Page 722 - Basic _ Clinical Pharmacology ( PDFDrive )

708 SECTION VII Endocrine Drugs

glucose-6-phosphatase, and glycogen synthase and the release of In addition to their effects on leukocyte function, gluco-
amino acids in the course of muscle catabolism. corticoids influence the inflammatory response by inhibiting
Glucocorticoids increase serum glucose levels and thus stimu- phospholipase A and thus reduce the synthesis of arachidonic
2
late insulin release but inhibit the uptake of glucose by muscle acid, the precursor of prostaglandins and leukotrienes, and of
cells, while they stimulate hormone-sensitive lipase and thus platelet-activating factor. Finally, glucocorticoids reduce expres-
lipolysis. The increased insulin secretion stimulates lipogenesis sion of cyclooxygenase 2, the inducible form of this enzyme, in
and to a lesser degree inhibits lipolysis, leading to a net increase in inflammatory cells, thus reducing the amount of enzyme available
fat deposition combined with increased release of fatty acids and to produce prostaglandins (see Chapters 18 and 36).
glycerol into the circulation. Glucocorticoids cause vasoconstriction when applied directly
The net results of these actions are most apparent in the fasting to the skin, possibly by suppressing mast cell degranulation. They
state, when the supply of glucose from gluconeogenesis, the release also decrease capillary permeability by reducing the amount of
of amino acids from muscle catabolism, the inhibition of periph- histamine released by basophils and mast cells.
eral glucose uptake, and the stimulation of lipolysis all contribute The anti-inflammatory and immunosuppressive effects of
to maintenance of an adequate glucose supply to the brain. glucocorticoids are largely due to the actions described above. In
humans, complement activation is unaltered, but its effects are
D. Catabolic and Antianabolic Effects inhibited. Antibody production can be reduced by large doses of
Although glucocorticoids stimulate RNA and protein synthesis in the steroids, although it is unaffected by moderate doses (eg, 20 mg/d
liver, they have catabolic and antianabolic effects in lymphoid and of prednisone).
connective tissue, muscle, peripheral fat, and skin. Supraphysiologic The anti-inflammatory and immunosuppressive effects of these
amounts of glucocorticoids lead to decreased muscle mass and weak- agents are widely useful therapeutically but are also responsible for
ness and thinning of the skin. Catabolic and antianabolic effects on some of their most serious adverse effects (see text that follows).
bone are the cause of osteoporosis in Cushing’s syndrome and impose
a major limitation in the long-term therapeutic use of glucocorticoids. F. Other Effects
In children, glucocorticoids reduce growth. This effect may be par- Glucocorticoids have important effects on the nervous system.
tially prevented by administration of growth hormone in high doses, Adrenal insufficiency causes marked slowing of the alpha rhythm
but this use of growth hormone is not recommended. of the electroencephalogram and is associated with depression.
Increased amounts of glucocorticoids often produce behavioral
E. Anti-Inflammatory and Immunosuppressive Effects disturbances in humans: initially insomnia and euphoria and sub-
Glucocorticoids dramatically reduce the manifestations of inflam- sequently depression. Large doses of glucocorticoids may increase
mation. This is due to their profound effects on the concentration, intracranial pressure (pseudotumor cerebri).
distribution, and function of peripheral leukocytes and to their Glucocorticoids given chronically suppress the pituitary release
suppressive effects on inflammatory cytokines and chemokines and of ACTH, growth hormone, thyroid-stimulating hormone, and
on other mediators of inflammation. Inflammation, regardless of luteinizing hormone.
its cause, is characterized by the extravasation and infiltration of Large doses of glucocorticoids have been associated with the devel-
leukocytes into the affected tissue. These events are mediated by a opment of peptic ulcer, possibly by suppressing the local immune
complex series of interactions of white cell adhesion molecules with response against Helicobacter pylori. They also promote fat redistribu-
those on endothelial cells and are inhibited by glucocorticoids. After tion in the body, with increase of visceral, facial, nuchal, and supracla-
a single dose of a short-acting glucocorticoid, the concentration vicular fat, and they appear to antagonize the effect of vitamin D on
of neutrophils in the circulation increases while the lymphocytes calcium absorption. The glucocorticoids also have important effects on
(T and B cells), monocytes, eosinophils, and basophils decrease. the hematopoietic system. In addition to their effects on leukocytes,
The changes are maximal at 6 hours and are dissipated in 24 hours. they increase the number of platelets and red blood cells.
The increase in neutrophils is due both to increased influx into Cortisol deficiency results in impaired renal function (particu-
the blood from the bone marrow and to decreased migration larly glomerular filtration), augmented vasopressin secretion, and
from the blood vessels, leading to a reduction in the number diminished ability to excrete a water load.
of cells at the site of inflammation. The reduction in circulating Glucocorticoids have important effects on the development
lymphocytes, monocytes, eosinophils, and basophils is primarily the of the fetal lungs. Indeed, the structural and functional changes
result of their movement from the vascular bed to lymphoid tissue. in the lungs near term, including the production of pulmonary
Glucocorticoids also inhibit the functions of tissue macro- surface-active material required for air breathing (surfactant), are
phages and other antigen-presenting cells. The ability of these stimulated by glucocorticoids.
cells to respond to antigens and mitogens is reduced. The effect Recently, glucocorticoids were found to have direct effects
on macrophages is particularly marked and limits their ability on the epigenetic regulation of specific target genes by altering
to phagocytose and kill microorganisms and to produce tumor the activities of DNA methyltransferases and other enzymes par-
necrosis factor α, interleukin 1, metalloproteinases, and plasmino- ticipating in epigenesis. This is of particular importance in the
gen activator. Both macrophages and lymphocytes produce less prenatal treatment of pregnant mothers or treatment of young
interleukin 12 and interferon-γ, important inducers of Th1 cell infants and children, when the effects of glucocorticoids may be
activity, and cellular immunity. long-term or even permanent. These effects may predispose these