DRUGS USED IN THE TREATMENT OF ASTHMA - ANTI-INFLAMMATORY AGENTS

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DRUGS USED IN THE TREATMENT OF ASTHMA -
ANTI-INFLAMMATORY AGENTS
Dr Stuart Wilson
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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
• responses to stress
• inflammatory responses

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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 anti-inflammatory
  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

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MOLECULAR MECHANISM OF ACTION OF STEROID HORMONES

• 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)

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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 Ad
hesion molecules Inflammatory enzymes Inflammatory
receptors
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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.

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GLUCOCORTICOID EFFECTS UPON GENE TRANSCRIPTION
THAT ARE RELEVANT TO INFLAMMATION IN BRONCHIAL
ASTHMA (Example 2)
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CELLULAR EFFECTS OF GLUCOCORTICOIDS RELEVANT TO
ASTHMA
From Barnes, P.J. (2006). Eur. J. Pharmacol. 533,
2-14.
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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

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• 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)
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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 C-fibres 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

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• 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