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

suppression of inflammation is of enormous clinical
utility and has made these drugs among the most frequently
prescribed agents. Similarly, glucocorticoids are
of immense value in treating diseases that result from
undesirable immune reactions. These diseases range
from conditions that predominantly result from humoral
immunity, such as urticaria (Chapter 65), to those that
are mediated by cellular immune mechanisms, such as
transplantation rejection (Chapter 35). The immunosuppressive
and anti-inflammatory actions of glucocorticoids
are inextricably linked, perhaps because they both
involve inhibition of leukocyte functions.
Multiple mechanisms are involved in the suppression of
inflammation by glucocorticoids. Glucocorticoids inhibit the production
by multiple cells of factors that are critical in generating the
inflammatory response. As a result, there is decreased release of
vasoactive and chemoattractive factors, diminished secretion of
lipolytic and proteolytic enzymes, decreased extravasation of leukocytes
to areas of injury, and ultimately, decreased fibrosis.
Glucocorticoids can also reduce expression of pro-inflammatory
cytokines, as well as COX-2 and NOS2. Some of the cell types and
mediators that are inhibited by glucocorticoids are summarized in
Table 42–3. The net effect of these actions on various cell types is to
diminish markedly the inflammatory response.
The influence of stressful conditions on immune defense
mechanisms is well documented, as is the contribution of the HPA
axis to the stress response (Elenkov and Chrousos, 2006). This has
led to a growing appreciation of the importance of glucocorticoids
as physiological modulators of the immune system, where glucocorticoids
appear to protect the organism against life-threatening consequences
of a full-blown inflammatory response (Chrousos, 1995).
Stresses such as injury, infection, and disease result in the
increased production of cytokines, a network of signaling molecules
that integrate actions of macrophages/monocytes, T lymphocytes,
and B lymphocytes in mounting immune responses. Among these
cytokines, interleukin (IL)-1, IL-6, and tumor necrosis factor α
(TNF-α) stimulate the HPA axis, with IL-1 having the broadest
range of actions. IL-1 stimulates the release of CRH by hypothalamic
neurons, interacts directly with the pituitary to increase the
release of ACTH, and may directly stimulate the adrenal gland to
produce glucocorticoids. As detailed earlier, the increased production
of glucocorticoids, in turn, profoundly inhibits the immune system
at multiple sites. Factors that are inhibited include components of
the cytokine network, including interferon γ (IFN-γ), granulocytemacrophage
colony-stimulating factor (GM-CSF), interleukins (IL-1,
IL-2, IL-3, IL-6, IL-8, and IL-12), and TNF-α. Thus, the HPA axis
and the immune system are capable of bidirectional interactions in
response to stress, and these interactions appear to be important for
homeostasis (Chrousos, 1995).
Absorption, Transport, Metabolism,
and Excretion
Absorption. Hydrocortisone and numerous congeners,
including the synthetic analogs, are orally effective.
Certain water-soluble esters of hydrocortisone and its
Table 42–3
Effects of Glucocorticoids on Components of Inflammatory/Immune Responses
CELL TYPE FACTOR COMMENTS
Macrophages Arachidonic acid and its metabolites Mediated by glucocorticoid inhibition of
and monocytes (prostaglandins and leukotrienes) COX-2 and PLA 2
.
Cytokines, including: interleukin Production and release are blocked. The cytokines
(IL)-1, IL-6, and tumor necrosis exert multiple effects on inflammation
factor-α (TNF-α)
(e.g., activation of T cells, stimulation of
fibroblast proliferation).
Acute phase reactants
These include the third component of complement.
Endothelial cells ELAM-1 and ICAM-1 ELAM-1 and ICAM-1: critical for leukocyte localization.
Acute phase reactants
Cytokines (e.g., IL-1)
Same as above, for macrophages and monocytes.
Arachidonic acid derivatives
Basophils Histamine, LTC 4
IgE-dependent release inhibited by glucocorticoids.
Fibroblasts Arachidonic acid metabolites Same as above for macrophages and monocytes.
Glucocorticoids also suppress growth factor–induced
DNA synthesis and fibroblast proliferation.
Lymphocytes Cytokines (IL-1, IL-2, IL-3, IL-6, Same as above for macrophages and monocytes.
TNF-α, GM-CSF, interferon-γ)
ELAM-1, endothelial-leukocyte adhesion molecule-1; ICAM-1, intercellular adhesion molecule-1.