Asthma Therapy Flashcards
How do B2 agonists work?
They activate B2 adrenergic receptors and cause bronchodilation
Which B2 agonists are short acting?
Salbutamol
Which B2 agonists are long acting?
Salmeterol and Formoterol
Name a non selective B agonist
Isoprenaline
Why is it important for B agonists to be selective?
To prevent stimulation of the heart
occurs with isoprenaline
How does salbutamol achieve selectivity?
It has an extended catechol group by one carbon
Why are salmeterol and formoterol longer acting?
They have an extended side chain
This increases the lipophilicity of the drugs and allows them to interact with the cell membrane, increasing their residence time
Why is salbutamol short acting?
It is not lipophilic so doesnt interact with the membrane
Acts as a soluble receptor at the B2 GPCR
Why is Formoterol intermediate acting?
Acts as both a soluble ligand and deposits into the lipid membrane around the receptor
Why does Salmeterol have a slower onset and the longest action?
It does NOT act as a soluble ligand
It must first diffuse into the membrane where it interacts with the receptor while adjacent to it
What is the mechanism of action of B agonists?
They bind to the B2 receptor which is Gs linked to AC AC increases the levels of cAMP Activates PKA PKA inactivates MLCK Muscle cannot contract
What type of drug is Theophylline?
Phosphodiesterase inhibitor
How do Phosphodiesterase inhibitors work?
Inhibit PDEIII which is an enzyme that breaks down cAMP
Therefore increased levels of cAMP -> Muscle cannot contract as well
They also inhibit PDEIV in leukocytes which increases intracellular cAMP and decreases leukocyte activation (especially eoinophils and macrophages)
What are the main problems with Phosphodiesterase inhibitors?
PDEIII is not just in the airways
It is also in the CNS so can cause adverse effects there
Why are Glucocorticoids useful in asthma?
They reduce inflammation
How do Glucocorticoids work?
They reduce gene transcription of inflammatory mediators
They also promote apoptosis of eosinophils
They also reduce PLA2 activity (inhibit its transcription) - This enzyme converts membrane phospholipids to AA
What are the main Glucocorticoids used?
Prednisolone and Budesonide
How do leukotriene inhibitors (LTRAs) work?
They block the LTC4 and LTD4 receptors (cysLT) and so prevent bronchoconstriction
What are the main Leukotriene inhibitors (LTRAs) used?
Montelukast and Zafirlukast
How does Zileuton work?
Inhibits leukotriene synthesis by inhibiting 5-lipoxygenase
Why do Montelukast and Budesonide work well together?
Montelukast is good for the early phase (with some late phase action)
Budesonide is good for the late phase response
Why is inhibiting IL-5 potentially good in asthma?
It drives eosinophil production and recruitment
Why are Disodium Cromoglycate (DSCG) and Nedocromil (both Cromones) useful in asthma?
They inhibit mast cell degranulation
Allergic asthma is driven by mast cell degranulation
DSCG also inhibits sensory nerve transmission
Prevents the release of neurokinins, bradykinin and SO2 which cause bronchoconstriction
Also inhibits eosinophil chemotaxis
DSCG and Nedocromil are useful in which type of asthma?
Allergic (atopic)
Is DSCG effective against the early or late stage response?
Both
Why are antihistamines not effective in asthma?
The mast cells in the airways don’t contain much histamine
How does Omalizumab?
It is an anti-lgE mAB
Do people with the Gly/Gly have a better or worse response to long term treatment?
Better
Do people with the Arg/Arg have a better or worse response to long term treatment?
Worse (gradually lose control) - Can only take drugs when needed
