26 Pharmacology 4: Anti-Inflammatory Drugs Flashcards Preview

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Flashcards in 26 Pharmacology 4: Anti-Inflammatory Drugs Deck (26):
1

Asthma

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

  • 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

2

Inflammatory mediators in asthma

  • 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

3

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

  • 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)

4

Glucocorticoid physiology

  • Synthesis
  • Secretion
  • Physiological effects

  • 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

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...

  • 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

6

Effects of glucocorticoids on components of inflammatory / immune responses

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

  • 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

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

  • 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

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...

  • 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.

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...

  • 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

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...

  • 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

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...

  • 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

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...

  • 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

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...

  • 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

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 

  • 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

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...

  • 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

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 

  • 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

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 

  • 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.
  • IMPORTANT CONCEPT 8: New generation synthetic glucocorticoids
    • More rapid metabolism in the liver
    • Overcome potential side effects due to ingested hormone upon aerosol delivery

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 

  • 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

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 

  • 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

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) 

  • 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

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...

  • 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

22

Other anti-inflammatory agents

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

  • 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)

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

  • 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

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

  • 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

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...

  • 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®])

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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...

  • 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

Decks in Pulm Class (47):