Aran Johal – HT19 WK7

Briefly describe asthma and the drugs (with their mechanism of action) used to treat it

INTRO
Asthma is defined as a chronic inflammatory disorder of the airways that can cause recurrent episodes of
wheezing, breathlessness, chest tightness and cough. The airway obstruction associated with asthma sets
it apart from COPD, in which the obstruction is usually not reversible. The disruption of the normal airflow
into the lungs is what precipitates the symptoms that were previously mentioned. Bronchospasm appears to
be the most presenting feature but is not usually the major contributing factor to the pathogenesis, which is
it being a condition of chronic inflammation. In this essay, I shall discuss the pathophysiology of asthma and
then go on to discuss the various mechanisms by which it can be treated.

PATHOPHYSIOLOGY
The cause of the inflammation and bronchial hyper-reactivity in asthma is due to epithelia and smooth muscle
cells, with the pathophysiology being split into an immediate and late stage. The immediate phase is initiated
by the inhalation of a stimuli that activates airway epithelia, resulting in the secretion of cytokines that trigger
dendritic cell maturation, as well as chemokines and interleukins. Stem cell-factor is also released which act
on KIT receptors of mast cells leading to their recruitment to the surface of the airway where IgE sensitised
mast cells can be activated by the allergens. This initiates degranulation and release of bronchoconstrictors
such as histamine, leukotrienes and prostaglandins, as well as IL4, IL5 and IL13.
It is the histamine and leukotrienes that are pivotal in the early stages of the disease and they trigger the
same intracellular signalling cascade in smooth muscle cells which produces constriction. The binding of
these agonists to their receptive Gq-couple GPCR activates the membrane bound enzyme phospholipase C,
which cleaves PIP2 into IP3 and DAG; IP3 is released in the cytosol and binds the IP3 receptor on the
sarcoplasmic reticulum which is a ligand gated calcium ion channel. IP3 binding initiates the release of calcium
ions into the cytosol, and this can then bind calmodulin which directly phosphorylates myosin light-chain
kinase, and therefore activates it, which results in the phosphorylation of myosin light chain. Cross-bridge
cycling is then able to occur which can lead to contraction. DAG is able to activate PKC, which phosphorylates
an inhibitor of myosin light chain phosphatase, preventing the dephosphorylation back to its inactive state.
The late phase of an asthma attack is mediated by influx of TH2 lymphocytes and eosinophils. The
lymphocytes secrete further IL4, IL5 and IL13, with IL5 being
responsible for eosinophil differentiation in bone marrow
whereas IL4 and IL13 are involved in inducing B cells to
undergo immunoglobulin class switching to produce IgE.
Allergen sensitisation occurs when the allergen is
endocytosed and processed in dendritic cells into smaller
peptides, which are presented as part of a peptide: MHC II
complex on the cell surface. The antigen presenting cells then
encounter T cell receptors of naïve CD4 T cells, which causes
their activation and differentiation into TH2 cells.
Aran Johal – HT19 WK7
The airway is covered with a sheet of epithelial cells that establish the mucocilairy apparatus that defend
against the inhaled pathogens. Despite this protective feature, they are also linked to the increase in airway
resistance in asthmatics. IL13 is critical in this process due to it causing the over production of mucus in
asthma; IL13 produces a transcriptional signature too which deems asthmatics either T H2 high or TH2 low
which is observed by the amount of IL13 induced periostin protein. IL13 production is seen in T H2 high
asthmatics and results in mucous metaplasia, which is correlated to high epithelial MUC5AC mRNA
expression. This encodes for a gel-like mucin that is secreted into the airway.
Ordonez et al. suggested that this increased mucus generation could be as a result of a chronic element of
asthma. In 2007, they quantified the expression of the mucin gene using PCR in 13 individuals with mild to
moderate asthma and 12 control subjects and also carried out immunohistochemical staining of
endobronchial biopsies. A 3-fold higher level of mucin gene expression within the unstimulated asthmatics
was found and they also noticed an increase in goblet cell number within their epithelium, suggesting some
form of goblet cell metaplasia was occurring when an attack was not present.

CORTICOSTEROIDS
TH2 mediated inflammation in asthmatic airways are known to be suppressed by corticosteroids through the
inhibition of the expression of cytokines, chemokines and adhesion molecules. The encoding genes of these
are regulated by transcription factors like NFκB activator protein I. Free corticosteroids are able to diffuse
across the cell membrane where they are able to interact with cytoplasmic glucocorticoid receptors, resulting
in the activation of these receptors and causing their translocation to the nucleus. This is where the
transcriptional activity of target genes is modulated by gene transactivation and gene transrepression. They
bind transcription factors P65 and P50, which prevents their binding to sites on the NFκB necessary for
transcription initiation. Inhaled corticosteroids are highly effective at suppressing airway inflammation, but
don’t influence the cause of the disease even when treatment starts early in childhood, meaning they are a
treatment of the symptoms only. Animals that have undergone adrenalectomy show how endogenous
glucocorticoids maintain a low level of anti-inflammatory tone, as the lack of glucocorticoid production leads
to a heightened response to minor inflammatory
stimuli.
Prolonged administration of glucocorticoids can lead
to a series of unwanted events, as patients may begin
to show symptoms similar to those of Cushing’s
syndrome caused by tumour growth in the adrenal
glands leading to excess cortisol production. This
causes the characteristic features of moon face with
red cheeks, abnormal fat distribution and poor wound
healing.

β2 AGONISTS
The main drugs used as bronchodilators are β2-adrenoreceptor agonists as they dilate the bronchi through
the activation of this Gs couple GPCR. The activation of the GPCR leads to an increase in intracellular cAMP,
Aran Johal – HT19 WK7
which activates PKA leading to the phosphorylation and inactivation of MLCK, thus inhibiting contraction and
alleviating bronchospasm. Calcium dependent K+ channels are also opened, which relieves
bronchoconstriction as well. Inhaled agents like salbutamol are the most effective bronchodilators and are
used on an ‘as needed’ basis for rapid relief. Longer lasting agents like salmeterol are given by inhalation,
but last over 8-12h as opposed to 3-5 like salbutamol. The composition of the drug stems from salbutamol,
as was it was manipulated by adding a hydrophobic hydrocarbon to the skeleton of salbutamol, allowing
portioning within the cell membrane.
β2 agonists, despite their wide use, are not without their side effects. They can cause facial flushing,
palpitation, tremor, cardiac arrhythmias, tachycardia and anxiety, with the latter factor being particularly
important as it may make a patient more anxious; anxiety can exacerbate asthma so use of these agents has
to be carefully judged.

METHYLXANTHINES
Theophylline is used is the main therapeutic drugs of this class and has a relaxant effect that is attributable
to inhibition of phosphodiesterase enzymes leading to a decrease in cAMP and cGMP. Type IV
phosphodiesterase is implicated in inflammatory cells and has some anti-inflammatory effects. It activates
histone deacetylase and reverses the resistance to the anti-inflammatory effect of corticosteroids. It
suppresses inflammation by inducing the recruitment of the nuclear enzyme histone deacetylase 2 to multiple
inflammatory genes, leading to deacetylation of the hyperacetylated genes, thereby suppressing
inflammation.
Theophylline has a small therapeutic window with serious cardiovascular and CNS effects occurring when
plasma concentration exceeds 200μm/L, producing dysrhythmias and seizures. It is metabolised by the P450
enzymes in the liver, meaning if drugs are present that could inhibit this enzyme like erythromycin, the
concentration could dramatically rise in the blood and lead to complications.

IgE THERAPY
IgG antibodies specific for the C3 domain of IgE that block IgE binding of the high affinity receptor, FcεRI.
These antibodies were shown to inhibit allergen-induced inflammatory responses. Omalizumab is a
humanised IgE specific, non-anaphylactic IgG1 that has been developed for the treatment of severe allergic
asthma. If in concentrations in excess of IgE, omalizumab is able to effectively outcompete FcεRI for IgE,
desensitising mast cells and eosinophils to activation. It also has the capacity to bind membrane bound IgE
on IgE expressing B cells which is part of the B cell receptor, so it can inhibit the B cells or even cause their
lysis. Clinical trials in those with poorly controlled
IgE mediated asthma have shown omalizumab
administered subcutaneously 2-4 times a week
improves symptom control and allows patients to
be manged with lower doses of inhaled
corticosteroids. The levels of circulating free IgE
decrease rapidly after the first dose, but 16
Aran Johal – HT19 WK7
weeks of treatment is required before optimal clinical effects are seen.

MAST CELL INHIBITORS

The archetypal mast-cell stabilising drug sodium cromoglicate was introduced in 1968 and was followed by
nedocromil sodium in 1984. Both drugs, after inhalation, inhibit the allergen-induced early and late phase
response in upper and lower airways and conjunctiva, which is where mucosal mast cells are involved in the
allergic response. Both drugs inhibit the flux of chloride ions in mast cells, epithelial cells and neurons to
increase their threshold for activation.
These drugs are thought to prevent histamine release, but it was shown that histamine has very little effect
in producing asthmatic symptoms through introduction of compounds more potent in inhibition of mast cell
release, which do not alleviate symptoms.
The other potential mechanism of these drugs is to depress neuronal reflexes that lead to increased ACh
release of the vagus nerve through suppressing stimulation of irritant receptors.

CYTOKINE-BASED IMMUNOTHERAPY
The sentinel role of TH2 cytokines in orchestrating allergic inflammation means they and their receptors are
key therapeutic targets. IL4 is one of these key targets; IL4 and IL13 have a key role in the immunoglobulin
isotype switching of B cells to make IgE and IL4 is crucial in maintaining TH2 cell phenotypes. Blocking the
production or inhibiting IL4 effects will have profound effects on the allergic phenotype. A soluble recombinant
human IL4R, altrakincept, consist of the extracellular portion of human IL4α and is non-immunogenic. A small
trial of nebulized inhaled altrakincept for 12 weeks in patients with mild to moderate asthma indicated efficacy
by allowing withdrawal from treatment with inhaled corticosteroids without relapse. Phase III trials failed to
confirm this efficacy for the treatment of asthma due to concerns over its bioavailability.
IL13 regulates IgE production, eosinophilic inflammation, airway smooth muscle hyperplasia, induction of
goblet cell hyperplasia with mucus production and the recruitment of immune cells to the airway space. IL13
binds the low affinity IL13α1 subunit and a high affinity complex of IL13α1 and IL4Rα, which leads to the
phosphorylation-dependent activation of JAK and STAT proteins. A non-signalling, high affinity binding chain
(IL13α2) strongly inhibits the activation of IL13. Selective blockade of IL13 has been achieved in mice using
a soluble form of this chain which competes for binding to IL13 but not IL4. This led to the reversal of airway
hyper-responsiveness and mucus production in allergen exposed sensitised mice.

CONCLUSION
Overall, asthma is a condition that can be treated in many ways due to its diverse range of symptoms and
cytokine involvement. The current treatments are largely symptomatic treatments, which predominantly deal
with bronchodilation and an anti-inflammatory mediation. Other methods are in current development and look
promising when looking at a treatment that can prevent the onset of the attack through administration of
monoclonal antibodies.