ADRENOCORTICAL STEROIDS ADRENAL GLANDS Adrenal medulla catecholamines Adrenal cortex: o Zona glomerulosa: mineralocorticoids o Zona fasciculata: glucocorticoids

ids o Zona reticularis: E, P, androgens Adrenocorticosteroids Glucocorticoids: intermediary metabolism o CORTISOL Mineralocorticoids: regulation of salt retention o ALDOSTERONE Corticosteroids with: o Androgenic activity: DHEA major androgen endogenous precursor of E in women after menopause o Estrogenic activity Estrone - major endogenous estrogen source after menopause Synthesis: o Cholesterol precursor Converted to pregnenolone : rate-limiting step Precursor of corticosteroids and androgens 11-hydroxylation: required for mineralocorticoid and glucocorticoid acitvity Endproducts: androstenedione, aldosterone, cortisol GLUCOCORTICOIDS Secreted into bloodstream Bound to CBG (transcortin) 80&, albumin (10%) o Increased binding: pregnancy, increased transcorting levels, TH o Decreased: androgens T1/2: 90m o Increased: Stress, hypothyroidism , liver disease, large dosage of hydrocortisone administration Metabolized in liver: o 11B-HSD2: cortisone o 11b-HSD1: active metabolites o Glucuronidation and sulfation Excreted in urine

Anti-inflammatory/Immunosuppressive Effects: o Inhibit early and late manifestations of inflammation reduced leukocyte infiltration neutrophils levels are increased, decrease movement of lymphocytes (T and B cells, monocytes, eosinophils, basophils) from vasculature to lymphoid tissue) Anti-inflammatory o Reduction of prostaglandin and leukotriene synthesis (resulting from phospholipase A2 activation) o Reduction of cyclooxygenase in inflammatory cells (reducing prostaglandin synthesis) o inhibit COX-II gene expression. o decrease capillary permeability by: reducing kinin activity reducing bacterial endotoxin activity reducing basophils histamine release

Unwanted Effects Large doses or prolonged administration: o Suppressed response to infection or injury o Sudden withdrawal: acute adrenal insufficiency o Water and electrolyte imbalance o Cushings o Osteoporosis o Hyperglycemia diabetes o Growth retardation in children o Euphoria, depression, psychotic symptoms o Glaucoma, inc ICP, fever, hypercoagulability, abnormal menses, oral thrush, candidiasis COMPLICATIONS OF GLUCOCORTICOID THERAPY Hematologic/immunologic leukocytosis lymphoppenia, eosinopenia altered inflammatory response GI peptic ulcer fatty liver pancreatitis, N, V Metabolic hyperglycemia, hyperlipidemia protein wasting obesity Musculoskeletal myopahty growth failure Osteopenia Eye cataract, post succapsular inc intraocular pressure General cushingoid features, truncal obesity withdrawal syndrome CNS insomnia, depression nervousness psychosis Fluid and Electrolyte Na retention, K loss (-) Ca balance HPN Endocrine suppression of HPA antagonism with insulin, PTH, TH Skin thinning of skin, purple striae ecchymosis, acne, hirsutism

Pharmacodynamics MA: o Bind to nuclear receptors: member of superfamily incl: Mineralocorticoids, sex hormones, TH, vit D, retinoic acid o Bind to receptors in cytoplasm, translocate to the nucleus and bind to positive or negative glucocorticoid response elements to cause changes in transcription Physiologic Effects as homeostatic hormone permits the organism to withstand environmental changes In absence of adrenal cortex, survival is only possible if food, water, and salt are always available and there are no large fluctuations in temperature Action: make glucose available to brain and other tissues at all times Major metabolic effects: CHO and CHON metabolism o Decrease uptake and use of glucose o Increase gluconeogenesis o Increase glycogen storage o Decrease CHON synthesis, inc CHON breakdown Muscle wasting Hepatic effects: o Stimulate glycogen synthase o Increase glucose production from protein stimulating insulin release (-) Ca balance: o Inhibit GI absorption o Increase renal excretion Mineralocorticoid activity: o Na retention and K loss Adipocytes: o Lipolysis: catecholamine-induced: o fat redistribution o effects most prominent in the fasting state Catabolic Effects: o lymphoid tissue, connective tissue, muscle, fat , skin o High (supraphysiologic) glucocorticoid levels: decreased muscle mass, weakness o reduced growth in children (not prevented by growth hormone) o osteoporosis in Cushing's syndrome

SYNTHETIC CORTICOSTEROIDS Source: o Synthesized from cholic acid (from cattle sources) or o Synthesized from steroid sapogenins (diosgenin) -- plants Short- medium- acting o Hydrocortisone o Cortisone o Prednisone o Prednisolone o Methylprednisolone o Meprednisone Intermediate-acting o Triamcinolone o Fluprednisone Long-acting o Betamethasone o dexamethasone Mineralocorticoids o Fludrocortisone o Desoxycorticosterone

Pharmacokinetics Complete oral absorption Routes: IM, IV, dermal, inhalation molecular alterations give rise to differences in:

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o affinity for mineralocorticoid or glucocorticoid receptors o extent of protein binding o stability o spectrum of metabolic products prednisone converted to active product - prednisolone

congenital adrenal hyperplasia

Clinical Use Replacement therapy o Adrenal insufficiency: Glucocorticoid + mineralocorticoid Cortisol Inflammatory states o Rheumatoid arthritis o Asthma o Collagen diseases: SLE o Ulerative colitis, Crohns o Nephrotic syndrome o Granulomatous dse: sarcoidosis HIV-related disorders: P carinii pneumonia Demyelinating peripheral neuropathy Tb meningitis leukemia Shock Lung maturation in the fetus o Betamethasone injected to mother if delivery is anticipated before 34 weeks DX: Cushing's Syndrome: o Dexamethasone suppression test Contraindications: o Peptic ulcer, heart disease, HPN with congestive heart failure, infetions, psychosis, glaucoma, herpes simplex, DM Precautions o Hyperglycemia, glycosuria, Na retention with edema and HPN, hypokalemia, osteoporosis MINERALOCORTICOIDS Mineralocorticoids o Aldosterone most important o Desoxycorticosterone o Fludrocortisone most commonly prescribed salt-retaining hormone

FLUDROCORTISONE Synthetic corticosteroid most widely used mineralocorticoid With glucocorticoid and mineralocorticoid activity used in management of adrenocortical insufficiency SYNTHESIS INHIBITORS AND GLUCOCORTICOID INHIBITORS Metyrapone Aminoglutethimide Ketoconazole Mifepristone Mitotane Trilostane

METYRAPONE selective inhibitor of steroid synthesis o inhibit 11B-hydroxylation which interferes with cortisol and corticosterone synthesis o Inhibit aldosterone synthesis Use: o DX: Differential dx: adrenal insufficency: test the feedback HPA mechanism o Cushings: Safest in pregnant pts Major adverse effects: o salt and water retention, hirsuitism o GI disturbance and DZ AMINOGLUTETHIMIDE Aromatase inhibitor: blocks cholesterol to pregnenolone conversion o (-) adrenal steroids o Inhibits conversion of androgens to estrogens Use: o with ketoconazole or metyrapone: reduce steroid secretion in patients with Cushing's syndrome (due to adrenocortical cancer -not responding to mitotane) Enhance clearance of dexamethasone KETOCONAZOLE Antifungal - imidazole derivative potent, nonselective adrenal and gonadal steroid synthesis inhibitor o Block testicular and andrenal androgen synthesis use for treating patients with Cushing's disease AE: gynecomastia, hepatotoxicity MIFEPRISTONE Synthetic partial agonist steroid Progesterone R antagonist Glucocorticoid R antagonist treatment of Cushing's syndrome o Ectopic ACTH production, adrenal Ca MITOTANE Inhibit biosynthetic pathways in adrenal cortex o Alter steroid peripheral metabolism; alter cortisone metabolism: hypocortisolism Use: tx of adrenal ca Drug withdrawn in US but available on a compassionate basis TRILOSTANE Interfere with synthesis of adrenal and gonadal hormones 3-17 hydroxysteroid dehydrogenase inhibitor Similar to amoniglutethimide MINERALOCORTICOID ANTAGONIST Spironolactone Eplerenone Drospirenone

ALDOSTERONE Regulation: o Increase: K+ in ECF and angiotensin II ACTH, angiotensin No significant feedback control on ACTH secretion o Decrease: Atrial natriuretic hormoone High Na K deficiency Function: o Act on distal tubule: o Increased resorption of Na and water o Increased renal excretion of K o also sweat, salivary glands, GI mucosa, across cells membranes o Conserve Na and water Mechanism of Action: o bind to cytoplasmic receptor (e.g.renal collecting tubule principal cells) o subsequent steps similar to those described for glucocorticoids (receptors similar to cortisol) Pharmacokinetics In individuals with moderate salt intake secreted at 100-200 mg/d T1/2 : 15-20 min Not firmly bound to plasma proteins Metabolism similar to steroids: o Conjugated as tetrahydroaldosterone Excreted in urine Excessive aldosterone (secondary to tumor/overdosage): o hypernatremia o hypokalemia o metabolic alkalosis o hypertension o increased plasma volume DESOXYCORTICOSTERONE precursor to aldosterone secretion controlled by ACTH o Not increased by low Na diet o enhanced in abnormal conditions e.g.: adrenal carcinoma

SPIRONOLACTONE pharmacologic antagonist o Competitive aldosterone antagonist o Use: Tx of primary hyperaldosteronism (Conns) Secondary hyperaldosteronism hypoK Antiadrogen: hirsutism o Eplerenone: no effect on androgen receptors

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