Adrenocorticosteroids &Adrenocortical antagonists By M.D. , Ph.D. Shahid Beheshti University of Medical Science
Adrenocorticosteroids Introduction Classification Mechanism of Action Glucocorticoids (Adverse) Effects Clinical Application Special Issues Contraindications Glucocorticoid Antagonists Drug Pictures
Introduction Having important effects on intermediary metabolism and immune function (glucocorticoid). Cortisol Having principally salt-retaining activity (Mineralocorticoid). Aldosterone Having androgenic or estrogenic activity. Cortisol secretion follows a circadian rhythm Dehydroepiandrosterone sulfate (DHEAS) that peak in the early morning & after meals
Glucocorticoids (Adverse) Effects Permissive effects: The response of vascular and bronchial smooth muscle to catecholamines is diminished in the absence of cortisol. The lipolytic response of fat cells to catecholamines is attenuated in the absence of glucocorticoids. Metabolic effects Stimulate gluconeogenesis and glycogen synthesis in the fasting state. Gluconeogenesis, muscle catabolism and lipolysis contribute to an adequate glucose supply to the brain.
Glucocorticoids (Adverse) Effects cont,d Anti-inflammatory & immunosuppressive effects: Decrease in lymphocytes, monocytes, eosinophils & basophils. Inhibit the functions of macrophages. Reduce prostaglandin & leukotriene synthesis. Reduce expression of cyclooxygenase II. Cause vasoconstriction. Decrease capillary permeability. Inhibit complement effects. Reduce antibody production (large doses).
Glucocorticoids (Adverse) Effects cont,d Catabolic effects: Decreased muscle mass Weakness Thinning of the skin. Osteoporosis. Reduce growth in children.
Glucocorticoids (Adverse) Effects cont,d Other effects: Insomnia, euphoria, psychosis & depression. Increased intracranial pressure (pseudotumor cerebri). Peptic ulcer, by suppressing the local immune response against Helicobacter pylori. Increase in number of platelets & red blood cells.
Glucocorticoids (Adverse) Effects cont,d Other effects Cont,d: Antagonize the effect of vit. D on calcium absorption. Bacterial and mycotic infections, may be masked. Increased intraocular pressure (glaucoma). Severe proximal myopathy. Aseptic necrosis of the hip. Cataract.
Clinical Application of Glucocorticoids Adrenocortical insufficiency. Congenital Adrenal Hyperplasia. Adrenocortical hyperfunction. For diagnostic purposes. Almost any kind of inflammatory disease. Dexamethasone suppression test Stimulation of lung maturation in the fetus.
Dexamethasone Suppression Test Is used for the diagnosis of cushings syndrome. Dexamethasone, is given at 11 pm: Morning cortisol less than 3 mcg/dl => normal individual Greater than 5 mcg/dl => cushings syndrome The results are not reliable in the presence of depression, anxiety, concurrent illness, and other stressful conditions.
Dexamethasone Suppression Test Cont,d Large doses of dexamethasone helps to distinguish different types of Cushings syndrome High dose dexamethasone is given and the urine is assayed for cortisol or its metabolites (Liddles test). 50% suppression in hormone level => Cushings disease No suppression in hormone level: ACTH is low => cortisol-producing adrenal tumor ACTH is high => ectopic ACTH-producing tumor.
Adrenocortical insufficiency Chronic (addisons disease): Glucocorticoids that are long-acting and devoid of salt-retaining activity should NOT be administered to these patients. Acute: Treatment must be instituted immediately. Large amounts of parenteral hydrocortisone.
Congenital Adrenal Hyperplasia Reduction in cortisol and increase in ACTH (hyperplastic gland). The most common cause is 21β-hydroxylase deficiency. Dexamethasone administration to the mother protectes fetuses at risk from genital abnormalities. Negative feedback on ACTH
Congenital Adrenal Hyperplasia Cont,d Defect in 11β-hydroxylase. Hypertension with or without hypokalemic alkalosis. Defect in 17 α-hydroxylase. Hypogonadism Hypertension and hypokalemia. The affected newborn will be in acute adrenal crisis. Treatment consists of correction of electrolytes and intravenous hydrocortisone in stress doses.
Adrenocortical hyperfunction Cushings Syndrome: The most common cause is an ACTH-secreting pituitary adenoma (Cushings disease). May also be due to tumors or nodular hyperplasia of the adrenal gland or ectopic production of ACTH. Treatment is surgery followed by large doses of hydrocortisone. Aldosteronism: Is due to adrenal adenoma, hyperplastic gland or malignant tumor. Treatment (and diagnosis) is by spironolactone.
Special Issues In inflammation & allergy, use less frequent – higher doses. In less than 2 weeks treatment, adverse effects are unusual. Daily doses of 100 mg of hydrocortisone for longer than 2 weeks suppress adrenal gland. Chronic therapy with these drugs should be undertaken with great care. If possible, the drug should be given as a single morning dose.
Special Issues Cont,d When large doses are required for prolonged periods, try alternate-day administration after control is achieved. In prolonged treatment, at the time of severe stress the dose should be raised up to ten times for 72 hr. In prolonged therapy, obtain a chest x-rays and a tuberculin test. Glucocorticoid therapy can Therapy should not be decreased or stopped abruptly. reactivate dormant disease Patients treated with corticosteroids should be on high It takes 2-12 months for the HPA axis to function proteinacceptably, and cortisol levels diets. return to and potassium-enriched may not normal for another 6-9 months
Glucocorticoid Antagonists Metyrapone: Inhibits 11-hydroxylation, interfering with cortisol and corticosterone synthesis. It is the only adrenal-inhibiting medication that can be administered to pregnant women with Cushings syndrome. The adverse effects are salt - water retention and hirsutism. Ketoconazole: Is a potent inhibitor of adrenal and gonadal steroid synthesis. These effects are seen only at high doses. Has been used for the treatment of Cushings syndrome.
Glucocorticoid Antagonists Cont,d Mifepristone (RU 486) Has strong antiprogestin activity. High doses exert antiglucocorticoid activity by blocking the glucocorticoid receptor. Only for inoperable patients with ectopic ACTH secretion or adrenal carcinoma who have failed to respond to other therapies.
Glucocorticoid Antagonists Cont,d Aminoglutethimide: Blocks the conversion of cholesterol to pregnenolone and reduces the synthesis of all hormonal steroids. It is used with dexamethasone or hydrocortisone to reduce estrogen production in breast carcinoma. Spironolactone: Reverses manifestations of primary aldosteronism It is also an androgen antagonist so is used in treatment of hirsutism. This effect is seen in 2 months and maximizes in 6 months.