Transcript Respiration-3

DRUGS USED IN THE TREATMENT OF
ASTHMA - ANTI-INFLAMMATORY AGENTS
Dr Stuart Wilson
DRUGS USED IN THE TREATMENT OF
ASTHMA - ANTI-INFLAMMATORY AGENTS
CORTICOSTEROIDS
Adrenal cortex synthesises two major classes of steroid hormone that
are released into the circulation. Not pre-stored, but synthesised and
released on demand.
Glucocorticoids – the main hormone is cortisol (hydrocortisone) regulates numerous processes that are essential to life, e.g:
carbohydrate and protein metabolism
Hypothalamus
responses to stress
inflammatory responses
Synthesis and release of cortisol
Cortisol
regulated by adrenocorticotrophic
hormone (ACTH) released from the
anterior pituitary. Release of ACTH is
partially under negative feedback
control by the level of cortisol in the
blood (see Endocrinology block)
Pituitary
ACTH
+
Adrenal
cortex
Mineralocorticoids – mainly aldosterone - regulates the retention
of salt (and water) by the kidney
Synthesis and release of aldosterone are regulated mainly by the
renin-angiotensin system (see Cardiovascular and Renal blocks)

Naturally occurring steroids may possess both glucocorticoid
and mineralocorticoid actions. The latter are unwanted in
treatment of inflammatory conditions

Synthetic derivatives of cortisol, that have little, or no,
mineralocorticoid activity are frequently used for their antiinflammatory effect in the treatment of asthma and many other
conditions. They have no direct bronchodilator action and are
ineffective in relieving bronchospasm when given acutely
MOLECULAR MECHANISM OF ACTION OF STEROID
HORMONES
 Steroid hormones
are lipophilic
molecules - enter cells by diffusion
across the plasma membrane (1)
1
2
3
Nucleus
4
Transcription (5)
mRNA (6)
Translation (7)
Proteins (8)
 Within the cell, they combine with an
intracellular receptor
(2) producing
a conformational change exposing a
DNA-binding domain (3). In the
case of the glucocorticoids, the
inactive receptor is located in the
cytoplasm
 The receptor steroid complex moves
to the nucleus (4) and binds to
steroid response elements in DNA
 The transcription of specific genes (5)
is either ‘switched-on’ (induced) or
‘switched off’ (repressed) to alter
mRNA levels (6) and the rate of
synthesis (7) of mediator proteins (8)
GLUCOCORTICOID EFFECTS UPON GENE TRANSCRIPTION THAT
ARE RELEVANT TO INFLAMMATION IN BRONCHIAL ASTHMA
Many tens of genes are regulated by glucocorticoids acting at GREs,
or by modifying chromatin (via deacetylation of histones – not
discussed here)
Gene activation (generally high doses of glucocorticoids)
Examples:
Annexin-1 (lipocortin-1)
-adrenoceptors
IB- (inhibitor of the inflammatory transcription factor NF-B)
Gene repression (occurs with low doses of glucocorticoids)
Examples:
Cytokines
Chemokines
Adhesion molecules
Inflammatory enzymes
Inflammatory receptors
GLUCOCORTICOID EFFECTS UPON GENE TRANSCRIPTION THAT
ARE RELEVANT TO INFLAMMATION IN BRONCHIAL ASTHMA
(Example 1)
Gene induction
Increased synthesis of annexin-1 (lipocortin-1), a polypeptide
inhibiting the enzyme phospholipase A2, decreases the formation of
leukotriene spasmogens (LTC4, LTD4) and chemotaxins (LTB4) by
reducing the formation of precursor arachidonic acid.
Membrane phospholipid
X
Phospholipase A2
Arachidonic
acid
Lipocortin-1 blocks
5-lipoxygenase
LTB4
(chemotaxin)
Infiltration of
eosinophils
LTA4
LTC4 & LTD4
CysLT receptor
activation and
bronchoconstriction
GLUCOCORTICOID EFFECTS UPON GENE TRANSCRIPTION THAT
ARE RELEVANT TO INFLAMMATION IN BRONCHIAL ASTHMA
(Example 2)
Gene repression
 Decreased formation of protein cytokines that: 1) recruit and
activate eosinophils and 2) promote the production of IgE and
expression of IgE receptors
Glucocorticoids block
Th2
X
B
P
IgE
B
P
IgE
Cytokines
B
CELLULAR EFFECTS OF GLUCOCORTICOIDS RELEVANT TO ASTHMA
From Barnes, P.J. (2006). Eur. J. Pharmacol. 533, 2-14.
CLINICAL USE OF GLUCOCORTICOIDS IN ASTHMA
Glucocorticoids suppress the inflammatory component of asthma – (1)
prevent inflammation and (2) resolve established inflammation
Short term, they do not alleviate early stage bronchospasm caused by
allergens, or exercise, but long term treatment is effective very effective
(particularly in combination with a long-acting 2-adrenoceptor agonist)
In mild/moderate asthma:

Glucocorticoids (often beclomethasone) are given by inhalation
from a metered dose inhaler (to minimise many unwanted systemic
effects)

Efficacy develops over several days
The most common adverse effects (due to deposition of steroid in
the oropharynx) are:
1) dysphonia (hoarse and weak voice)
2) oropharyngeal candidiasis (thrush)
In chronic, severe, or rapidly deteriorating asthma
Oral prednisolone may be used in combination with an inhaled
steroid to reduce the oral dose required and minimise unwanted
systemic effects. Bronchodilator drugs are co-administered
(See lectures by Prof. Lipworth for greater clinical detail)
CROMOGLYCATES

Are second line drugs used prophylactically in the treatment
of asthma (particularly children)

Have no direct effect upon bronchial smooth muscle

Have an uncertain molecular mechanism of action. A decrease
in the sensitivity of irritant receptors associated with sensory Cfibres that trigger exaggerated reflexes and reduction of
cytokine release are potential mechanisms
SPECIFIC AGENT
Sodium cromoglycate

delivered by inhalation

can reduce both phases of an asthma attack, but efficacy may
take several weeks to develop

Is the anti-inflammatory of choice in some children
RECENT APPROACHES TO THE TREATMENT OF ASTHMA
THAT INVOLVE ANTI-INFLAMMATORY ACTIONS
Monoclonal antibodies directed against IgE (e.g. omalizumab)
• Binds IgE via Fc to prevent
attachment to Fc receptors
– suppresses mast cell
response to allergens
• Reduces the expression of
Fc receptors on various
inflammatory cells
From Strunck, R.C. and Bloomberg, G.R. (2006)
N. Engl. J. Med. 354, 2689-2695.