Drugs Affecting Airway and Lung Remodeling Flashcards
What is the effect of glucocorticoids in asthma?
Reductions in:
- activity, recruitment and survival of eosinophils; T lymphocytes - activation of mast cell cytokine production - macrophage cytokine production - in proliferation, cytokine and collagen production by smooth muscle and fibroblasts - chemokines that recruit leukocytes are suppressed as well as TNFalpha, IL-5 etc. but some are not such as IL-4 - -> Decrease inflammatory cell number and activation - -> Decrease probability and severity of episode of asthma - They do not reduce the granulation effect of the mast cell.
Explain the GCS mechanism.
Two major genomic actions however there are other mechanisms and actions as well
- Many cells have GRE in their nucleus that can influence the transcription of types of genes (+/-) –> can lead to anti-inflammatory impact
- Inhaled GCS indicated if need β2-agonist >3 times/week (ie. Mild persistent asthma)
- -> They are an indication of the severity of the asthma
What are some examples of topical GCS?
Topical (inhaled GCS):
- beclomethasone diproprionate
- budesonide [available in combination with LABA]
- fluticasone propionate [available in combination with LABA]
- mometasone
- ciclosenide
These are started at the effective dose and then ‘stepped down’.
What are some examples of systemic GCS (oral)?
Systemic (oral GCS)
- prednisolone - oral administration
A. Several days - for acute exacerbations
B. Chronically - severe asthma only
What are some adverse effects of GCS?
Inhaled: well tolerated
- -> dysphonia
- -> oral candidiasis
- -> decreased serum cortisol
- -> Can be used as a mouthwash but it reduces local absorption
Oral: dose and indication-limiting SEs
- -> osteoporosis
- -> diabetes
- -> muscle wasting
- -> hypertension growth suppression (used cautiously in children)
- -> suppression of adrenal/pituitary/hypothalamic axis
- -> need to wean off chronic use to avoid “withdrawal”
Give some features of Methyxanthines & Phosphodiesterase Inhibitors?
Theophylline
- PDE inhibition/smooth muscle relaxant
- Adenosine antagonism
- HDAC2 activation
- relevant mechanism not known
Dose-limiting side effects:
- -> nausea, vomiting diarrhea, CNS stimulation (low safety margin)
- -> cardiostimulation (dysrythmias)
Selective PDEIs eg Roflumilast
- Reduced incidence and severity of side effects compared with theophylline
- -> approved for COPD
What are some features of COPD?
- COPD is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients.
- Its pulmonary component is characterized by airflow limitation that is not fully reversible.
- The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases.
- There is loss of lung parenchyma, small airways inflammation, fibrosis and thickening and pulmonary hypertension
What are some COPD risk factors?
- genes
- exposure to particles:
- -> tobacco smoke
- -> occupational dusts, organic and inorganic
- -> indoor air pollution from heating and cooking with biomass in poorly ventilated dwellings
- -> outdoor air pollution
- lung growth and development
- gender
- age
- respiratory infections
- socioeconomic status
- asthma/bronchial hyperreactivity
- chronic bronchitis
What is the method of Classification of Severity of Airflow Limitation in COPD?
In patients with FEV1/FVC 80% predicted
GOLD 2: Moderate 50%
What are some options for COPD Therapeutics?
Beta2-agonists
- -> Short-acting beta2-agonists (SABA) - -> Long-acting beta2-agonists (LABA)
Anticholinergics
- -> Short-acting anticholinergics (SAMA) - -> Long-acting anticholinergics (LAMA)
Combinations
- -> Combination short-acting beta2-agonists + anticholinergic in one inhaler - -> Combination long-acting beta2-agonist + anticholinergic in one inhaler - -> Combination long-acting beta2-agonists + corticosteroids in one inhaler - An inhaled corticosteroid combined with a long-acting beta2-agonist is more effective than the individual components in improving lung function and health status and reducing exacerbations in moderate to very severe COPD. - Combination therapy is associated with an increased risk of pneumonia. - Addition of a long-acting beta2-agonist/inhaled glucorticosteroid combination to an anticholinergic (tiotropium) appears to provide additional benefits.
Methylxanthines
Inhaled corticosteroids
- Regular treatment with inhaled corticosteroids improves symptoms, lung function and quality of life and reduces frequency of exacerbations for COPD patients with an FEV1
What are some other COPD Treatments?
- Influenza vaccines can reduce serious illness. Pneumococcal polysaccharide vaccine is recommended for COPD patients 65 years and older and for COPD patients younger than age 65 with an FEV1
What is an exacerbation in COPD?
Treat Exacerbations –> An exacerbation of COPD is: “ an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day to-day variations and leads to a change in medication.”
What are some methods to manage exacerbations in COPD?
In order to manage exacerbations:
Oxygen: titrate to improve the patient’s hypoxemia with a target saturation of 88-92%.
Bronchodilators: Short-acting inhaled beta2-agonists with or without short-acting anticholinergics are preferred.
Systemic Corticosteroids: Shorten recovery time, improve lung function (FEV1) and arterial hypoxemia (PaO2), and reduce the risk of early relapse, treatment failure, and length of hospital stay. A dose of 40 mg prednisone per day for 5 days is recommended.
What are some features of Idiopathic Pulmonary Fibrosis?
- fatal interstitial lung disease (media survival - 2.8 years)
- Scarring thickens and stiffens alveolar walls
- impaired oxygen transfer
- increased respiratory work
- respiratory failure
- Annual incidence of ~8 per 100,000 mainly in 60+ years of age
- There have been recent successes:
Pirfenidone - TGFβ modifier
Nintedanib - Tripe kinase inhibitor- These decelerate annular rate of loss of lung function (FVC)
What are some features of Pulmonary Arterial Hypertension?
Pulmonary Arterial Hypertension:
- Idiopathic
- Familial (mutation in BMPII receptors)
- Secondary
- -> Pulmonary Fibrosis
- -> COPD
- -> Altitude
- These all lead to chronic hypoxia
