advair®
• LABA therapy

Answer 18

• Advair®
  
  • One type of combination drug that contains fluticasone and salmeterol
  • Improves clinical outcome to a greater extent than increasing ICS dose alone
  • Leads to an enhancement of the anti-inflammatory action of glucocorticoids at lower doses due in part to increased nuclear localization of GR
• LABA therapy
  
  • Does not appear to have any clinically important anti-inflammatory or pro-inflammatory effect
  • Decreases BAL fluid albumin levels, suggesting a possible modulating effect on microvascular leakage
• The effectiveness of combined LABA and glucocorticoid treatment may also be due to…
  
  • Effects of the steroid on ß2-adrenergic receptor function
• Glucocorticoids vs. ß2-adrenergic receptors
  
  • Increase transcription of the ß2-adrenergic receptor gene and protein expression in human lung cells
  • Enhance the coupling of the ß2-adrenergic receptor to Gs at the expense of coupling to Gq, which can promote pro-inflammatory effects of ß2 adrenergic agonists.
• IMPORTANT CONCEPT 9: New generation synthetic glucocorticoids can be combined with…
  
  • Eong acting ß2-adrenergic receptor agonists for effective management of asthma

Question 19

Pharmacology of glucocorticoids for the treatment of asthma:
New approaches for glucocorticoid treatment of asthma

• The anti-inflammatory actions of glucocorticoids
• “Dissociated” glucocorticoids
• The use of intermittent short course versus regular daily use of inhaled glucocorticoids in patients with mild asthma
• IMPORTANT CONCEPT 10: New generation synthetic glucocorticoids or non-steroidal GR ligands

Answer 19

• The anti-inflammatory actions of glucocorticoids
  
  • Mainly but not exclusively due to gene repression
• “Dissociated” glucocorticoids
  
  • Unleash the gene repression activity of the GR while having little or lessened impact on the gene activation activity of the receptor
  • Still have antiinflammatory activity but reduced side effects.
• The use of intermittent short course versus regular daily use of inhaled glucocorticoids in patients with mild asthma
  
  • Some studies: no differences in asthma control with the two distinct regimens
  • Meta-analysis: daily use of inhaled glucocorticoids lead to superior asthma control and a reduction in the need for rescue medication
• IMPORTANT CONCEPT 10: New generation synthetic glucocorticoids or non-steroidal GR ligands
  
  • Maintain gene repression
  • Limit gene activation by the GR (i.e. dissociated glucocorticoids)
  • May hold promise as anti-inflammatory drugs with reduced side effects

Question 20

Pharmacology of glucocorticoids for the treatment of asthma:
The need for new therapies

• Existing therapies for asthma, particularly combination inhalers
• However, ~5% of adult and 20% of pediatric asthma patients experience…
• Nonadherence
• One of the major issues with compliance in all asthma patients
• Ultra-long-acting ß2- agonists: Indacaterol
• IMPORTANT CONCEPT 11: New ultra-long-acting ß2 agonists (alone or in combination with glucocorticoids)

Answer 20

• Existing therapies for asthma, particularly combination inhalers
  
  • Relatively effective, safe, and inexpensive
  • Limits the impetus to develop new drugs
• However, ~5% of adult and 20% of pediatric asthma patients experience…
  
  • Persistent symptoms with frequent exacerbations despite high dose therapy
• Nonadherence
  
  • A problem, particularly for patients with difficult asthma
  • Significantly lowers their asthma-specific quality of life
• One of the major issues with compliance in all asthma patients
  
  • The complexity of inhaler use and frequency of dosing
• Ultra-long-acting ß2- agonists: Indacaterol
  
  • Quick onset of action
  • Full ß2 agonist with a longer duration of action than salmeterol
  • Broad therapeutic window
  • Limited adverse effects (i.e. transient cough)
  • A single dose to patients with intermittent or mild-to-moderate persistent asthma provided sustained (i.e. 24 hr) bronchodilatory control
  • May also provide bronchodilatory control in COPD patients (ongoing studies)
• IMPORTANT CONCEPT 11: New ultra-long-acting ß2 agonists (alone or in combination with glucocorticoids)
  
  • Being developed to provide once-daily inhaler dosing to aid with patient compliance

Question 21

Pharmacology of glucocorticoids for the treatment of asthma:
Glucocorticoid resistance

• Corticosteroid-dependent (CD) asthma
• In CD patients, asthma conditions worsen if…
• Corticosteroid-resistant (CR) asthma
• The mechanisms responsible for CR or CD may involve…
• Asthmatic children exposed to a combination of chronic and acute stresses exhibit…
• An alternative form of the GR exists (i.e. GRß)
• Patients with CR asthma can be treated with…
• IMPORTANT CONCEPT 12: Disruptions in GR expression and signal transduction can contribute to…and underlie…

Answer 21

• Corticosteroid-dependent (CD) asthma
  
  • A situation of reduced responsiveness to glucocorticoids
  • Common among smokers
  • Requires high inhaled or oral doses for disease control
• In CD patients, asthma conditions worsen if…
  
  • Glucocorticoid doses are reduced
• Corticosteroid-resistant (CR) asthma
  
  • A rare form of CD asthma found in 1/1,000 asthma patients
  • A failure to improve lung function by more than 15% after treatment with high doses of prednisolone (30-40 mg daily) for 2 weeks
• The mechanisms responsible for CR or CD may involve…
  
  • Disruptions in GR function
  • Reduced nuclear translocation of the GR
  • Disruptions in histone modifications in chromatin of GR regulated genes
• Asthmatic children exposed to a combination of chronic and acute stresses exhibit…
  
  • Decreased expression of GR mRNA in lymphocytes that could be associated with worsening outcome
• An alternative form of the GR exists (i.e. GRß)
  
  • Does not bind natural glucocorticoids
  • Can also function to limit the action of the bona fide GR (GR)
  • CR asthma may also be associated with the increased expression of GRß
• Patients with CR asthma can be treated with…
  
  • Long-acting inhaled ß2-agonists, as they often have a good bronchodilator response to these agents
  • Theophylline may also be effective, but its effects are not mediated by its inhibition of PDE
  • Its effectiveness may be due to its action at the genome level to decrease the extent of chromatin-associated histone protein acetylation (i.e. through the increased activity of histone deacetylase [HDAC] enzymes)
• IMPORTANT CONCEPT 12: Disruptions in GR expression and signal transduction can contribute to…and underlie…
  
  • Corticosteroid-resistant (CR) asthma and underlie the worsening effects of stressful events on asthma symptoms

Question 22

Other anti-inflammatory agents

• Anti-inflammatory drugs
• The characteristic histologic feature of asthma
• Relevant and promising targets of asthma therapy

Answer 22

• Anti-inflammatory drugs
  
  • Prevent inflammatory cell infiltration and the release, synthesis, and effects of inflammatory mediators
• The characteristic histologic feature of asthma
  
  • Eosinophilic inflammation of the airways
• Relevant and promising targets of asthma therapy
  
  • Factors that promote the accumulation, activation, and survival of eosinophils
  • Include…
    
    • Cytokines (IL-5, GM-CSF, and IL-3)
    • Cysteinyl leukotrienes
    • Adhesion molecules specific for eosinophils (VCAM-1, VLA-4)

Question 23

Other anti-inflammatory agents:
IL-5 (Mepolizumab) and IL-4 monoclonal antibodies

• IL-4 and IL-5
• Since the extent of eosinophilic airway inflammation is related to the risk of severe asthma, these patients…
• Treatment with an IL-5 monoclonal antibody (Mepolizumab) was found to…
• IL-4 monoclonal antibody (Dupilumab) in patients with persistent, moderate-to-severe asthma, elevated eosinophils (blood and sputum) and symptoms that were not well controlled with medium-dose to high-dose ICSs plus LABAs

Answer 23

• IL-4 and IL-5
  
  • Secreted by TH2 cells
  • Recruit eosinophils from the bone marrow and maintains them in an activated state
• Since the extent of eosinophilic airway inflammation is related to the risk of severe asthma, these patients…
  
  • Are particularly difficult to manage
  • Often require oral systemic ICS
• Treatment with an IL-5 monoclonal antibody (Mepolizumab) was found to…
  
  • Reduce asthma exacerbations and the oral dose of glucocorticoids needed for asthma control
• IL-4 monoclonal antibody (Dupilumab) in patients with persistent, moderate-to-severe asthma, elevated eosinophils (blood and sputum) and symptoms that were not well controlled with medium-dose to high-dose ICSs plus LABAs
  
  • Efective in reducing asthma exacerbations, improving lung function and reducing levels of TH2-associated inflammatory markers

Question 24

Other anti-inflammatory agents:
Cromones

• Cromone drugs (aka cromoglycates)
• The best-known specific action of chromones
• The current hypotheses proposed to explain the effects of these drugs
• Cromone use
• Pros
• Availability

Answer 24

• Cromone drugs (aka cromoglycates)
  
  • Cromolyn sodium (Intal®)
  • Nedocromil sodium (Tilade®)
• The best-known specific action of chromones
  
  • Block or attenuate the effects of immunologic and non-immunologic stimuli in both asthmatics and normal individuals
  • Potent effects in preventing both early and late asthmatic responses to inhaled allergens such as pollen
  • Reduce airway reactivity resulting from exposure to a range of inhaled irritants such as sulfur dioxide and cold air
• The current hypotheses proposed to explain the effects of these drugs
  
  • Enhanced phosphorylation of a cell membrane protein that is responsible for the termination of mediator release from mast cells (stabilization of the mast cell membrane)
  • Suppressed firing of sensory C-fiber nerve endings
  • Inhibitory actions on other inflammatory cells that may participate in allergic inflammation including macrophages and eosinophils
  • Inhibition of the synthesis of IgE antibody by B-lymphocytes
  • Effects on specific chloride channels in mast cells and sensory neurons
• Cromone use
  
  • Widely used in pediatrics
  • Limited efficacy in adult populations
• Pros
  
  • Extremely safe
  • Side effects are very rare
• Availability
  
  • The two chromones are available for inhalation by either metered dose inhaler or nebulizer solution

Question 25

Other anti-inflammatory agents:
Anti-leukotrienes

• The generation of cysteinyl leukotrienes (CysLT) (e.g. LTC4, LTD4 and LTE4) from arachadonic acid
• What regulates the actions of CysLTs
• CysLTs
• Several leukotriene-modifying drugs have been developed for clinical use including…

Answer 25

• The generation of cysteinyl leukotrienes (CysLT) (e.g. LTC4, LTD4 and LTE4) from arachadonic acid
  
  • Requires the action of the 5-lipoxygenase enzyme (5-LOX)
  • Regulated by various stimuli, cell types, genetics of the host, and cytokine stimulation
• What regulates the actions of CysLTs
  
  • Expression, distribution, and activation of specific receptors
• CysLTs
  
  • Induce bronchospasm by local effects on smooth muscle, mucus, and edema
  • Their modulation of the immune response, collagen deposition, and recruitment and activation of inflammatory cells increase chronic airway obstruction and bronchial hyper-responsiveness
• Several leukotriene-modifying drugs have been developed for clinical use including…
  
  • Leukotriene receptor antagonists (Zafirlukast [ACCOLATE®]
  • Montelukast [SINGULAIR®])
  • A 5’-lipoxygenase enzyme inhibitor (i.e. Zileuton [ZYFLO®])

Question 26

Other anti-inflammatory agents:
Anti-IgE therapy:
Omalizumab (XOLAIR®)

• General
• IgE
• Particularly effective in…
• Benefit was greatest in patients that had been both…
• Cons
• IMPORTANT CONCEPT 13: Anti-inflammatory drugs that act on selective targets may be effective for the treatment of…

Answer 26

• General
  
  • A recombinant humanized monoclonal antibody against IgE that is being used for asthma treatment
  • Reduces the amount of Fc€RI on the surface of basophils further enhancing its anti-inflammatory actions
• IgE
  
  • When bound to Omalizumab, IgE is unable to bind to IgE receptors (Fc€RI) on mast cells and thereby blocks the inflammatory process at an early step
• Particularly effective in…
  
  • Inner city children with asthma
• Benefit was greatest in patients that had been both…
  
  • Sensitized and exposed to cockroach allergen
  • Sensitized to dust mites, two major relevant indoor allergens
• Cons
  
  • Expensive
  • Long-term safety in children has not been established
• IMPORTANT CONCEPT 13: Anti-inflammatory drugs that act on selective targets may be effective for the treatment of…
  
  • Patients using inhaled or systemic corticosteroids with poorly controlled asthma