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

Chemistry. The adrenal cortex secretes cortisol (hydrocortisone)
and, by modification of its structure, it was possible to develop
derivatives, such as prednisone, prednisolone, and dexamethasone,
with enhanced corticosteroid effects but with reduced mineralocorticoid
activity (Chapter 42). These derivatives with potent glucocorticoid
actions were effective in asthma when given
systemically but had no anti-asthmatic activity when given by
inhalation. Further substitution in the 17 ester position resulted in
steroids with high topical activity, such as beclomethasone dipropionate,
triamcinolone, flunisolide, budesonide, and fluticasone
propionate, which are potent in the skin (dermal blanching test)
and were later found to have significant anti-asthma effects when
given by inhalation (Figure 36–8).
Mechanism of Action. Corticosteroids enter target cells and bind to
glucocorticoid receptors (GR) in the cytoplasm (Chapter 42). There
is only one type of GR that binds corticosteroids and no evidence
for the existence of subtypes that might mediate different aspects of
corticosteroid action (Barnes, 2006a). The steroid-GR complex
moves into the nucleus, where it binds to specific sequences on the
upstream regulatory elements of certain target genes, resulting in
increased (or rarely, decreased) transcription of the gene, with subsequent
increased (or decreased) synthesis of the gene products. GR
may also interact with protein transcription factors and coactivator
molecules in the nucleus and thereby influence the synthesis of certain
proteins independently of any direct interaction with DNA. The
repression of transcription factors, such as activator protein-1 (AP-1)
and NF-B, is likely to account for many of the anti-inflammatory
effects of steroids in asthma. In particular, corticosteroids reverse
the activating effect of these pro-inflammatory transcription factors
on histone acetylation by recruiting HDAC2 to inflammatory genes
that have been activated through acetylation of associated histones
(Figure 36–9). GRs are acetylated when corticosteroids are bound
and bind to DNA in this acetylated state as dimers, whereas the
acetylated GR has to be deacetylated by HDAC2 in order to interact
with inflammatory genes and NF-B (Ito et al., 2006).
There may be additional mechanisms that are also important
in the anti-inflammatory actions of corticosteroids. Corticosteroids
have potent inhibitory effects on MAP kinase signaling pathways
through the induction of MKP-1, which may inhibit the expression
of multiple inflammatory genes (Clark, 2003).
Anti-Inflammatory Effects in Asthma. The mechanisms of action
of corticosteroids in asthma are still poorly understood, but their
efficacy is most likely related to their anti-inflammatory properties.
Corticosteroids have widespread effects on gene transcription,
increasing the transcription of several anti-inflammatory genes and
suppressing transcription of many inflammatory genes. Steroids have
inhibitory effects on many inflammatory and structural cells that are
activated in asthma and prevent the recruitment of inflammatory
cells into the airways (Figure 36–10). Studies of bronchial biopsies
in asthma have demonstrated a reduction in the number and activation
of inflammatory cells in the epithelium and submucosa after
regular ICS, together with a healing of the damaged epithelium.
Indeed, in patients with mild asthma the inflammation may be completely
resolved after inhaled steroids.
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CHAPTER 36
PULMONARY PHARMACOLOGY
H 3 C
HO
H 3 C
H 2 C
C
OH
O
OH
H 3 C
HO
H 3 C
H 2 C O C C 2 H 5
C
O
O
OCOC 2 H 5
CH 3
HO
H 3 C
H 2 C
O C
H 3 C
OH
O
O
C
H
CH 2 CH 2 CH 3
Cl
Cl
O
O
O
HYDROCORTISONE
BECLOMETHASONE
DIPROPIONATE
BUDESONIDE
SCH 2 F
H 2 C
OH
H 2 C
OH
HO
H 3 C
H 3 C
C
O
OCOC 2 H 5
CH 3
HO
H 3 C
H 3 C
C
O
O
O
C
CH 3
CH 3
H 3 C C O
HO O
C
CH 3
H 3 C
O CH 3
F
F
O
O
O
F
F
FLUTICASONE PROPIONATE
FLUNISOLIDE
TRIAMCINOLONE ACETONIDE
Figure 36–8. Chemical structures of commonly used inhaled corticosteroids, showing changes from hydrocortisone nucleus.