1. Adrenocorticosteroids & Adrenocortical AntagonistsBy
S. Bohlooli, PhD
School of Medicine, Ardabil University of Medical Sciences

2. ADRENOCORTICOSTEROIDS
THE NATURALLY OCCURRING GLUCOCORTICOIDS
SYNTHETIC CORTICOSTEROIDS

3. THE NATURALLY OCCURRING GLUCOCORTICOIDS; CORTISOL (HYDROCORTISONE)
Pharmacodynamics
MECHANISM OF ACTION
PHYSIOLOGIC EFFECTS
METABOLIC EFFECTS
CATABOLIC AND ANTIANABOLIC EFFECTS
ANTI-INFLAMMATORY AND IMMUNOSUPPRESSIVE EFFECTS
OTHER EFFECTS

4. Adrenocortical hormone biosynthesis
Figure Outline of major pathways in adrenocortical hormone biosynthesis. The major secretory products are underlined. Pregnenolone is the major precursor of corticosterone and aldosterone, and 17-hydroxypregnenolone is the major precursor of cortisol. The enzymes and cofactors for the reactions progressing down each column are shown on the left and across columns at the top of the figure. When a particular enzyme is deficient, hormone production is blocked at the points indicated by the shaded bars. (Modified after Welikey et al; reproduced, with permission, from Ganong WF: Review of Medical Physiology, 17th ed. Originally published by Appleton & Lange. Copyright ã 1995 by The McGraw-Hill Companies, Inc.)

5. Chemical structures of several glucocorticoids
Figure Chemical structures of several glucocorticoids. The acetonide-substituted derivatives (eg, triamcinolone acetonide) have increased surface activity and are useful in dermatology. Dexamethasone is identical to betamethasone except for the configuration of the methyl group at C16: in betamethasone it is beta (projecting up from the plane of the rings); in dexamethasone it is alpha.

6. Mechanism of Action
Figure A model of the interaction of a steroid, S (eg, cortisol), and its receptor, R, and the subsequent events in a target cell. The steroid is present in the blood in bound form on the corticosteroid-binding globulin (CBG) but enters the cell as the free molecule. The intracellular receptor is bound to stabilizing proteins, including two molecules of heat shock protein 90 (Hsp90) and several others, denoted as "X" in the figure. This receptor complex is incapable of activating transcription. When the complex binds a molecule of cortisol, an unstable complex is created and the Hsp90 and associated molecules are released. The steroid-receptor complex is able to enter the nucleus, bind to the glucocorticoid response element (GRE) on the gene, and regulate transcription by RNA polymerase II and associated transcription factors. A variety of regulatory factors (not shown) may participate in facilitating (coactivators) or inhibiting (corepressors) the steroid response. The resulting mRNA is edited and exported to the cytoplasm for the production of protein that brings about the final hormone response.

7. The glucocorticoid receptor polypeptide
Figure 2-6. Mechanism of glucocorticoid action. The glucocorticoid receptor polypeptide is schematically depicted as a protein with three distinct domains. A heat-shock protein, hsp90, binds to the receptor in the absence of hormone and prevents folding into the active conformation of the receptor. Binding of a hormone ligand (steroid) causes dissociation of the hsp90 stabilizer and permits conversion to the active configuration.

8. Some commonly used natural and synthetic corticosteroids for general
Activity1
Agent
Anti-Inflammatory
Topical
Salt-Retaining
Equivalent Oral Dose (mg)
Forms Available
Short- to medium-acting glucocorticoids
Hydrocortisone (cortisol) 1 20
Oral, injectable, topical
Cortisone
0.8 25
Oral
Prednisone 4
0.3 5
Prednisolone
Oral, injectable
Methylprednisolone
Meprednisone2

9. Some commonly used natural and synthetic corticosteroids for general
Activity1
Agent
Anti-Inflammatory
Topical
Salt-Retaining
Equivalent Oral Dose (mg)
Forms Available
Intermediate-acting glucocorticoids
Triamcinolone 5 53 4
Oral, injectable, topical
Paramethasone2 10 2
Oral, injectable
Fluprednisolone2 15 7
1.5
Oral
Long-acting glucocorticoids
Betamethasone
25-40
0.6
Dexamethasone 30
0.75

10. Metabolic effect Gluconeogensis Muscle protein catablism Lipolysis
Lipogenesis
Increase in insulin release
Decrease in glucose uptake in muscle

11. Catabolic effect Muscle protein catabolism Wasting of Steoporesis
Lymphoid
connective tissue
Fat
Skin
Steoporesis
Growth inhibition in children

12. Immunosuppressive effects
Inhibit cell-mediated immunologic functions
Lymphotoxic
Important in the therapy of hematologic cancers

13. Anti-inflammatory effects
Dramatic effect of distribution and function of leukocyte
Increase neutrophils
Decrease lymphoctes, eosinophils, basophils, monocytes
Inhibition of leukocyte migration
Inhibition of PLA2
Decreased production of COX2
Decrease in IL2, IL3, and PAF

14. Other effects Need for normal excretion of water load Effect of CNS:
Low level: depression
High level: behavioral changes
Large doses: stimulation of gastric acid secretion and peptic ulcer

15. Clinical Pharmacology
DIAGNOSIS AND TREATMENT OF DISTURBED ADRENAL FUNCTION
Adrenocortical insufficiency
Chronic (Addison's disease)
Acute
Adrenocortical hypo- and hyperfunction
Congenital adrenal hyperplasia
Cushing's syndrome
Aldosteronism
Use of glucocorticoids for diagnostic purposes
CORTICOSTEROIDS AND STIMULATION OF LUNG MATURATION IN THE FETUS
CORTICOSTEROIDS AND NONADRENAL DISORDERS

16. CORTICOSTEROIDS AND NONADRENAL DISORDERS
Many disorders respond to coticosteroids
Inflammatory or immunologic diseases:
Asthma, organ transplant rejection, collagen disease
Hematopoietic cancers
Neurolgic disorders
Chemotherapy induced vomiting
Hypercalcemia
Mountain sickness
Hasten maturation of the fetal lungs

17. Toxicity METABOLIC EFFECTS OTHER COMPLICATIONS ADRENAL SUPPRESSION
Growth inhibition, diabetes, muscle wasting, salt retention, psychosis,
OTHER COMPLICATIONS
Peptic ulcer,
masking of bacterial and fungal disease clinical finding
acute psychosis ,growth retardation
ADRENAL SUPPRESSION

18. Contraindications & Cautions
SPECIAL PRECAUTIONS
monitored carefully for the development of :
hyperglycemia, glycosuria, sodium retention with edema
hypertension, hypokalemia, peptic ulcer, osteoporosis, and hidden infections

19. CONTRAINDICATIONS Great caution in patients with: Peptic ulcer
Heart disease or hypertension with heart failure
Psychoses
Diabetes
Osteoporosis
Glaucoma

20. ANTAGONISTS OF ADRENOCORTICAL AGENTS
SYNTHESIS INHIBITORS
Metyrapone
Aminoglutethimide
Ketoconazole
Trilostane
GLUCOCORTICOID ANTAGONISTS
Mifepristone (RU 486)