DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

INFLAMMATORY CELLS
Eosinophil
STRUCTURAL CELLS
Epithelial cells
1049
Numbers
( apoptosis)
Cytokines
Numbers
Cytokines
T-lymphocyte
Mast cell
Macrophage
CORTICOSTEROIDS
Endothelial cells
Airway smooth
muscle
Mucus gland
Cytokines
Mediators
Leak
β 2 Receptors
Cytokines
CHAPTER 36
PULMONARY PHARMACOLOGY
Mucus secretion
Dendritic cell
Numbers
Figure 36–10. Effect of corticosteroids on inflammatory and structural cells in the airways.
corticosteroids suppress inflammation in the airways but do not cure
the underlying disease. When steroids are withdrawn there is a recurrence
of the same degree of airway hyperresponsiveness, although in
patients with mild asthma it may take several months to return.
Effect on 2
Adrenergic Responsiveness. Corticosteroids increase
adrenergic responsiveness, but whether this is relevant to their
effect in asthma is uncertain. Steroids potentiate the effects of agonists
on bronchial smooth muscle and prevent and reverse receptor
desensitization in airways in vitro and in vivo (Barnes, 2002;
Giembycz et al., 2008). At a molecular level, corticosteroids increase
the transcription of the 2
receptor gene in human lung in vitro and
in the respiratory mucosa in vivo and also increase the stability of its
messenger RNA. They also prevent or reverse uncoupling of 2
receptors to G s
. In animal systems, corticosteroids prevent downregulation
of 2
receptors.
2
Agonists also enhance the action of GR, resulting in
increased nuclear translocation of liganded GR receptors and
enhancing the binding of GR to DNA. This effect has been demonstrated
in sputum macrophages of asthmatic patients after an ICS
and inhaled LABA (Usmani et al., 2005). This suggests that 2
agonists
and corticosteroids enhance each other’s beneficial effects in
asthma therapy.
Pharmacokinetics. The pharmacokinetics of oral corticosteroids are
described in Chapter 42. The pharmacokinetics of inhaled corticosteroids
are important in relation to systemic effects (Barnes et al.,
1998b). The fraction of steroid that is inhaled into the lungs acts
locally on the airway mucosa but may be absorbed from the airway
and alveolar surface. Thus, a portion of an inhaled dose reaches the
systemic circulation. Furthermore, the fraction of inhaled steroid that
is deposited in the oropharynx is swallowed and absorbed from the
gut. The absorbed fraction may be metabolized in the liver (firstpass
metabolism) before reaching the systemic circulation (Figure
36–3). The use of a spacer chamber reduces oropharyngeal deposition
and therefore reduces systemic absorption of ICS, although this
effect is minimal in corticosteroids with a high first-pass metabolism.
Mouth rinsing and discarding the rinse have a similar effect,
and this procedure should be used with high-dose dry powder steroid
inhalers with which spacer chambers cannot be used.
Beclomethasone dipropionate and ciclesonide are prodrugs
that release the active corticosteroid after the ester group is cleaved
by esterases in the lung. Ciclesonide is available as a MDI (ALVESCO)
for asthma and as a nasal spray for allergic rhinitis (OMNARIS).
Budesonide and fluticasone propionate have a greater first-pass
metabolism than beclomethasone dipropionate and are therefore less
likely to produce systemic effects at high inhaled doses.