PT6: COPD Mechanisms & Pharmacology

Question 1

what is COPD

Answer 1

a disease state characterised by progressive airflow limitation that is not fully reversible, associated with an abnormal inflammatory response of the lungs to noxious particles or gases, primarily cigarette smoke

Question 2

what are some other conditions associated with COPD

Answer 2

chronic bronchitis (productive cough, excessive sputum produciton)
emphysema (alveolar wall destruction, irreversible enlargement of terminal air space)

Question 3

what are the long term consequences of COPD

Answer 3

pulmonary hypertension, cyanosis, hypoxia, right heart failure

Question 4

what are the pharmocological characteristics of COPD

Answer 4

reduced airflow and little variation
limited hyperresponsivemess
neutrophil-rich sputum
Th1 & Tc1 activation
goblet cell hyperplasia
peribroncial fibrosis

Question 5

what are the acute exacerbations of COPD

Answer 5

bacterial infection in up to 50% of stable COPD

viral infection is associated with acute exacerbation

Question 6

what are the mechanisms of airflow reduction in COPD

Answer 6

occlusion of airway by mucous

thickened airway wall, inflammatory cell infiltrate, peribronchial fibrosis, increased airway smooth muscle

Question 7

how is mucous formed

Answer 7

by mucous glands (glandular structure in airway wall)

by goblet cells (found on airway surface)

Question 8

what is the cause of mucous hypersecretion in COPD

Answer 8

goblet cell hyperplasia/metaplasia, enlargement of mucous gland, reduces airflow through bronchi

Question 9

how is mucous production controlled

Answer 9

by neuronal input and inflammatory mediators

Question 10

what is the therapy for COPD

Answer 10

mycolytics:
n-acetyl cysteins (breaks disulphide bonds in mucin, anti-oxidant activity, limited benefit)
DNAse (no efficacy on mucous removal demonstrated in COPD but are used in CF)
muscarinic antagonists:
block parasympathetic stimulation of secretion

Question 11

what is responsible for COPD inflammation

Answer 11

leukocyte infiltration, leukocyte products, increased cytokines

Question 12

what are the consequences of inflammation

Answer 12

epithelial damage leading to decreased ciliary funciton, increased mucous secretion from goblet cells, mucous cell hyperplasia, increased bronchial permeability
stimulation of sensory nerves, leading to neurogenic inflammation and cough

Question 13

what is the mechanism of COPD

Answer 13

machrophages and neutrophils release proteases, reactive oxygen species
macrophages and epithelial cells also release fibroblast growth factors
cytotoxic T cells

Question 14

what is the function of proteases in COPD

Answer 14

break down connective tissue, stimulate mucous hypersecretion, proteases are normall balances by inhibitors

Question 15

what is the function of reactive oxidant species in COPD

Answer 15

damage epithelium, activate inflammatory genes, further damage

Question 16

what bronchodilators are used in COPD

Answer 16

bronchoconstriction not major cause of airway obstruction, so B2 agonists often have a limited effect
muscarinic antagonists used

Question 17

what muscarinic antagonists are used

Answer 17

ipratropium bromide gives some improvement, tiotropium & aclindinium have pharmacokinetic advantages

Question 18

what is the effect of phosphodiesterasespde III & IV in airway smooth muscle

Answer 18

inhibition leads to bronchodilation

Question 19

what is the effect of PDE IV in leukocytes

Answer 19

PDE inhibitors increase intracellular cAMP; inhibits chemotaxis, granule release, respiratory burst, inhibits TNFalpha release

Question 20

why do bronchodilators not work in COPD

Answer 20

occlusion not due to bronchoconstriction (tissue remodelling, secretion)

Question 21

why do anti-inflammatory glucocorticoids not work in COPD

Answer 21

oxidative stress results in decreased steroid sensitivity (impaired glucocorticoid receptor function)
neutrophil apoptosis inhibited by glucocorticoids

Question 22

what is emphysema

Answer 22

permanent enlargement of airspaces distal to the terminal bronchiole, destruction of alveolar walls

Question 23

what are lung elastases

Answer 23

strongly implicated in emphysema, derived from neutrophils and macrophages, degrade elastin/basement membrane/connective tissue, increased after smoking, serpins (serine protease inhibitors) inactivated by oxidant stress

Question 24

what are antiproteases

Answer 24

alpha1-antitrypsin augmentation therapy in patients with deficiency
elastase inhibitors

Question 25

what are antioxidants

Answer 25

vit C & E
N-acetyl cysteine
omega 3