Asthma & pharmacology

Question 1

Discuss asthma vs COPD

Answer 1

Look at table on OneNote

Question 2

What diseases may COPD describe?

Answer 2

Emphysema (destruction of alveolar walls, producing a small number of large alveoli)

Chronic bronchitis (long-standing inflammation and hence obstruction of the bronchi or bronchioles)

Question 3

What can asthma attacks be divided into?

Answer 3

• immediate phase (0-3 hours) → bronchospasms manifest

- delayed phase (4-8h) → inflammation

Question 4

What type of hypersensitivity reaction is asthma?

Answer 4

T1 → triggered by antigen (dust, smoke, pollen)

Question 5

What happens in asthma following antigen exposure?

Answer 5

• antigen recognised and phagocytosed by resident DC n bronchioles
• present it of MHC molecules (largely MHCII exogenous pathway, but also MHCI va cross-presentation)
• activation of mainly CD4+ Y cells in secondary lymphoid tissue - especially Th2
• activated T cells release cytokines → stimulates inflammatory response
• IL-5 → eosinophil recruitment and activation
• IL-4 and IL-13 → class switching in B cells, changing the antibodies they produce from IgM to allergen-specific IgE
• B cells go to airways and secrete allergen-specific IgE → bind to mast cells & eosinophils, sensitising them for activation upon secondary exposure

Question 6

In asthma, what happens upon secondary exposure to antigen?

Answer 6

• binding of these immune cell-bound antibodies causes cross-linking to occur → cell degranulation
• release of mediators (e.g. histamine, PGs, leukotrienes) → inflammation → mucus production & bronchoconstriction

Question 7

Describe non-allergic asthma

Answer 7

Less well understood

• thought to be a more cel-mediated response to self-antigens, characterised by a Th1-skewed immune response
• could be neurally mediated (anxiety can trigger asthma attacks)

Question 8

Describe acute phase of asthma

Answer 8

• bronchoconstriction & mucosal oedema and mucus hypersecretion

Question 9

Describe delayed phase of asthma

Answer 9

1. mast cell degranulation causes an influx of inflammatory cells - especially Th2, eosinophils
2. the inflammation causes endothelial damage → eosinophils release toxic proteins (e.g. eosinophil cationic protein, major basic protein) which damage endothelium → increases hypersensitivity of the bronchioles and irritant receptors and C fibres are more accessible to irritant stimuli → predisposes patient to asthma
3. Mucus hypersecretion → caused by PGs, leukotrienes and IL-3 → airway narrowing and traps irritants that could potentially elicit further attacks (occurs due to goblet cells hyperplasia)
4. inflammatory exudate enters bronchiolar tissue → oedema → contributes further to airway collapse → trapping of air, reduction in compliance

Question 10

Chronic effects of asthma

Answer 10

• thickening of bronchiolar walls and fibrosis
• hyperplasia and hypertrophy of the airway SM
• persistant eosinophilia → eosinophils become increasingly fragile (degranulate more quickly) → asthma attacks may get more frequent over time

Question 11

Discuss eosinophilic asthma and non-eosinophilic asthma

Answer 11

• eosinophilic = high number of eosinophils
• non-eosinophilic = low eosinophils, but my have neutophils, mixed granulocyte inflammatory cells or may be very few inflammatory cells

Question 12

What drugs can cause asthma/make it worse?

Answer 12

Aspirin - blocks COX and shifts to leukotriene production instead of PG

Beta blockers - blocks B2 → bronchoconstriction

Question 13

What do eosinophils do in asthma?

Answer 13

• release leukotrienes (inflammatory mediators) and other cytokines
• can release proteases → these can damage the respiratory tract

Question 14

Mechanism pathway for B2 agonists

Answer 14

• Gs → AC → cAMP → PKA → MLCK phosphorylation → decreased MLCK activity → decreased phosphorylation of myosin regulation light chain → relaxation

Question 15

Describe B2 agonists

Answer 15

β2 agonists may be short-acting agonists (SABAs) or long-acting (LABAs).

• Salbutamol is a commonly prescribed SABA for acute relief
• LABAs (e.g. salmeterol) are typically used as maintenance treatment, often in combination
  with anti-inflammatory treatments.

Question 16

Describe side effects of beta agonists

Answer 16

facial flushing, tremor, palpitations, peripheral vasodilation, headache,
dry mouth, and anxiety, through action on systemic β receptors

These receptors are also susceptible to desensitisation – the activated βγ subunit of the
Gs-protein binds kinases, which phosphorylate serine and threonine residues of the
receptor, causing it to be blocked by β-arrestin before it is eventually internalised by the
cell

Question 17

Describe phosphodiesterase inhibitors for asthma w/ examples

Answer 17

e.g. aminophylline or theophylline

Increase levels of cAMP in SM → same effect of B2 agonists

Question 18

Adverse effects of phosphodiesterase inhibitors

Answer 18

• insomnnia, nervousness

- narrow therapeutic window - if too high can have serious effects → dysrhythmia, seizures

Question 19

Describe LAMAs

Answer 19

Long acting muscarinic antagonists
example = ipratropium
Gq M3 → blocking SM contraction

Question 20

Side effects of LAMAs

Answer 20

Few unwanted effects because they’re given by aerosol and is a highly polar
compound, so not well absorbed into the circulation  hence generally safe, well-
tolerated

Question 21

Describe steroids to treat asthma

Answer 21

e. g. beclomethasone
- inhibit phospholipase A2 (enzyme that converts membrane phospholipids to arachidonic acid), thus lowering the production of prostaglandins and leukotrienes
- also immunosuppressive at high doses → reduce production of pro-inflammatory cytokines, bronchorelaxation effects

Question 22

Adverse effects of steroids

Answer 22

• risk of desensitisation
• immunosuppressive effect means that risk of infection is increased (oropharyngeal candidiasis)
• side effects: mild cushing’s like phenotype → truncal obesity, easy bruising, poor wound healing, muscle wasting, oedema, osteoporosis, moonface, hypertension
  Also CNS effects → euphoria, depression, psychosis

Question 23

Example of anti-leukotrienes

Answer 23

• e.g. zurfirlukast

Question 24

List all drugs for asthma treatment

Answer 24

Bronchodilators:
- B2 agonists 
- phosphodiesterase inhibitors 
- muscarinic antagonists
Anti-inflammatories:
- Steroids 
-leukotriene receptor antagonists

Question 25

Complications of asthma

Answer 25

• pneumothorax (due to high airway pressure)
• right heart failure (due to pulmonary hypertension)
• recurrent infection

Question 26

What can be used to assess therapeutic response?

Answer 26

Measurement of:

1. peak expiratory flow (maximum speed of expiration)
2. forced expired volume in 1 second (FEV1)
3. FEV1/vital capacity ratio → represents the proportion of a person’s vital capacity (the maximum amount of air a person can expel after max inhalation) that they are able to expire in the first second of forced expiration (FEV1)

Question 27

Draw spirometry results

Answer 27

OneNote

Question 28

Difference between obstructive and restrictive lung disease

Answer 28

Obstructive = difficulty exhaling → COPD, asthma
Restrictive = Difficulty inhaling → obesity, scoliosis → lungs are resistive in fully expanding
Same symptoms really

Question 29

Difference in obstructive and restrictive spirometry results

Answer 29

Obstructive:

• Reduced FEV1 (<80% of the predicted normal)
• Reduced FVC (but to a lesser extent than FEV1)
• FEV1/FVC ratio reduced (<0.7)

Restrictive:

• Reduced FEV1 (<80% of the predicted normal)
• Reduced FVC (<80% of the predicted normal)
• FEV1/FVC ratio normal (>0.7)