Adrenocorticosteroids & Adrenocortical Antagonists By S. Bohlooli, PhD School of Medicine, Ardabil University of Medical Sciences

ADRENOCORTICOSTEROIDS THE NATURALLY OCCURRING GLUCOCORTICOIDS SYNTHETIC CORTICOSTEROIDS

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

Adrenocortical hormone biosynthesis Figure 39-1. 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.)

Chemical structures of several glucocorticoids Figure 39-3. 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.

Mechanism of Action Figure 39-4. 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.

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.

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

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

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

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

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

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

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

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

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

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

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

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

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