Pharmacology Of Airways Obstruction

Question 1

What is asthma?

Answer 1

Chronic inflammatory condition mediated by eosinophil release of IgE that results in airway obstruction due to bronchoconstriction. Shortness of breath, coughing and dyspnoea are characteristics of this condition which can be triggered by allergens or exertion.

Question 2

What are the structural changes to the airways in asthma?

Answer 2

Chronic asthma which has severely progressed to become irreversible due to oedema, scarring and fibrosis with high eosinophil infiltration The basement membrane thickens as there is epithelial cell transition -> mesenchymal and there is smooth muscle hypertrophy which severely obstructs the airways.

Question 3

What is the mechanism of asthma?

Answer 3

Environmental trigger stimulates the epithelial cells to express TSLP (thymic Stromal lymphopoietin) and induce Th2 cells activation. These release:

IL-4 for IgE activation which triggers mast cell degranulation.
IL-5 for eosinophil activation that releases inflammatory cytokines and causes endothelial damage.

Question 4

What are the phases in asthma?

Answer 4

After allergen inhalation there is:
Inhalation phase where IgE activation causes mast cells degranulate and release histamines and cytokines for smooth muscle contraction and airway tightening

Late phase where there is localisation of eosinophils, basophils and neutrophils to the lungs for inflammation and bronchoconstriction.

Question 5

What are the features of asthma?

Answer 5

Airway hyperresponsiveness
Bronchoconstriction
Airway obstruction

Question 6

How does bronchoconstriction occur?

Answer 6

Activation of Gq protein coupled receptors on bronchial smooth muscle with increase in intracellular calcium because there is:
a decrease in cAMP via:Histamine on H1 receptor and Leukotrines on CysLT1.
Adenosine acts on A1 receptors.
Acetylcholine acts on M3 Gq protein coupled receptors.

Question 7

What is the mechanism of COPD?

Answer 7

Macrophages driven response caused by inhalation of irritants like cigarette smoke. This causes epithelial cells to release chemokines for monocytes -> macrophages and recruitment of neutrophils and T lymphocytes. Includes:
Chronic bronchitis
Emphysema
Fibrosis of lungs due to recruitment of fibroblasts

Question 8

What is the mechanism of chronic bronchitis?

Answer 8

Neutrophils release proteases that cause hypersecretion of mucus by goblet cells that leads to bronchi inflammation and airway obstruction. This results in chronic productive cough as a result of irritants such as smoking that causes hypertrophy

Question 9

What is the cause of emphysema?

Answer 9

Macrophages, neutrophils and T cells release proteolytic enzymes which cause destruction of the alveolar wall.

Question 10

What are the classes of drugs to treat asthma?

Answer 10

Beta agonists
Muscarinic antagonists
Leukotriene modifiers
Steroids
Phosphodiesterase inhibitors.

Question 11

Which medication is used to prevent bronchoconstriction?

Answer 11

Phosphodiesterase inhibitors

Muscarinic antagonists against M3 due to parasympathetic innervation for bronchoconstriction

Beta agonists upregulate the B2 receptor for increase in intracellular cAMP and decrease in Ca2+ to prevent bronchoconstriction.
->SABA: Short acting beta agonists
->LABA: Long acting beta agonists

Question 12

What are the short-acting beta agonists?

Answer 12

Cause bronchodilaton between 2-6 hours and have a rapid onset of action. Includes salbutamol and terbutaline.
They cause an increase in CAMP on smooth muscle to prevent contraction andbronchsconsmiction.

Question 13

What are the long acting beta agonists?

Answer 13

Lipophilic with prolonged receptor occupancy of B2 and last 12 hours. Includes salmeterol and formoterol. They should only be used alongside inhaled corticosteroids.

Tiotropium
Salmeterol causes slow and prolonged action.
Formoterol causes rapid and prolonged action and is the preferred drug.

Question 14

How do leukotriene antagonists work?

Answer 14

Inhibit the CysLT1 receptor for bronchoconstriction of smooth muscle and to reduce eosinophils recruitment. Leukotrienes are produced from arachidionic acid via 5-lipooxygenase activity and should be given in conjunction with steroids, because they do not affect production.

Question 15

How do inhaled corticosteroids work?

Answer 15

They reduce inflammation by:

Low dose corticosteroids act on glucocorticoid receptors to translocate to the nucleus to decrease histone acetylation for gene transcription of inflammatory mediators
High dose corticosteroids act on glucocorticoid receptors to translocate to the nucleus and act on promoter gene regions for transcription of anti-inflammatory mediators.

Question 16

How do phosphodiesterase inhibitors work?

Answer 16

They reduce intracellular cAMP by causing breakdown into AMP to induce bronchodilation.

Question 17

What are the features of inhaled corticosteroids?

Answer 17

Delivered directly to the lungs and so a lower dose and reduced side effects compared to oral corticosteroids so Cushing’s syndrome can be avoided. They are given for uncontrolled asthma, and prescribed with a SABA

Question 18

How are inhaled corticosteroids distributed?

Answer 18

Half of the dose will be removed from the liver via first pass metabolism so 50% remaining to take effect, reducing the chance of Cushing’s syndrome occurring. However, desensitisation occurs over time.

Question 19

When should steroids be avoided in asthma?

Answer 19

Patients with a low eosinophils because it indicates a non-inflammatory issue.

Question 20

What is the biological therapy available in asthma?

Answer 20

Monoclonal antibodies which bind to IgE and inhibits the action for inflammation.

Question 21

What is reflux associated chest disease?

Answer 21

Caused by acid reflux entering the trachea and resulting in irritation of the bronchi that results in epithelial damage and an eosinophilic response that results in bronchial inflammation and chronic cough. This may lead to aspiration pneumonia and exacerbate COPD and asthma.

Question 22

What is the role of IL-13?

Answer 22

Mediates eosinophilia activation, mucus secretion and airways hyper-responsiveness.

Question 23

What is Type 1 respiratory failure?

Answer 23

Caused by ventilation-perfusion mismatch which results in disrupted gas exchange. This is characterised by low O2 with normal CO2.
Restrictive lung disease is a cause of this.

Question 24

What are the types of Type 1 respiratory failures?

Answer 24

Reduced perfusion but normal ventilation, which occurs in pulmonary embolism.

Normal perfusion but low ventilation which occurs in bronchoconstriction such as asthma and pulmonary oedema. This disrupts the gas gradient for gas exchange.

Question 25

What is Type 2 respiratory failure?

Answer 25

Alveolar hypoventilation occurs which results in high CO2 levels and low O2 with respiratory acidosis due to:

Airway obstruction in COPD
Reduced compliance of the lungs or chest wall muscles: Rib fracture, Pneumonia and obesity
Drugs such as opiates which reduce ventilation.

Question 26

When should oxygen therapy be avoided for patients?

Answer 26

Patients with COPD.

Question 27

What causes drive to breathe in healthy people?

Answer 27

In healthy individuals, drive to breath is due to increased CO2 detected by central chemoreceptors activating increased breathing rate. Peripheral chemoreceptors located in the carotid body and aortic arch transmit information to the central chemoreceptors in the medulla, between the 9th and 10th cranial nerves.

Question 28

What causes drive to breathe in COPD patients?

Answer 28

They have overinflated lungs due to low ventilation, which results in chronically high CO2 established over a long period of time that desensitises the central chemoreceptors. There is a reliance on the peripheral chemoreceptors that are oxygen sensitive so COPD patients have a drive to breathe due to hypoxaemia. Therefore providing oxygen therapy will worsen overinflated lungs and suppress the respiratory drive, resulting in reduced breathing rate, unconsciousness and death.

Question 29

What should be avoided when treating reflux associated chest disease?

Answer 29

PPI inhibitors because they do not treat the reflux, they only reduce acid secretions. Only given if the COPD patient has heartburn.

Question 30

What are the treatments for reducing COPD exacerbation in GI reflux?

Answer 30

Metaclopramide
Domperidone
Baclofen
Azithromycin

Question 31

How does metaclopromide work?

Answer 31

Inhibits dopamine receptors for the relaxation of the lower oesophageal sphincter.

Question 32

How does domperidone work?

Answer 32

Inhibits dopamine receptors for the relaxation of the lower oesophageal sphincter.

Question 33

How does baclofen work?

Answer 33

GABA agonist for the constriction of the lower oesophageal sphincter.

Question 34

How does azithromycin work in reflux disease?

Answer 34

Activates motilin hormone receptors for increased oesophageal motility of food and gastric emptying.

Question 35

What is the treatment of COPD?

Answer 35

Combination inhaler containing
Long acting muscarinic antagonists and Long acting beta agonists

Or

Long acting beta agonists AND Inhaled corticosteroids.

Or

Azithromycin

Question 36

What is the risk of taking combination LABA and Inhaled corticosteroids?

Answer 36

Reduces eosinophilic inflammation however there is a greater idk of infection from pneumonia. This is typically prescribed for COPD patients so it is important that they are up to date with vaccines.

Question 37

Why is azithromycin prescribed for COPD?

Answer 37

It is a macrolide antibiotic which inhibits 50s ribosomal subunit. It reduces inflammation via reducing neutrophil chemo taxis and infiltration to respiratory epithelia.

Question 38

What are the BTS/SGN guidelines?

Answer 38

Guidelines for the treatment and management of asthma

Question 39

What is the role of IL -4 in asthma?

Answer 39

Causes IgE activation for mast cell degranulation for the release of histamine and prostaglandin.

Question 40

What is the role of IL -5 in asthma?

Answer 40

Eosinophil activation.

Question 41

Which acetylcholine receptor is responsible for airway control?

Answer 41

Muscarinic 3 receptor which causes increase in intracellular Ca2+ for bronchoconstriction at rest.

Question 42

How do oral corticosteroids work?

Answer 42

They induce greater side effects in patients and are given for severe asthma which can’t be controlled by inhaled corticosteroids. Oral corticosteroids include prednisone.

Question 43

What is the impact of adenosine in asthma?

Answer 43

Adenosine is given to treat supraventricular arrythmia by blocking the AV node however, it causes bronchoconstriction in asthma patients.