2- therapeutics of obstructive airway disease Flashcards
what do the preventer/controller drugs do?
anti-inflammatory
what are the reliever drugs mechanisms (rough)?
bronchodilators
what bronchodilators prescribed?
beta 2 agonists, muscarinic antagonists
why do muscarinic antagonists bronchodilate?
post ganglionic parasympathetic release acetylcholine that acts on muscarinic receptors to make bronchoconstriction = so muscarinic antagonist medication
*M3 receptors are what is being acted on - they are Gq proteins so phosphorylate Ca2+ via phospholipase C etc so bronchoconstriction
why is it better to give drugs that act further up inflammatory cascade rather than just salbutamol to make muscles feel better once cascade already occurred?
airway smooth muscle is twitchy and hypersensitive - because sensitised by inflammatory cascade activated from above = so want to damp down inflammatory cascade from above to prevent twitchy smooth muscle in first place
→one of key treatment goals of asthma should be patient requires hardly any or if at all beta 2 agonists (like salbutamol)
if twitchy smooth muscle and needs a lot of salbutamol, its not under control and need to make higher dose of getting type 2 inflammation under control
what are they type 2 biomarkers?
- eosinophils = IL5
- IgE = IL 4
- FeNO = IL13
what is the pyramid for asthma treatment?
- reliever = short acting beta agonist (salbutamol)
- 1st line controller = inhaled corticosteroid
- 2nd line controller is addition to 1st line = long acting beta agonist, long acting muscarinic antagonists, leukotriene blocker receptor antagonist, theophylline (in order)
- short term oral corticosteroids (long term has bad effects like rheumatoid, immunosuppression), long term use biologics (monoclonal antibodies) which are more targeted & precise so less side effects so long term
what is bad about oral corticosteroids? (why only used for longterm)
suppress cytokines 4,5,13 (type 2) but also suppress type 1 cytokines (1,6, tnf alpha) which makes problems like rheumatoid etc etc
= just suppress like everything
what is new 2nd track way of guidelines for asthma where reliever & controller in one inhaler?
- patients perceive benefits of salbutamol as faster acting whereas steroid diffuses into cell membrane and onto nucleus which means people overuse blue inhaler and underuse brown so you just suppress the pain and not treating underlying problem
- 1 inhaler good as means that people can’t uncouple use of reliever (blue) & controller (brown) hence why in top table the preferred reliever has low dose ICS-formoterol
= use more when you need it and less when you don’t
what is important corticosteroid?
BDP (Beclometasone dipropionate)
why can corticosteroids cause pneumonia in COPD?
because corticosteroids suppress lots due to local immune suppression & impaired mucociliary clearance
& altered microbiome
what is an example of oral corticosteroid that can only be given short term?
prednisolone
is corticosteroids used as monotherapy or combination?
monotherapy or combination for asthma
only in combination for COPD
how does steroid affect the peak flow and diurnal variation?
the average value improves and amplitude of diurnal variation become smaller (attenuated)
what is function of spacer device?
particles go into spacer and slows down and makes particles smaller which means will travel further into lungs = improves lung deposition
large particles get left in chamber (inhaler without spacer means large particles get left on vocal cords etc and cause problems like oropharyngeal & laryngeal side effects), also can get thinning of muscle in vocal cords = hoarseness so never use without spacer device
what are breath actuated inhalers?
twist base to activate dry powder and you suck in and de-aggregates dry powder (automatically works when breathe in = no pressing on inhaler)
problem = can’t use with spacer so can get side effects but is easier to use
what releases leukotrienes?
cells like eosinophils, basophils, mast cells,neutrophils
what are the 2 different pathways of leukotrienes?
= Leukotrienes are a family of lipid mediators derived from the metabolism of arachidonic acid
- can go be arachadonic converted in COX pathway making prostaglandins + thromboxanes
- the other pathway is 5-lipoxygenase pathway producing leukotriene D4 (plays important roles in allergic & inflammatory diseases e.g. asthma + allergic rhinitis)
what are some functions of leukotriene D4? and how is it treated?
- contraction & proliferation of airway smooth muscle
- edema
- increased mucus secretion
- decreased mucus transport
- eosinophil influx leading to cationic protein release and epithelial cell damage
= treated with anti-leukotrienes e.g. montelukast
what is example of anti-leukotriene?
montelukast (oral)
= it’s effective but not as potent as inhaled steroid so used 2nd line to steroid
when are anti-leukotrines effective?
exercise induced bronchoconstriction (athletes) & allergic rhinitis (with anti-histamine)
is type 2 disease just like asthma in airways?
no, it can effect lots of areas (in past lecture) like hives, eczema etc
what is an anti-IgE drug?
omalizumab
what is an anti-IL5/anti-IL5Ra drug?
anti- IL5 = mepolizumab or anti IL5Ra = benralizumab (better)
what is anti- IL4R⍺ drug?
dupilumab
what is ant-TSLP drug?
Tezepelumab
explain the bucket analogy for drugs?
3 holes in bucket = IL4,5,13
tap coming dripping in is TSLP (Thymic stromal lymphopoietin)
if eosinophils main driver then blocking IL-5 is good (as biggest hole)
if high IgE & high FeNO the want dupilumab
but if all 3 high then blocking 1 or 2 holes won’t fix so want to block TSLP (the tap) with tezepelumab
*can’t use drugs to block holes as too much money
why not just always use tezepelumab as anti-TSLP?
because doesn’t completely turn off tap - not as good as blocking holes downstream
how does omalizumab work?
= anti IgE monoclonal antibody
Omalizumab inhibits the binding to the high-affinity IgE
receptor- inhibits allergic response and mediator release from
basophils/mast cells
how does mepolizumab and benralizumab work?
anti-IL5
= block effects of Th2 cytokine lL-5 which is responsible for eosinophilic inflammation in asthma
why is theophylline not that good as a bronchodilator?
narrow therapeutic window, meaning the difference between a safe and effective dose and a toxic dose is small
what is an example of a PDE4 inhibitor?
phosphodiesterase 4 inhibitor = roflumilast (oral)
(it’s an add-on drug to long lasting bronchodilators)
what are mucolytics?
drugs that reduce sputum viscosity and aide sputum expectoration (and
reduce exacerbations) in COPD/Bronchiectasis
example = Carbocisteine and acetylcysteine (both oral)
what are the aims for treatment of persistent asthma?
Abolish symptoms, min short acting beta agonists use, normalise FEV1, reduce peak expiratory flow variability, reduce exacerbations, Avoid oral corticosteroids,prevent airway remodelling, avoid triggers
what drugs should be given for persistent asthma?
- Suppress inflammatory cascade with inhaled steroid +/-leukotriene receptor antagonists
- +/- Stabilise smooth muscle with LABA/LAMA
what are some aims for COPD treatment?
- try get to stop smoking (stopping at any point in COPD diagnosis is benficial)
- promote immunisation so less (covid, influenza , pneumoxoc)
- pulmonary rehab
- if low level oxygen, give oxygen supplementation
- pharmacotherapy
= reduce acute exacerbations (usually virally induced) and try to prevent decline in lung function
what are the 2 different inhalers that can be used in COPD management?
- long acting beta agonist & long acting muscarinic antagonist
- triple inhaler (also has corticosteroids)
which inhaler should be used in COPD if
a) raised eosinophil blood count?
b) normal eosinophil blood count?
a) triple inhaler needed
b) long acting beta agonist & long acting muscarinic antagonist
what inhaled steroids have greater pneumonia risk?
any inhaled steroid that starts with letter F so try to avoid in COPD
= never use F word only use B word in COPD
what is treatment of acute COPD exacerbation?
- Nebulised high dose salbutamol + ipratropium
- Oral prednisolone
- Antibiotic (amoxicillin/doxycycline) if infection
- O2 titrated against PaO2/PaCO2
- Physio to aide sputum expectoration
- Non invasive ventilation to allow higher FiO2
- ITU Intubated assisted ventilation to buy time if reversible
component (eg pneumonia)
