Adrenocorticosteroids & adrenocortical antagonists

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Adrenocorticosteroids & adrenocortical antagonists

  1. 1. Adrenocorticosteroids &Adrenocortical antagonists By M.D. , Ph.D. Shahid Beheshti University of Medical Science
  2. 2. Adrenocorticosteroids Introduction Classification Mechanism of Action Glucocorticoids (Adverse) Effects Clinical Application Special Issues Contraindications Glucocorticoid Antagonists Drug Pictures
  3. 3. 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
  4. 4. Classification Short- to medium-acting glucocorticoids Intermediate-acting glucocorticoids Hydrocortisone (cortisol) Cortisone Triamcinolone Prednisone Long-acting glucocorticoids Prednisolone Methylprednisolone MineralocorticoidsBetamethasone Dexamethasone Fludrocortisone
  5. 5. Some commonly used natural and synthetic corticosteroids for general use. Activity Anti- Salt- Oral Dose Agent Topical Inflammatory Retaining (mg)Short- to medium-acting glucocorticoids Hydrocortisone (cortisol) 1 1 1 20 Cortisone 0.8 0 0.8 25 Prednisone 4 0 0.3 5 Prednisolone 5 4 0.3 5 Methylprednisolone 5 5 0 4 Meprednisone2 5 0 4Intermediate-acting glucocorticoids Triamcinolone 5 53 0 4 Paramethasone2 10 0 2 Fluprednisolone2 15 7 0 1.5Long-acting glucocorticoids Betamethasone 25-40 10 0 0.6 Dexamethasone 30 10 0 0.75Mineralocorticoids Fludrocortisone 10 0 250 2
  6. 6. 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.
  7. 7. 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).
  8. 8. Glucocorticoids (Adverse) Effects cont,d Catabolic effects:  Decreased muscle mass  Weakness  Thinning of the skin.  Osteoporosis.  Reduce growth in children.
  9. 9. 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.
  10. 10. 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.
  11. 11. 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.
  12. 12. 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.
  13. 13. 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.
  14. 14. 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.
  15. 15. 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
  16. 16. 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.
  17. 17. 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.
  18. 18. 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.
  19. 19. 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
  20. 20. Contraindications Peptic ulcer  Psychoses Heart disease  Diabetes Hypertension  Osteoporosis Varicella  Glaucoma Tuberculosis
  21. 21. 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.
  22. 22. 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.
  23. 23. 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.
  24. 24. Estradiol gel
  25. 25. Hydrocortisone
  26. 26. tetracosactide
  27. 27. triamcinolone oral paste
  28. 28. Summary In English
  29. 29. Thank you Any question?

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