Week 4- Asthma Flashcards
Factors that influence lung function
inflammation(airway and tissue), changes to airway smooth muscle, epithelial damage, mucous plugging, alveolar damage, fibrosis(airway and tissue), tumours, obesity
Define
What is spirometry
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
Parameters that can be measured with lung function test?
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
FEV1
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
FVC
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
How does a spirometry graph change as someone has an obstructive disease?
- things like asthma and COPD
- have difficulty breathing out
How does a spirometry graph change as someone has a restrictive disease?
involves difficulty breathing in and is more for diseases like IPF and silicosis
The use of bronchodilators in lung function tests(spirometry)
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
Peak Expiraotry flow meters
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
Why is it hard to detect COPD?
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
Inhalation as a drug administrative route?
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 )
Droplet size of lung treatments and where they reach
How many people die of Asthma every year? who is most affected?
over 400/year. affects more older women
Use of adrenaline in asthma attacks?
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
How thunderstorm adthma occured
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
Is risk of infection with COVID-19 higher in those with asthma or not?
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
Define
Asthma
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)
Classifications of Asthma
- 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)
To diagnose asthma patients must…
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
Histology of asthma
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
Pathogenesis of asthma
increased muscle and narrower airway means that when exposed to triggers airways contract too easily and too much( airway hyperresponsiveness)
T helper cell responses in healthy airways vs asthmatic airways
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)
Which parts of asthma can we easily treat and which parts can we not?
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
Most athmatic patients take…
a low dose regular preventer( inhaled corticosteriod in low dose as maintenance therapy) and SABA reliever as needed
Treatment overview for asthmatics
Why do we use relievers?
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
Why are preventers or controllers needed in asthma?
they target the later chronic phase of asthma and reduce inflammation
How to target airway contraction?
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
SABAs
Driver of airway contraction on a cellular level
- bronchocontricotr agonsits(Ach,Cys-LTs,Histamine) signal via GPCRs to inrease levels of IP3
- Increased IP3 causes intracellular release of Ca+ from sarcoplasmic reticulum
- Ca activates Ca-Calmodulin
- Ca-Calmodulin activates MLCK(myosin light chain kinase) which phosphorylates MLC to cause contraction
How we use B2 agonists to relax the airway on a cellular level?
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
Advantages and disadvantages of SABAs
Why LABAs arent used as a sole therapy?
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
When are LABAs used?
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
B-adrenoceptor antagonists in asthma?
CONTRAINDICATED.
commonly used in hypertension but even B1 selective antagonists cannot be used as there is still potential for B2 mediated constriction
Adjunct treatments only (bronchodilaotrs)
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
glucocorticoids
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
Transactivation
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)
Transrepression
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
What do inhaled glucocorticoids do?
oral corticosteroids
adverse events in coricosteroids
LTRAs
Omalizumab
Mepolizumab
