Drugs Affecting Airway and Lung Remodelling Flashcards
How are glucocorticoids used in asthma?
To reduce the activity, recruitment and persistence of inflammatory cells, reduce mast cell and macrophage cytokine production and also reduce proliferation, cytokine and collagen production by smooth muscles and fibroblasts
What is the mechanism of action of glucocorticoids?
Binds intracellular receptor that dimerises, migrates to the nucleus and interacts with DNA to modify gene transcription by binding to glucocorticoid response element, a promoter region in a large number of genes
Which genes are influenced by glucocorticoids in the treatment of asthma?
increased expression of beta 2 adrenoceptors, increased expression of annexin-1, increased expression of serpin A3
What does annexin-1 do?
Turns odd ongoing inflammation by counteracting the activity of phospholipase A2 to stop the synthesis of leukotrienes and prostaglandins
What does serpin A3 do?
Inhibits proteases
How else do glucocorticoids influence gene expression?
The monomer of the receptor can bind to other transcription factors e.g. AP1 and inhibit their activity to down regulate expression of genes that are pro inflammatory
Which pro inflammatory genes are suppressed?
cytokines, PLA2, iNOS, COX-2, ICAM-1, E-selectin
What is mutual antagonism in glucocorticoids?
If a large number of receptors are binding to transcription factors to prevent their action then there are less receptor available to dimerise and act as its own transcription factor
Which asthma patients are prescribed glucocorticoids?
Patients who need to use a beta agonist more than 3 times a week
What are budesonide and fluticasone propionate?
Glucocorticoids (inhaled)
What is prednisolone?
An oral glucocorticoid
What are the adverse effects of inhaled glucocorticoids?
dysphonia, oral thrush, decrease in serum cortisol which may lead to adrenal atrophy
What are the adverse effects of oral glucocorticoids?
osteoporosis, diabetes, muscle wasting, hypertension, growth suppression
What is the important difference between the pathology of asthma and COPD?
COPD airway obstruction is not reversible due to more severe fibrosis and loss of alveolar attachments to airways
What is the cellular mechanism of COPD?
Smoke interacts with alveolar macrophages which release cytokines and lead to infiltration of Th1 cells, CD8 T cells and neutrophils. Neutrophils release proteases which destroy alveolar walls and cause mucus hyper secretion. Smoke also damages epithelial cells which leads to fibrosis.
