Infection & immunology Malcolm Watson Asthma treatment Flashcards
What are modulators?
Type of smooth muscle growth regulator Bind to cytokines that cause cell growth and stop them having an effect Examples include Heparin Nitric oxides Prostaglandin E2
What are mitogens?
A type of smooth muscle growth regulator Cause cell growth in the air ways leading to hyperresponsiveness Examples Platelet derived growth factor Endothelin Cytokines Histamine
What are eNANCs?
Excitatory non adrenergic non Cholinergic neurotransmitters
Examples Neurokinin A and B. Subs P
They stimulate increased excitatory nerve activity in lungs, leads to muscle contraction and broncho constriction
What are iNANCs?
Inhibitory non adrenergic non Cholinergic transmitters
Can either by dilator Neuropeptides e.g CGRP, VIP
Or Nitric oxide
Stop smooth muscle contraction in lungs
Leads to broncho dilation
What colour is a mucous plug from the airways? Why?
It’s whiteish
Because it’s full of white blood cells and NOT bacteria
So it’s sterile inflammation
Plug formed from Mucosal oedema
Name two excitatory molecules causing broncho constriction
Name four inhibitory molecules causing bronco dilation
Excitatory:
eNANCs
ACETYLCHOLINE acting of M3 receptor
Inhibitory: iNANCs NO Adrenaline acetylcholine acting on M2 receptors
Which two interleukins produced by TH2 cells overlap receptors and so have similar action?
IL-4 and IL-13
What does intrinsic allergy mean?
Non atopic
Usually in Middle Ages onwards
Hyperresponsiveness
More severe airflow limitations than extrinsic
What can cause a cough in asthma?
Prostanoids
PGE2 can sensitise irritant receptors
This can cause a cough
Also relaxes smooth muscle and decrease leukocyte activation
Salbutamol is a beta adrenoceptor agonist. What effect does it have in the lungs?
It’s a bronchodilator
SELECTIVE Beta 2 agonist
Not anti inflammatory
2 long acting selective beta 2 agonist drugs?
Formoterol
Salmeterol
Example of a non selective beta 2 agonist?
Isoprenaline
Salmeterol is very lipophillic. What are the consequences of this?
It had a slow onset of action as it accumulates in the membrane before it slowly diffuses to bind to the Beta 2 receptor. Once it’s bound it has a long duration of actions as it’s lipophillic so is happy to sit near the membrane
Formeterol is neither lipophillic or Hydrophillic. How does it interact with the beta 2 receptor?
It forms a DEPOT in the lipid membrane.
From here it leaches out to interact with the receptor. It has a long duration of action and fast onset so is perfect…
How do beta 2 adrenoceptor agonists like salmeterol help to stop people wheezing by dilating bronchioles? What’s the mechanism…1) bind to B2 receptors…..
1) bind to receptor (a GPCR) activates Galpha subunit
2) formation of cAMP from ATP
3) cAMP activates PKA
4) PKA causes K+ channels to open so cell is no longer polarised! inactivates MLCK and decreases calcium levels
This all means NO contraction
Boom
What kind of drug is Theophylline?
A phosphodiesteRase inhibitor
PDE breaks down cAMP, so inhibiting it leads to increased cAMP.
cAMP activates PKA: decreases calcium, opens K+ channels: no contraction…….bronchodilation!!!
Why do we have to be careful with dosing of theophylline?
It has a narrow therapeutic window
When a beta 2 agonist binds to the Beta 2 recptor, a GPCR, G alpha or the g beta gamma subunit may be activated.
The. G alpha one leads to PKA activation
What does the G beta gamma one lead to?
G beta gamma one leads to activation of MLC phosphatases
Prednisolone and Budesonide are both used in asthma. What kind of drugs are these?
glucocorticoids
How do glucocorticoids work?
Regulate gene transcription
inhibit cytokine transcription
Inhibit inflammatory leukocyte migration
Promote eosinophil apoptosis (get rid of these)
Indirectly inhibit phospholipase A activity
One action of glucocorticoids is that they can indirectly inhibit phospholipase A2.
What does this do?
PLA2 is needed to convert membrane phospholipids Into arachnidonic acid
AA is then needed to make prostaglandins and leukotrienes, both causing inflammation
Inhibiting PLA2 is therefore anti inflammatory
What PDEs does theophylline inhibit?
PDE III found in airway smooth muscle This inhibition leads to bronchodilation Also PDE IV in leukocytes This increases intracellular cAMP Inhibits chemotaxis and granule release
What are montelukast and zafirlukast?
What about Zileuton?
Leukotriene receptor antagonists
Cause bronchodilation
Zileuton is a leukotriene SYNTHESIS inhibitor. Does this by blocking 5- lipoxygenase
Membrane phospholipids—–arachnidonic acid—–5-lipoxygenase—leukotrienes (LTB4, LTC4, LTD4).
What drugs can act here and where?
ZILEUTON can inhibit 5-lipoxygenase
Montelukast can inhibit leukotriene synthesis, specifically LTC4 and LTD4
What antibodies have been trialled in asthma?
Anti IL-5 antibodies
Reduced eosinophil levels
As an anti allergic therapy in asthma we can target mast cell degranulation using Cromones.
What 2 can you think of ?
Disodium cromoglycate (DSCG) Nedocromil
Other actions of these 2:
Inhibit sensory nerve fibre excitation so inhibit NKA, BK
Also inhibit eosinophil chemotaxis
Have to be treated with these for a few weeks before benefits seen
How do mast cell stabilisers work in allergic asthmas?
They inhibit mediator release from lung mast cells.
Have to be treated with these for a few weeks before benefits seen
Disodium cromoglycate (DSCG) inhibits sensory nerve fibre excitation in airways. How..?
Antigen in airway
Damages epithelial cells
Signals sent down sensory nerves then Vagal sensory afferent then CNS the vagus efferent then constriction of muscles.
DSCG stops transmission down vagus sensory AFFERENT.
Chlorpheniramine, astemizole and cetirizine are all ANTI histamines. They are ___ receptor antagonists. So very useful for allergic rhinitis (hay fevers). Are they used in asthma?
H1 receptor antagonists
Not useful in asthma
What is Omalizumab?
How’s it thought to be useful in asthma?
An anti-IgE antibody
By preventing binding of IgE to mast cells therefore decreasing mast cell degranulation and decreasing severe allergic asthma!!!
Problem is it’s not responsive to glucocorticoids
What have there been gene Polymorphisms in that are associated with asthma and allergy?
The genes coding for the
Beta adrenoceptor
And 5- lipoxygenase
If a patient has a beta adrenoceptor polymorphism what can this mean for beta 2 agonist drugs like salbutamol?
Means they can loose benefit
May loose affinity for the new receptors
If a patient has a polymorphism in the gene coding for their lipoxygenase enzymes what can happen?
Lipoxygenase inhibitor drugs will become LESS effective
Asthma worsens
FEV1 (forced expiratory volume) decreases!!
