Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

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Glucocorticosteroids and antihistamines
Michael J Day
GLUCOCORTICOSTEROIDS
Relevant pathophysiology
Endogenous glucocorticosteroids are derived from the
adrenal cortex and have pleotropic metabolic effects on
numerous cells and tissues throughout the body. The
pharmacological correlates of the endogenous glucocorticoids
are among the most commonly used drugs in
companion animal medicine. These agents are used
chiefly for their anti-inflammatory and immunosuppressive
effects; however, these properties are not selective
and the corticosteroids will also affect other body
systems, potentially giving rise to unwanted side effects.
Therefore the most important consideration in administering
glucocorticoid therapy is to achieve a balance
between control of clinical disease and the potential
induction of side effects.
The glucocorticoid hormones pass through the membrane
of cells within the target tissue, where they bind
to intracytoplasmic steroid receptors. The complex of
steroid and receptor then passes to the nucleus and
associates with DNA to alter gene transcription and
ultimately the production of proteins that control a
wide range of cellular processes (e.g. structure, enzyme
synthesis and activity, membrane permeability).
Metabolic effects
The major metabolic effects of glucocorticoids are gluconeogenesis,
protein catabolism and lipolysis. In addition
to enhancing gluconeogenesis in extrahepatic tissues
and increasing hepatic storage of glycogen, the glucocorticoids
reduce the uptake and utilization of glucose
by tissues and may decrease expression of the insulin
receptor by these target cells. The ensuing hyperglycemia
leads to increased release of insulin from pancreatic
β-cells.
Glucocorticoids cause reduced tissue protein synthesis
and increased protein catabolism, resulting in
increased levels of protein within the liver and plasma,
and associated muscle atrophy. The increased lipolysis
mediated by glucocorticoids results in mobilization of
fatty acids and redistribution of fat, particularly to the
liver.
Other metabolic effects include:
● the antagonism of release or effect of antidiuretic
hormone
● reduced intestinal absorption
● enhanced secretion of gastric acid
● reduced production and altered nature of gastric
mucus
● cutaneous atrophy
● increased tissue mobilization of calcium that may
lead to osteoporosis and soft tissue mineralization
● inhibition of chondrocyte growth.
Increased levels of glucocorticoids lead to reduced production
of hypothalamic corticotropin-releasing hormone
(CRH) and pituitary adrenocorticotropic hormone
(ACTH) via the ‘negative feedback loop’ of the hypothalamic-pituitary
axis (HPA), and may also influence thyroid
hormone levels via depression of TSH production.
The production of other pituitary hormones (prolactin,
luteinizing hormone, follicle-stimulating hormone)
is also suppressed by glucocorticoids. Glucocorticoids
may also have a range of mineralocorticoid effects,
including mediating the retention of Na + , Cl − and water,
and increasing the excretion of K + and H + by distal
tubules.
Anti-inflammatory effects
The anti-inflammatory effects of glucocorticoids are
numerous, and endogenous production is one means
of downregulating the inflammatory response when
no longer required, in order to prevent unwanted
(‘bystander’) damage to normal tissue.
In this context, glucocorticoids are antagonistic to:
● capillary blood flow and vasodilation (and
therefore edema formation, and loss of protein and
leukocytes from the vasculature into inflamed tissue
and subsequent migration of these cells)
● vasoproliferation
● platelet aggregation
● fibrin deposition
● fibroblast proliferation and formation of collagen.
Glucocorticoids suppress the inflammatory function of
leukocytes (specifically granulocytes, mast cells and
monocyte-macrophages) by stabilizing the membranes
of these cells. This prevents release of inflammatory
mediators such as histamine and arachidonic acid
metabolites of both the cyclo-oxygenase and lipoxygenase
pathways. They also inhibit particular metabolic
pathways, e.g. production of proinflammatory cytokines
such as IL-1, IL-6 and TNF-α.
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