Corticosteroids & Antagonists
GLUCOCORTICOIDS
Mechanism of Action
• Corticosteroids enter the cell and bind to
cytosolic receptors that transport the steroid into
the nucleus.
• The steroid-receptor complex alters gene
expression by binding to glucocorticoid response
elements (GREs) or mineralocorticoid-specific
elements
Organ and Tissue Effects
Metabolic effects
• Glucocorticoids stimulate gluconeogenesis.
• As a result, blood glucose rises, muscle protein is
catabolized, and insulin secretion is stimulated.
• Both lipolysis and lipogenesis are stimulated, with a net
increase of fat deposition in certain areas (eg, the face
and the shoulders and back).
Catabolic effects
• Glucocorticoids cause muscle protein catabolism.
• In addition, lymphoid and connective tissue, fat,
and skin undergo wasting under the influence of
high concentrations of these steroids.
• Catabolic effects on bone can lead to
osteoporosis.
• children, growth is inhibited
Immunosuppressive effect
• Inhibit Cell mediated immunologicalresponse
• Lymphotoxic
• Donot interfere with developent of normal
acquired immunity but delay rejection in
patients of organ transplant
These agents are actively
lymphotoxic and, as such, are
important in the treatment of
hematologic cancer
Anti-inflammatory effects
• Increase neutrophils
• Decrease eosinophil,basophil and lymphocyte
• Migrationof leuckocyte inhibited
• Inhibition of phospholipase A2
• Decrease mRNA for COX-2
• Decrease IL2 ,IL3 and PAF
Other Effects
• When given in large doses, these drugs may
cause profound behavioral changes.
• Large doses also stimulate gastric acid
secretion and decrease resistance to ulcer
formation
Short acting(half Intermediate Long acting(36hrs+)
life=less than 12 hrs) acting(t1/2=12-36hrs)
Cotisone Prednisone Dexamethasone
Hydrocortisone Prednisolone Betamethasone
methylprednisolone
Fludocortisone
triamcinolone
The cortisol molecule also has a small but The physiologic secretion of cortisol is
significant saltretaining (mineralocorticoid) regulated by adrenocorticotropin
effect . This is an important cause of (ACTH) and varies during the day
hypertension in patients with a (circadian rhythm); the peak occurs in
cortisolsecreting adrenal tumor or a the morning and the trough occurs
pituitary ACTH-secreting tumor (Cushing’s about midnigh
syndrome)
Special glucocorticoids have been developed for use in
asthma and other conditions in which good surface activity
on mucous membranes or skin is needed and systemic
effects are to be avoided.
Beclomethasone and budesonide readily penetrate the
airway mucosa but have very short half-lives after they enter
the blood, so that systemic effects and toxicity are greatly
reduced
Clinical Uses(Adrenal disorders)
• Addison’s disease
• acute adrenal insufficiency associated with
life-threatening shock, infection, or trauma
Glucocorticoids are also used in certain
types of congenital adrenal hyperplasia,
in which synthesis of abnormal forms of
corticosteroids are stimulated by ACTH.
In these conditions, administration of a
potent synthetic glucocorticoid
suppresses ACTH secretion sufficiently to
reduce the synthesis of the abnormal
steroids.
Nonadrenal disorders
• Asthma Corticosteroids are the therapy
• organ transplant rejection of choice for cases of 1,25-
dihydroxyvitamin D (calcitriol)
• collagen diseases mediated hypercalcemia.
• rheumatic disorders Steroids inhibit 1-α-hydroxylase
• hematopoietic cancers conversion of 25-hydroxyvitamin
D (calcidiol) into 1,25-
• neurologic disorders dihydroxyvitamin D (calcitriol)
• chemotherapy-induced vomiting therefore lessening intestinal
• hypercalcemia, calcium absorption
• mountain sickness
Toxicity
• Growth inhibition
• Diabetes
• Muscle wasting
• Osteoprosis
• Salt retention
• Reduce wound healing
• Psychosis
• Pitutary suppression
• Weight gain
• Peptic ulcer
MINERALOCORTICOIDS
uses
• Adrenal insufficiency (Addison’s disease)
Toxicity
• Salt and fluid retention
• congestive heart failure
• signs and symptoms of glucocorticoid excess
Glucocorticoid receptor
antagonist
Mifepristone
Uses
• Medical abortion
• very rarely Cushing’s syndrome
Toxicity
• Vaginal bleeding in females
• abdominal pain
• gastrointestinal upset
• Diarrhea
• headache
Mineralocorticoid receptor
antagonists
Spironolactone
• Pharmacologic antagonist of mineralocorticoid
receptor, weak antagonism of androgen
receptors
Uses
• Aldosteronism from any cause
• hypokalemia due to other diuretics
• postmyocardial infarction
• Hyperkalemia
• gynecomastia (spironolactone, not
eplerenone)
• additive interaction with other K-retaining
drugs
