Week 4- Asthma

Question 1

Factors that influence lung function

Answer 1

inflammation(airway and tissue), changes to airway smooth muscle, epithelial damage, mucous plugging, alveolar damage, fibrosis(airway and tissue), tumours, obesity

Question 2

Define

What is spirometry

Answer 2

this is lung function test that uses specialsied equipment, involves taking a big deep breath, blowing out as past a syou can then taking a deep breath

you need a trained resp specialist.

Someone has to concentrate when doing this test so their use is limited in the elderly and children.

Whilst it is safe it is a physically demanding test

Question 3

Parameters that can be measured with lung function test?

Answer 3

Peak expiratory flow, vital capacity(maximum capacity air blown out), and FEV1(forced expiratory volume in 1 second). FEV1 is often sued to determine lung health

Question 4

FEV1

Answer 4

the measure of how quick full lungs can be emptied as it measures the volume expired in 1 second after full inspiration and at maximal expiration

Question 5

FVC

Answer 5

FORCED VITAL CAPACITY- the volume expired from full inspiration to full expiration.

This is often compared to reference values of normal lung lung function for the same sex, age and height

Question 6

How does a spirometry graph change as someone has an obstructive disease?

Answer 6

• things like asthma and COPD
• have difficulty breathing out

Question 7

How does a spirometry graph change as someone has a restrictive disease?

Answer 7

involves difficulty breathing in and is more for diseases like IPF and silicosis

Question 8

The use of bronchodilators in lung function tests(spirometry)

Answer 8

Used in COPD to assess severity so vital capacity can be maximized.

In asthma patients, the obstructive values usually improve, this occurs less so with other diseases and therefore this can be used as diagnostic marker

Question 9

Peak Expiraotry flow meters

Answer 9

other lung function test.

generally an at-home test for peak expiratory flow rare in mL/min.

depends on age, sex, height but in males(450-700) and females(300-500). but often it is lower in the morning and improve as the day progresses

20% variability in asthmatics

A NORMAL PRE-BRONCHODILATOR PEF MAY RULE OUT CLINICALLY SIGNIFICANT COPD

Question 10

Why is it hard to detect COPD?

Answer 10

often people have really normal test values until the disease is really advanced. More tests that are more sensitive to mild COPD are trying to developed

Question 11

Inhalation as a drug administrative route?

Answer 11

Delivery via this route is dependant on…

• good inhaler technique
  
  • why inhalers and spacers are used in children
• particle/droplet size
  
  • trying to generate more that deposti to the distal lung as this is where many pathologies of the lung are seen
• lipid solubility of drug as this determines duration of action
• systemic effect potential in swallowed drugs makes this a better choice ( local admin is good )

Question 12

Droplet size of lung treatments and where they reach

Answer 12

Question 13

How many people die of Asthma every year? who is most affected?

Answer 13

over 400/year. affects more older women

Question 14

Use of adrenaline in asthma attacks?

Answer 14

Alot of death occured after past adrenaline administration because of the affect of adrenaline on people with CVD( heart attacks). Caused an increase in death

Question 15

How thunderstorm adthma occured

Answer 15

High pollen day(extreme level >100 grains/m3) and high wind day meant that whole pollen grains from flowery grasses were swept up into the clouds. As a storm developed and the moisture(a very humid and hot day which contributed) fragmented the pollen, the pollen exploded all over the city. The pollen became respirable when rain fell and breathed in. Affecetd both people who were vulnerable and those that didn’t know they were

Question 16

Is risk of infection with COVID-19 higher in those with asthma or not?

Answer 16

it is not, a study of more than 500,000 found that asthma prevalence in covid affected group was similar to population prevalence.

However there were effects on severity and mortality- if ashtmatics were being well managed and they were being treated, the severity of COVID was less severe ( less hosp and ICU admissions)

But if you have asthma you do have higher odds of more severe diseases but not death in comparison to non-ashtmatics

Question 17

Define

Asthma

Answer 17

Chronic inflamm lung disease that leads to reversible narrowing of the airways, associated with increased airway hyperresponsiveness. Imbalance in airway contraction and relaxation

Recurring episodes of breathing problems( shortness of breath, wheezing, chest tightness, night time or early morning coughing)

Question 18

Classifications of Asthma

Answer 18

• Extrinsic/ Allergic
  
  • most common
  • involves IgE ABs and mast cell degranulation( release bronchocontrictive mediators)
  • triggered by exposure to allergens
• Intrinsic/ Non-allergic
  
  • thought to be more severe
  • non specific bronchial hyperactivity / hyperresponsive airwats
  • triggered by cold or infection or exercise( but exercise reduced freq of attacks)

Question 19

To diagnose asthma patients must…

Answer 19

have a mix of compatible resp symptoms including responses to triggers, evidence of reversible airway obstruction or variable airflow obstruction.

If these criteria arent met but asthma si still suspected then an increased response to bronchoprovocation/asthma attack via methacholine is tested

Recently, sputum has been used to diagnose via the presence of inflamm cells

Question 20

Histology of asthma

Answer 20

excessive mucous( causes a barrier to inhaler therapy and is obstructive)

basement membrane/epithelial layer thickening to show fibrosis

more smooth muscle and therefore more contraction

Question 21

Pathogenesis of asthma

Answer 21

increased muscle and narrower airway means that when exposed to triggers airways contract too easily and too much( airway hyperresponsiveness)

Question 22

T helper cell responses in healthy airways vs asthmatic airways

Answer 22

Healthy

• macophages clear allergen in airway wihtout inducing change in phenotype
  
  • Activated Th1–>releases Th1 cytokines–> activates macrophage–> low level phys response on airway

Allergic Asthmatics

• activated Th2–> Th2 cyotkines activates eosinophils(predom inflamm cell in allergic asthma), mast cells( mediators released after IgE activation) and plasma cells–> acute bronchoconstriction and chronic changes( fibrosis, more goblet cells, oedema, swelling, more smooth muscle cells and bigger size)

Question 23

Which parts of asthma can we easily treat and which parts can we not?

Answer 23

the indcution phase ( onset) and airway remodelling are hard to prevent and reverse

The inflammation and smooth muscle shortening is are both easier to manage and can be targeted with preventer mediations and relievers

Question 24

Most athmatic patients take…

Answer 24

a low dose regular preventer( inhaled corticosteriod in low dose as maintenance therapy) and SABA reliever as needed

Question 25

Treatment overview for asthmatics

Answer 25

Question 26

Why do we use relievers?

Answer 26

to target the immediate acute phase of asthma and relive airway smooth muscle spasm.

The consequences of the acute asthma attack are the later/chronic phase where preventers are needed

Question 27

Why are preventers or controllers needed in asthma?

Answer 27

they target the later chronic phase of asthma and reduce inflammation

Question 28

How to target airway contraction?

Answer 28

we know that there are mediaotrs of allergy( histamine, etc) and parasymp vagal efferents(Ach via M3 receptors) which cause contraction. these can be countered by causing relaxation via symp efforts to the adrenal medulla(circulating adrenaline) and these can be simulated using synthetic B2-adrenoreceptor agonists like short acting salbutamol

Question 29

SABAs

Answer 29

Question 30

Driver of airway contraction on a cellular level

Answer 30

1. bronchocontricotr agonsits(Ach,Cys-LTs,Histamine) signal via GPCRs to inrease levels of IP3
2. Increased IP3 causes intracellular release of Ca+ from sarcoplasmic reticulum
3. Ca activates Ca-Calmodulin
4. Ca-Calmodulin activates MLCK(myosin light chain kinase) which phosphorylates MLC to cause contraction

Question 31

How we use B2 agonists to relax the airway on a cellular level?

Answer 31

B2 agonists bind to GPCR–> GPCR is coupled vua Gs protein to Adenylate cyclase–>AC activation causes ATP to be converted to cAMP–>activates PKA which inhibits intracellular calcium release

activated PKA–> Activates MLCP which dephosphorylates MLC to reverse contraction

Question 32

Advantages and disadvantages of SABAs

Answer 32

Question 33

Why LABAs arent used as a sole therapy?

Answer 33

they mask the effects of inflammation, when people did have ashtma attack their airways may have been more relaxed but aorways were still full of mucous and swollen( airways still had potential to close completely when having an attack) which lead to increased mortality

Question 34

When are LABAs used?

Answer 34

only prophylactically and only in conjunction with other inhaled steroids( Step 3) as an alternative to increasing steroid dose

Can be used as protection against exercise-induced/nocturnal asthma

Question 35

B-adrenoceptor antagonists in asthma?

Answer 35

CONTRAINDICATED.

commonly used in hypertension but even B1 selective antagonists cannot be used as there is still potential for B2 mediated constriction

Question 36

Adjunct treatments only (bronchodilaotrs)

Answer 36

SAMAs and LAMAS –> block vagal tone and cause bronchodilation and decreased mucous secretions but have no effect on other mediators of contraction( only working on Ach and not the others like Cys-LTs and histamine)

Theophylline–> PDE inhibitor which prevents cAMP breakdown and thus causes bronchodilator. has a low potency but increases B agonist effectiveness. has a narrow therapeutic index and side effects because of actions at other PDEs

Question 37

glucocorticoids

Answer 37

reduce swelling and mucus to prevent muscle spasm to reduce severity/ prevent asthma attacks.

biggest issue is compliance and used in step 2 or 3

Question 38

Transactivation

Answer 38

steroid targets intracellular glucocorticoid receptor–>disscoaition of chaperone proteins to receptor–> translocation of R to nucleus–> R dimer forms to bind to glucocorticoid response elements on target genes which increases expression of anti-inflamm proteins( Annexin A1)

Question 39

Transrepression

Answer 39

after tranlsocation in nucleus the monomoeric glucocorticoid receptor which is bound to the drug binds to TFs(NFkB,AP-1) which normally promote expression of cytokines/enzymes that promote/ are mediators of constriction

Question 40

What do inhaled glucocorticoids do?

Answer 40

Question 41

oral corticosteroids

Answer 41

Question 42

adverse events in coricosteroids

Answer 42

Question 43

LTRAs

Answer 43

Question 44

Omalizumab

Answer 44

Question 45

Mepolizumab

Answer 45