Asthma

Question 1

Definition of asthma

Answer 1

Chronic inflammatory disorder of the airways

Question 2

2 lung function tests

Answer 2

PEFR- peak expiratory flow rate

FEV1- forced expiratory volume in 1 sec

Question 3

4 mechanisms for increased hyper responsiveness

Answer 3

Increased muscle contractility
Either bigger muscle cells (hypertrophy) or more muscle cells (hyperplasia)

Increased excitatory nerve activity- can be caused by ACh on M3 receptors or NANC molecules on neurokinin receptors

Decreased bronchodilator activity

Inflammation

Question 4

How does parasympathetic signalling in the lung work?

Answer 4

The para sympathetic nerve release ACh which acts on the M3 receptors on the smooth muscle cells

This causes Ca2+ to be released within the muscle cell which initiates a contraction

Question 5

How does Ipratropium work?

Answer 5

It is a non selective muscarininc antagonist that blocks both the M1 receptor on the nerve and the M3 receptor on the muscle

Only problem is that M2 is not blocked and therefore by negative feedback more ACh is released which can overcome the antagonist effect of ipratropium

Question 6

Why is tiotropium better than ipratropium?

Answer 6

Tiptropium blocks only the M3 receptor on the muscle cell

This means that ACh release is not inhibited hence the ACh can still effect the M2 receptor which will inhibit release of ACh

Question 7

Mechanisms of bronchodilation

Answer 7

Adrenaline acts on beta adrenceptors in the lung

Inhibitory NANC transmitters
CGRP and VIP- activates adenyl cyclase
NO- acts on soluble guanylate cyclase

Question 8

How do beta adrenoceptor agonists work?

Answer 8

Activates MLC phosphotase- dephosphorylates myosin chains

G protein is coupled to adenyl cyclase which:
ATP converted to cAMP which activates PKA (protein kinase A) which:
Opens K+ channels (causes hyperpolarisation)
Sequesters Ca2+ (brings it back into stores)
Inactivates MLCK

Question 9

Beta2 agonists?

Answer 9

In order of lipophilicity:
Salbutamol (short acting)
Formoterol
Salmeterol (long acting)

Question 10

Why are formoterol and salmeterol longer acting beta agonists?

Answer 10

Salmeterol interacts with the membrane and slowly diffuses out to the receptor

Formoterol forms a depot in the membrane and leaches out to act on receptor but itcan also interact directly with the receptor in the aqueous phase as it maintains an equilibrium between lipid/aq phase.

Question 11

How does theophylline work?

Answer 11

It inhibits phosphodiesterase (PDE) an enzyme that inactivates cAMP

Due to cAMP still working the dilating effect of the beta2 receptor has is enhanced

It does however have a narrow therapeutic window

Question 12

Effect of inflammation on airways

Answer 12

Causes epithelial damage
Exposes sensory nerves
Oedema and secretions lead to decreased airway diameter

In asthmatic patients you also get increased secretion and mucous plugging

Question 13

The difference between extrinsic and intrinsic asthma?

Answer 13

Extrinsic is young onset and caused by external allergens

Intrinisic is not caused by allergens and occurs later in life. Usually more severe

Question 14

Definition of anaphylaxis

Answer 14

Caused by a severe allergic reaction resulting in respiratory collapse

Question 15

How do allergies develop?

Answer 15

Genetic with the influence of many genetic loci

Driven by Th2 helper cells and the Th2 cytokines it releases

Associated with IgE antibodies

Question 16

Th1 and Th2 in allergies

Answer 16

Th1 cytokines suppresses Th2 cell production

An increased Th2:Th1 ratio is indicative of allergies

Th1 cytokines include IL-12 and interferon gamma
Th2 cytokines include IL-4,5,9 and 13

Question 17

How do these cytokines cause allergies?

Answer 17

IL-4 and 13 causes B cells to make more IgE antibodies

The IgE binds to FceR on mast cells and the cross linking causes degranulation

Histamines, cytokines, proteases and heparin are released causing the allergic reaction

Question 18

How long can it take for an allergy to develop?

Answer 18

The initial sensitisation may take years and are asymptomatic

This sensitisation increases over the years until re-exposure triggers mast cell release

Question 19

Antihistamine in allergies

Answer 19

Chlorpheneramine, cetirizine and astemizole are effective in relieving allergic rhinitis but not extrinsic asthma

This is due to the fact that mast cells in the lungs have low levels of histamines hence anti histamines are less effective

Question 20

What are ‘Cromones’?

Answer 20

Eg. Disoium cromoglycate, nedocromil

Known as ‘mast cell stabilisers’ as they inhibit mediator release from mast cells in the lungs

Effective in half of patients against early and late stage asthma

Also inhibits the chemotaxis of eosinophils and nerve fibre excitation

Question 21

What is Omalizumab?

Answer 21

An anti IgE antibody

Binds to the Fc portion of IgE preventing it from binding to mast cells

No oral admin and very expensive

Hence only approved for severe asthma unresponsive to glucocorticoids

Question 22

Immunotherapy

Answer 22

Licensed for allergies but not asthma

Give higher doses of antigen overtime under medical supervision

Also very expensive

Question 23

How do glucocorticoids work?

Answer 23

Regulates gene transcription

• inhibits cytokine transcription
• inhibits infammatory leukocyte migration

Indirectly inhibits Phospholipase A which stops the production of arachidonic acid which is responsible for prostaglandins and leukotrines (involved in inflammation)

Question 24

Leucotrines in asthma

Answer 24

LTC4 and LTD4 constrict airways and cause oedema via increasing vascular permeability

LTB4 attracts leukocytes increasing inflammation further

Question 25

How do leukotrine receptor antagonists (LTRA) work?

Answer 25

Eg. Montelukast and zafirlukast

Blocks the action of LTC4 and LTD4

Question 26

How do leukotrine synthesis inhibitors work?

Answer 26

Eg. Zileuton

Blocks 5 lipoxygenase which is responsible for the synthesis of leukotrines

Question 27

How do the leukotrine antagonists compare against glucocorticoids?

Answer 27

In an RCT glucocorticoid (beta agonist) consistently performed better

In labs LTRA’s were equivalent to glucocorticoids

Difference in genetics in the population may also account for variation in effect

Question 28

Anticytokines

Answer 28

There are high numbers of cytokines in the lungs of asthmatics

IL 13,4 and 5 help these eosinophils

Anti-IL-13(4) is only useful in a small amount of people and is not in the UK

Anti IL 5 are used in severe steroid resistant asthma