Infection & immunology Malcolm Watson Asthma treatment

Question 0

What are modulators?

Answer 0

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

Question 1

What are mitogens?

Answer 1

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

Question 2

What are eNANCs?

Answer 2

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

Question 3

What are iNANCs?

Answer 3

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

Question 4

What colour is a mucous plug from the airways? Why?

Answer 4

It’s whiteish
Because it’s full of white blood cells and NOT bacteria
So it’s sterile inflammation
Plug formed from Mucosal oedema

Question 5

Name two excitatory molecules causing broncho constriction

Name four inhibitory molecules causing bronco dilation

Answer 5

Excitatory:
eNANCs
ACETYLCHOLINE acting of M3 receptor

Inhibitory:
iNANCs
NO
Adrenaline 
acetylcholine acting on M2 receptors

Question 6

Which two interleukins produced by TH2 cells overlap receptors and so have similar action?

Answer 6

IL-4 and IL-13

Question 7

What does intrinsic allergy mean?

Answer 7

Non atopic
Usually in Middle Ages onwards
Hyperresponsiveness
More severe airflow limitations than extrinsic

Question 8

What can cause a cough in asthma?

Answer 8

Prostanoids
PGE2 can sensitise irritant receptors
This can cause a cough
Also relaxes smooth muscle and decrease leukocyte activation

Question 9

Salbutamol is a beta adrenoceptor agonist. What effect does it have in the lungs?

Answer 9

It’s a bronchodilator
SELECTIVE Beta 2 agonist

Not anti inflammatory

Question 10

2 long acting selective beta 2 agonist drugs?

Answer 10

Formoterol

Salmeterol

Question 11

Example of a non selective beta 2 agonist?

Answer 11

Isoprenaline

Question 12

Salmeterol is very lipophillic. What are the consequences of this?

Answer 12

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

Question 13

Formeterol is neither lipophillic or Hydrophillic. How does it interact with the beta 2 receptor?

Answer 13

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…

Question 14

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…..

Answer 14

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

Question 15

What kind of drug is Theophylline?

Answer 15

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!!!

Question 16

Why do we have to be careful with dosing of theophylline?

Answer 16

It has a narrow therapeutic window

Question 17

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?

Answer 17

G beta gamma one leads to activation of MLC phosphatases

Question 18

Prednisolone and Budesonide are both used in asthma. What kind of drugs are these?

Answer 18

glucocorticoids

Question 19

How do glucocorticoids work?

Answer 19

Regulate gene transcription
inhibit cytokine transcription
Inhibit inflammatory leukocyte migration
Promote eosinophil apoptosis (get rid of these)
Indirectly inhibit phospholipase A activity

Question 20

One action of glucocorticoids is that they can indirectly inhibit phospholipase A2.
What does this do?

Answer 20

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

Question 21

What PDEs does theophylline inhibit?

Answer 21

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

Question 22

What are montelukast and zafirlukast?

What about Zileuton?

Answer 22

Leukotriene receptor antagonists
Cause bronchodilation
Zileuton is a leukotriene SYNTHESIS inhibitor. Does this by blocking 5- lipoxygenase

Question 23

Membrane phospholipids—–arachnidonic acid—–5-lipoxygenase—leukotrienes (LTB4, LTC4, LTD4).
What drugs can act here and where?

Answer 23

ZILEUTON can inhibit 5-lipoxygenase

Montelukast can inhibit leukotriene synthesis, specifically LTC4 and LTD4

Question 24

What antibodies have been trialled in asthma?

Answer 24

Anti IL-5 antibodies

Reduced eosinophil levels

Question 25

As an anti allergic therapy in asthma we can target mast cell degranulation using Cromones.
What 2 can you think of ?

Answer 25

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

Question 26

How do mast cell stabilisers work in allergic asthmas?

Answer 26

They inhibit mediator release from lung mast cells.

Have to be treated with these for a few weeks before benefits seen

Question 27

Disodium cromoglycate (DSCG) inhibits sensory nerve fibre excitation in airways. How..?

Answer 27

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.

Question 28

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?

Answer 28

H1 receptor antagonists

Not useful in asthma

Question 29

What is Omalizumab?

How’s it thought to be useful in asthma?

Answer 29

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

Question 30

What have there been gene Polymorphisms in that are associated with asthma and allergy?

Answer 30

The genes coding for the
Beta adrenoceptor
And 5- lipoxygenase

Question 31

If a patient has a beta adrenoceptor polymorphism what can this mean for beta 2 agonist drugs like salbutamol?

Answer 31

Means they can loose benefit

May loose affinity for the new receptors

Question 32

If a patient has a polymorphism in the gene coding for their lipoxygenase enzymes what can happen?

Answer 32

Lipoxygenase inhibitor drugs will become LESS effective
Asthma worsens
FEV1 (forced expiratory volume) decreases!!