Drugs affecting airway and lung remodelling Flashcards Preview

Cardiovascular & Respiratory Pharmacology (Karen) > Drugs affecting airway and lung remodelling > Flashcards

Flashcards in Drugs affecting airway and lung remodelling Deck (26)
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1
Q

What is the function of glucocorticoids in asthma?

A
  • 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
2
Q

What is the mechanism of action of glucocorticoids?

A
  • 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)
3
Q

When are GCS indicated in asthma?

A
  • asthma requiring b2 agonist rescue therapy more than 3x/week (mild persistent asthma)
4
Q

What are the inhaled GCS used to treat asthma?

A

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
5
Q

How are GCS dosed in asthma?

A
  • start at an effective dose, then step down if full control is achieved
6
Q

What are the indications for oral GCS tx in asthma?

A

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
7
Q

What are the adverse effects of GCS?

A

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
8
Q

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

A
  • 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
9
Q

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

A

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
10
Q

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

A

alveolar macrophages and respiratory eptihelial cells

11
Q

What are the cellular mechanisms of cigarette smoke in COPD?

A
  • 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
12
Q

What are the effects of oxidative stress in COPD?

A
  • 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)
13
Q

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

A
  • 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)
14
Q

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

A
  • 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
15
Q

What is the role of neutrophils in COPD?

A
  • release elastase that breaks down ECM
    • induces epithelial cell apoptosis
  • promote mucous secretion
16
Q

What is the role of CD8 cells in COPD?

A
  • +IFNy
    • activates cytokine release and activates macrophages
  • release enzymes to induce apoptosis of airway epithelial cells and therefore loss of alveolar units
17
Q

What is the role of the alveolar macrophages in COPD?

A
  • 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
18
Q

What are the therapies for smoking cessation?

A
  • 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)
19
Q

How are bronchodilators used in COPD?

A
  • 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
20
Q

How are inhaled corticosteroids used in COPD?

A
  • 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
21
Q

What is the combination therapy used in COPD?

A
  • inhaled corticosteroids + LABA
    • more effective than either used alone
  • increased risk of pneumonia
  • addition of an anticholinergic (tiotropium bromide) may provide additional benefit
22
Q

What is the function of phosphodiesterase inhibitors in COPD?

A

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
23
Q

What is the progression of therapy in COPD?

A

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
24
Q

Why don’t anti-histamines work in asthma?

A
  • 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
25
Q

What is idopathic pumonary fibrosis?

A
  • 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
26
Q

What is pulmonary arterial hypertension (PAH)?

A
  • 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