What always obvious, as well as a genetic

What is Asthma
and What Are Its Causes?

Asthma
is a long-term inflammatory disease affecting the airways of the lungs,
characterised by attacks of breathlessness and wheezing of varying severity. (1) These symptoms during an asthma
attack are caused as a result of the smooth muscle of the airways excessively
contracting, known as bronchospasm. Asthma
attacks usually have environmental triggers, though these are not always
obvious, as well as a genetic component in many cases. Such triggers include
allergens such as the faecal matter of house dust mites or outdoor allergens
such as pollens or moulds, tobacco smoke, chemical irritants and air pollution.
Other not so obvious triggers must also be considered in a patient with suspected
asthma, such as exposure to cold air, emotional issues, and exercise induced
asthma. (1) Traditionally, asthma was assumed to be completely down to abnormalities
in the smooth muscle itself; studies in recent years, however, have shown that
airway smooth muscle taken from asthmatic patients would not have the same
contractile response to spasmotic agents such as histamine in vitro. Such
studies have now led to the understanding that the problem in asthma does not
lie only inherently within the affected tissue, but also with the control of
the tissue in vivo. (2)

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Initial Treatment
of a Patient Presenting with an Asthma Attack

The
first-line therapy for patients presenting with an asthma attack which has been
unresponsive to inhaled (low-dose) self-administered bronchodilators is to give
higher doses of the same drugs, usually by nebulisation. The go-to
bronchodilator for the treatment of acute asthma is salbutamol, a short-acting b2-adrenoceptor (selective)
agonist, or so-called “SABA”. As the name suggests, such drugs act to agonise the
b2-adrenoceptor
of the airway smooth muscle which are naturally stimulated by adrenaline in the
body. (3) Upon salbutamol binding to this
receptor, a G protein cascade known as the Gs pathway is stimulated,
resulting in the activation of the enzyme adenylyl cyclase. When activated,
this enzyme catalyses the dephosphorylation of ATP into cAMP, a highly reactive
molecule which positively acts to activate protein kinase A (4). The outcome of this cascade is
that the activated protein kinase A phosphorylates myosin phosphatase, subsequently
activating it. This enzyme acts to dephosphorylate myosin, reducing its potential
to form crossbridges with actin and thus downregulating muscle contraction; this
is a highly desirable outcome in a patient whose airways are in bronchospasm. (5)(6) If the patient is hypoxaemic,
controlled oxygen should be given to maintain oxygen saturations of 94-98%; it is
highly advisable that bronchodilators should be given with a controlled flow of
oxygen in the acute context. (7)

 

Should
the patient fail to make considerable improvement when given nebulised salbutamol
alone, other therapies can be introduced; this was the case for the patient
around whom this case study resolves. The additional treatment of choice would
be to add nebulised ipratropium in combination with the salbutamol being given.
(7) This drug is a short-acting
muscarinic receptor antagonist, known as a “SAMA” – it acts to compete with
acetylcholine at the M3 receptors at the synapses between parasympathetic
neurones and airway smooth muscle cells. In the absence of this competitor, the
binding of acetylcholine to M3 receptors results in the initiation
of the Gq/11 cascade. This G-protein activation results in
phospholipase C being upregulated, which converts PIP2 into IP3
– the latter of these is the ligand for a calcium channel in the
sarcoplasmic reticulum membrane, and so an increase in its concentration
results in calcium efflux from within it. This efflux stimulates muscle
contraction in the airway smooth muscle cells; thus, antagonising the M3
receptor which – when activated – results in this cascade will act to relax
smooth muscle cells. (8) Furthermore, studies have shown
that the bronchodilator effect of nebulised salbutamol in combination with
nebulised ipratropium is much greater than use of a b2-agonist alone.
(9)

 

In
a patient presenting with a severe to life-threatening acute exacerbation asthma,
other drugs may also have positive effects to reduce both the inherent risk to
their life initially and to aid recovery, reducing the length of
hospitalisation. The use of magnesium sulphate is something that may be
considered in patients presenting acutely with severe asthma (PEF