Drugs affecting airway and lung remodelling

Question 1

What is the function of glucocorticoids in asthma?

Answer 1

• decrease inflammatory cell numer and activation to decrease probability and severity of an episode of asthma
• reduce activity, recruitment, and survival of eosinophils and T cells
• reduced activation of mast cell cytokine production
• reduced macrophage cytokine production
• reduction in proliferation, cytokine and collagen production by smooth muscle and fibroblasts
• over time, leads to an improvement in FEV1
  
  • not a bronchodilatory effect

Question 2

What is the mechanism of action of glucocorticoids?

Answer 2

• intercellularly; diffuse across memrbrane to engage GC receptor

transactivation:

• receptor dimerizes (activates own transcription factor)
• translocates to the nucleus, and engages a specific sequence on the promoter region (GC response element)
  
  • b2-aR expression –> increased; beneficial to b2 agonists (SABAs, LABAs), maintains bronchodilator effectiveness
  • annexin-1 –> turns off inflammation
  • serpin A3 –> inhibits serin proteases, influencing inflammation and remodeling

transrepression:

• monomers of receptor bind to other transcription factors eg Jun Fos (activated protein 1), NFkB
  
  • eg binds to AP-1, inhibits its pro-inflammatory function
• represses transcription of:
  
  • cytokines and their receptors
  • inducible enzymes for inflammatory mediators (PLA2, iNOS, COX-2)
  • adhesion molecules (ICAM-1, E-selectin)
• this diminishes the amount of GR that can dimerize (reduces transactivation)

Question 3

When are GCS indicated in asthma?

Answer 3

• asthma requiring b2 agonist rescue therapy more than 3x/week (mild persistent asthma)

Question 4

What are the inhaled GCS used to treat asthma?

Answer 4

older:

• beclomethasone diproprionate

most commin (in combination with b2 agonists (LABA), or as monotherapy):

• budesonide
• fluticasone proprionate

newer (lower systemic effects due to rapid metabolism):

• mometasone
• ciclosenide

Question 5

How are GCS dosed in asthma?

Answer 5

• start at an effective dose, then step down if full control is achieved

Question 6

What are the indications for oral GCS tx in asthma?

Answer 6

eg prednisolone

• **several days **when asthma has not been controlled by maintenance therapy (acute exacerbations)
• chronically for severe asthma (corticosteroid-dependent)
  
  • resistance; asthmatics don’t achieve full airway function even when compliant on best possible meds
  • affects ~5% of asthmatics

Question 7

What are the adverse effects of GCS?

Answer 7

inhaled:

• usually well-tolerated
• dysphonia (change in voice), oral candidiasis (thrush), decreased serum cortisol levels

oral:

• dose and indication-limiting side effects
• osteoporosis, diabetes, muscle wasting, hypertension, grwoth suppression (used cautiously in children)
• suppression of adrenal/pituitary/hypothalamic axis
  
  • trophic hormones suppressed by the exogenous steroids
  • causes adrenal atrophy
  • need to wean off meds to avoid adrenal crisis and withdrawal

Question 8

What is the progressive indication of therapeutics and combinations in asthma?

Answer 8

• most patients will be on a GCS inhaler/rapid reliever
  
  • SABAs eg salbutamol, now also formoterol (LABA)
• some pt will have a LABA added if asthma is not controlled by relievers
• dosage is then increased if still not controlled
• beyond this, oral GCS therapy (prednisolone) may be required

Question 9

What are the pathological differences in airways between asthma and COPD?

Answer 9

asthma:

• remodel to have more muscle, eosinophilic inflammation

COPD:

• normal amount of muscle, lots of fibrosis
  
  • thickened by fibrosis rather than muscle
• loss of alveolar attachments makes airways more readily collapsible than airways in asthma

Question 10

What are the two cell types that drive thea inflammation of COPD in response to cigarrette smoke?

Answer 10

alveolar macrophages and respiratory eptihelial cells

Question 11

What are the cellular mechanisms of cigarette smoke in COPD?

Answer 11

• induces release of chemokines (CXC, CC)
  
  • recruit Th1 and CD8 NK cells and neutrophils
• neutrophils release proteases that degrade elastin
  
  • respiratory epithelial cells apoptose
• proteases and other cytokines activate epithelium to promote mucous release
• growth factors promote fibroblast activity, increasing collagen, and myofibroblast activity that induces the scarring of small airways in COPD

Question 12

What are the effects of oxidative stress in COPD?

Answer 12

• reduce secretion of protease inhibitors and alpha-1 antitrypsin
  
  • increase in degradation of elastin and apoptosis of respiratory epithelium
• recruits neutrophils through NFkB which +IL-8 (powerful chemoattractant of neu) and +TNF expression
• mucous hypersecretion
• oxidative products of AA (isoprostanes) that affect smooth muscle
• corticosteroid resistance
• cellular ageing
• also get nitric stress increasing nitric oxide and inflammation (macro recruitment)

Question 13

What is the causative difference of airflow limitation in asthma vs COPD?

Answer 13

• asthma is due to bronchoconstriction of the airway smooth muscle in response to allergens, it is reversible
  
  • mast cell recrutiment, CD4 (Th2) cell recruitment, eosinophil inflammation
• COPD is due to the fibrotic narrowing of the small airways and decreased parenchymal tethering that promotes alveolar collapse, it is irreversible
  
  • alveolar macrophages triggering CD8 (Th1) cells, neutrophils (elastase)

Question 14

What is the result of decreased alveolar tethering due to fibrosis in COPD (and loss of elasticity in emphysema)?

Answer 14

• air trapping at low lung volumes
• unloading of airway smooth muscle leads to collapse of the airways, trapping gas inside
  
  • ie there is not enough tension to keep them open on exhalation
• limits exercise tolerance

Question 15

What is the role of neutrophils in COPD?

Answer 15

• release elastase that breaks down ECM
  
  • induces epithelial cell apoptosis
• promote mucous secretion

Question 16

What is the role of CD8 cells in COPD?

Answer 16

• +IFNy
  
  • activates cytokine release and activates macrophages
• release enzymes to induce apoptosis of airway epithelial cells and therefore loss of alveolar units

Question 17

What is the role of the alveolar macrophages in COPD?

Answer 17

• increase secretion of neutrophils and monocytes (–> macros)
• induce CD8 t cells - degrade ECM with elastases
• smoke decreases phagocytotic ability
  
  • predisposition to infection in COPD pt

Question 18

What are the therapies for smoking cessation?

Answer 18

• varenicline (champix)
  
  • partial agonist at nicotinic receptors in CNS associated with reward of tobacco smoking conferred by nicotine (nicotinic replacement therapy)
• antidepressants in conjunction with behavioural interventions (quitline)

Question 19

How are bronchodilators used in COPD?

Answer 19

• LABAs and LAMAs give modest impacts, no benefit to prolonging life
• LABA are convenient and more effective than SABA
• reduce number of exacerbations and hopsitalizations
• improve health status
• can be beneficial in combination rather than increasing dose
  
  • eg with LAMAs or phosphodiesterase inhibitors

Question 20

How are inhaled corticosteroids used in COPD?

Answer 20

• indicated when FEV1 is less than 60% predicted
• associated with reduced frequency of exacerbations
• can be used in combination with LABA
• increased risk of pneumonia
• withdrawal from tx can lead to exacerbation

Question 21

What is the combination therapy used in COPD?

Answer 21

• inhaled corticosteroids + LABA
  
  • more effective than either used alone
• increased risk of pneumonia
• addition of an anticholinergic (tiotropium bromide) may provide additional benefit

Question 22

What is the function of phosphodiesterase inhibitors in COPD?

Answer 22

eg theophylline:

• narrow therapeutic index
• dose-limiting side effects (incurred at low dose): nausea, vomiting, diarrhea, CNS stimulation, cardiostimulation, dysrhythmias
• acts as smooth muscle relaxant, adenosine antagoinst; mechansim unknown
• some evidence of an effect on exacerbations and reversal of GCS resistance
• low dose + inhaled steroids (salmeterol) may improve activity

rofluminast

• more selective/better tolerability
• inhibits breakdown of cAMP which leads to reinforcement of actions of the beta agonist drugs

Question 23

What is the progression of therapy in COPD?

Answer 23

mild:

• preventative (flu vaccination) plus some SABA

moderate:

• add regular tx with one or more LABA, rehabilitation

severe:

• add inhaled GCS if repeated exacerbations

very severe:

• add long-term oxygen if chronic respiratory failure, consider surgical tx

Question 24

Why don’t anti-histamines work in asthma?

Answer 24

• other constrictor mediators are of far more significance than histamine:
  
  • cysteinyl leukotrienes are in far greater abundance and can constrict smooth muscle for protracted periods of time
  • PS nerves deliver ACh to muscarinic receptors causing smooth muscle contraction
  • neurogenic inflammatory mechanisms that deliver neuropeptides with constrictor effects
  • complement system generates C5a and C3a which are bronchoconstrictors

Question 25

What is idopathic pumonary fibrosis?

Answer 25

• fatal interstitial lung disease
• scarring thickens and stiffens alveolar walls causing:
  
  • impaired oxygen transfer
  • increased respiratory work
  • respiratory failure
• there are currently no effective therapies

Question 26

What is pulmonary arterial hypertension (PAH)?

Answer 26

• increased blood pressure in pulmonary arteries, veins, or capillaries
• leads to SOB, dizziness, fainting, peripheral oedema
• can be idiopathic, heritable, related to COPD or other pulmonary diseases