Asthma Flashcards
Definition of asthma
Chronic inflammatory disorder of the airways
2 lung function tests
PEFR- peak expiratory flow rate
FEV1- forced expiratory volume in 1 sec
4 mechanisms for increased hyper responsiveness
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
How does parasympathetic signalling in the lung work?
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
How does Ipratropium work?
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
Why is tiotropium better than ipratropium?
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
Mechanisms of bronchodilation
Adrenaline acts on beta adrenceptors in the lung
Inhibitory NANC transmitters
CGRP and VIP- activates adenyl cyclase
NO- acts on soluble guanylate cyclase
How do beta adrenoceptor agonists work?
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
Beta2 agonists?
In order of lipophilicity:
Salbutamol (short acting)
Formoterol
Salmeterol (long acting)
Why are formoterol and salmeterol longer acting beta agonists?
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.
How does theophylline work?
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
Effect of inflammation on airways
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
The difference between extrinsic and intrinsic asthma?
Extrinsic is young onset and caused by external allergens
Intrinisic is not caused by allergens and occurs later in life. Usually more severe
Definition of anaphylaxis
Caused by a severe allergic reaction resulting in respiratory collapse
How do allergies develop?
Genetic with the influence of many genetic loci
Driven by Th2 helper cells and the Th2 cytokines it releases
Associated with IgE antibodies
Th1 and Th2 in allergies
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
How do these cytokines cause allergies?
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
How long can it take for an allergy to develop?
The initial sensitisation may take years and are asymptomatic
This sensitisation increases over the years until re-exposure triggers mast cell release
Antihistamine in allergies
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
What are ‘Cromones’?
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
What is Omalizumab?
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
Immunotherapy
Licensed for allergies but not asthma
Give higher doses of antigen overtime under medical supervision
Also very expensive
How do glucocorticoids work?
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)
Leucotrines in asthma
LTC4 and LTD4 constrict airways and cause oedema via increasing vascular permeability
LTB4 attracts leukocytes increasing inflammation further
How do leukotrine receptor antagonists (LTRA) work?
Eg. Montelukast and zafirlukast
Blocks the action of LTC4 and LTD4
How do leukotrine synthesis inhibitors work?
Eg. Zileuton
Blocks 5 lipoxygenase which is responsible for the synthesis of leukotrines
How do the leukotrine antagonists compare against glucocorticoids?
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
Anticytokines
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
