Adrenocorticosteroids and Adrenocortical Antagonists Ma. Victoria M. Villarica, M.D. Fatima College of Medicine Adrenal Gland • Adrenal cortex – mineralocorticoids, glucocorticoids, adrenal androgens (androstenedione and dehydroepiadrosterone) • Adrenal medulla - catecholamines Adrenal Cortex • Outer zone (zona glomerulosa) – secretes mineralocorticoids - receptors for angiotensin II and express aldosterone synthase; do not atrophy • Inner zone (zona fasciculata and reticularis) – secrete glucocorticoids and adrenal androgens - expresses 17α-hydroxylase and 11βhydroxylase; results in atrophy ACTH • • • • a peptide of 39 amino acids amino acids 15 – 18: high affinity binding amino acids 6 – 10: receptor activation synthesized from pro-opiomelanocortin (POMC) ACTH • Stimulates the synthesis and release of adrenocortical hormones • Human ACTH – G-protein coupled receptor family → activates adenyl cyclase → ↑ intracellular cyclic AMP (2nd messenger for most steroidogenesis) Regulation of ACTH secretion • Hypothalamic – Pituitary – Adrenal axis (HPA axis) - 3 levels of regulation: 1. diurnal rhythm in basal steroidogenesis 2. negative feedback regulation 3. marked increases in steroidogenesis in response to stress Steroid hormone production • rate limiting step – conversion of cholesterol to pregnanolone • sources of cholesterol: circulating cholesterol (LDL), cholesterol esterase, de novo biosynthesis Adrenal Cortex • Produce and releases natural adrenocortical hormones • Uses: a. diagnosis and treatment of disorders of adrenal function b. treatment of inflammatory and immunologic disorders Adrenocorticosteroids Classification: A. Mineralocorticoids B. Glucocorticoids C. Gonadal Androgens A. Glucocorticoids Naturally-occurring: Cortisol Kinetics: 10-20 mg daily; circadian rhythm; bound to CBG (90%), albumin (5%); t ½ =60-90 mins.; liver; 1/3 excreted as dihydroxyketone metabolites B. Mineralocorticoids 1. Aldosterone – zona glomerulosa - promotes reabsorption of Na+ from the distal convoluted tubules and proximal collecting tubules; loosely coupled with K+ and H+ ions - secreted at a rate of 100-200ug/d; t ½ 15-20mins; excreted in the urine as tetrahydroaldosterone and 3-oxo-glucoronide 2. Deoxycortisone (DOC) – serves as precursor of aldosterone 3. Fludrocortisone – most widely used; both mineralocorticoid and glucocorticoid activity C. Adrenal Androgens - dehydroepiandrosterone (DHEA) and androstenedione - they do not stimulate or support major androgen dependent pubertal changes in humans) - used in SLE and women with adrenal insufficiency • Dynamics: MOA: bind to cytosol receptors (steroid receptor complex) alters gene expression by binding to glucocorticoid-response element (GREs) Physiologic effects Carbohydrate and protein metabolism: protect glucose-dependent tissues from starvation ( gluconeogenesis, glycogen synthesis) periphery: ↓glucose utilization, ↑protein breakdown (amino acids), activate lipolysis (glycerol) catabolic effects: decrease muscle mass, atrophy of lymphoid tissue, negative nitrogen balance, thinning of the skin Physiologic effects (cont.): • Lipid metabolism: redistribution of body fat (buffalo hump, moon facies, supraclavicular area with loss of fat in the extremities) induce lipolysis in adipocytes ( FFA) • Electrolyte and water balance: enhances the reabsorption of Na (aldosterone) renal excretion of free water and interferes with Ca uptake, while there is ↑Ca excretion by the kidneys (glucocorticoids) Physiologic effects (cont.) • Cardiovascular system: - mineralocorticoid-induced changes – hpn - enhance vascular reactivity to other vasoactive substances • Skeletal muscle: normal function (steroid myopathy) • CNS: neurosteroids (regulate neuronal excitability) Physiologic effects: • Formed elements of blood: minor effects on hgb and erythrocyte production; affect circulating WBC (Addison’s: lymphocytosis, ↑ mass of lymphoid tissue) • Anti-inflammatory and Immunosuppressive action • alter immune response of lymphocytes - ↓release of vasoactive and chemoattractive factors, - diminished secretion of lipolytic and proteolytic enzymes - decreased extravasation of leukocytes to injury - decreased fibrosis - effect on cytokine production Other effects: ↑amounts – insomnia, euphoria, depression, pseudomotor cerebri ↓amounts – psychiatric depression large doses – peptic ulcer, promote fat distribution; vit D antagonist on Ca absorption; ↑ # of platelets and RBCs absence – impaired renal function fetal lung effects Synthetic Steroids Kinetics: source – cholic acid (cattle) or steroid sapogenins (diosgenin, hecopenin); absorption: oral, IV, IM, sites of local administration prolonged effects: occlusive dressing, large areas – may cause suppression of HPA axis Kinetics (cont.) • Transport: 90% bound to CBG (transcortin – high affinity but low total binding capacity) and albumin (low affinity but high binding capacity) 10% unbound • Metabolism – liver • Excretion - kidneys Therapeutic Uses: A. Replacement Therapy 1. Adrenal Insufficiency a. Acute adrenal insufficiency ssx: GIT symptoms, dhn, hypoNa, hyperK, weakness, lethargy, hypotension cause: disorder of the adrenal abrupt withdrawal of glucocorticoids at high doses or prolonged use mgt: IV : D5 0.3%NaCl solution Monitor for fluid overload Hydrocortisone (cortisol) 100mg bolus, ffed by 100mg every 8 hrs. ; once stable, may give 25mg IM hydrocortisone every 68hrs.; thereafter, same mgt with chronic adrenal insufficiency 1. Adrenal Insufficiency (cont.) b. Chronic Adrenal Insufficiency (Addison’s disease) ssx:hyperpigmentation, wt. loss, inability to maintain fasting blood sugar, weakness, fatigue, hypotension cause: primary adrenal insufficiency, tuberculosis mgt: Hydrocortisone 20-30mg/day BID Fludrocortisone acetate 0.05 – 0.2mg/day (valuable indicator of adequate replacement: disappearance of hyperpigmentation and resolution of electrolyte abnormalities) -monitor plasma ACTH levels or measure urinary free cortisol; dosage adjustments for stress Therapeutic Uses (cont.) 2. Adrenocortical hypo- and hyperfunctioning a. Congenital Adrenal Hyperplasia ssx: after puberty with infertility, hirsutism, amenorrhea and acne; female pseudohermaphroditism; accelerated linear growth but height at maturity is reduced; salt wasters – CV collapse (volume depletion) cause: Genetic disorder; activity of enzymes required for the biosynthesis of corticosteroid is deficient (21 β hydroxylase) mgt: 1st seen as acute adrenal crisis oral hydrocortisone 0.6mg/kg/day BID or TID fludrocortisone acetate 0.05-0.2mg/day treatment in-utero: mothers at risk – glucocorticoid therapy is initiated before 10 weeks gestation ffed by genotyping and sex determination b. Cushing’s syndrome cause: pituitary adenoma, tumors of the adrenal gland ssx: round, phletoric face, truncal obesity, muscle wasting, thinning, purple striae and easy bruising of the skin, poor wound healing, osteoporosis mgt: surgery hydrocortisone 300 mg IV on the day of the surgery, then maintenance oral dose B. Stimulation of fetal lung maturation – betamethasone 12mg ffed by 12mg 18-24 hrs. later C.Nonendocrine Diseases 1. Rheumatic disorders – suppress the disease and minimize resultant tissue damage mgt: prednisone 10 mg/kg/day (taper thereafter by decreasing 1mg/kg/day every 2-3 wks) intraarticular injection: triamcinolone acetonide osteoarthritis : intraarticular injections with interval of 2-3 mos. to minimize complications C. Non-Endocrine Diseases (cont.) 2. Renal Disorders – nephrotic syndrome mgt: prednisone: 1-2 mg/kg x 6 wks, ffed. by gradual tapering over 6-8 wks or alternate-day therapy (diminished proteinuria in 85% pts in 2-3 wks and 95% pts will have remission in 3 mos. - membranous glomerulonephritis mgt: alternate-day prednisone 8-10 wks ffed by 1-2 month period of tapering C. Non-Endocrine Diseases (cont.) 3. Allergic Disease – epinephrine 0.5ml of a 1:1000 solution IM or SQ, repeated every 15 mins up to 3 doses is needed (anaphylaxis) - onset of action of glucocorticoid is delayed C. Non-Endocrine Diseases (cont.) 4. Bronchial Asthma – role of inflammation in the immunopathogenesis - onset of action is delayed for 6 – 12 hrs. mgt: IV methylprednisolone 60-120mg initially ffed. by oral prednisone 40-60mg daily as the attack resolves inhaled steroids – reduces bronchial hyperreactivity with les suppression of adrenal function (dysphonia or oropharyngeal candidiasis) C. Non-Endocrine Diseases (cont.) 5. Infectious Disease – P. carinii pneumonia – increases oxygenation and decreases the incidence of respiratory failure and mortality H. influenzae type b meningitis – decrease the long-term neurological impairment 6. Ocular disease – 0.1% dexamethasone - C/I: herpes simplex keratitis (clouding of the cornea) , glaucoma C. Non-Endocrine Diseases (cont.) 7. Skin diseases – inflammatory dermatoses 8. GIT diseases – inflammatory bowel disease 9. Hepatic diseases – prednisolone – 80% histologic remission in pts. with chronic, active hepatitis 10. Malignancies – ALL, lymphomas 11. Cerebral edema 12. Miscellaneous dis – Sarcoidosis (induce remission), thrombocytopenia (decrease bleeding tendency), organ transplantation, spinal cod injury D. Diagnostic Application • Dexamethasone suppression test – differentiates Cushing’s syndrome vs. stress and if Cushing’s syndrome, whether it’s an adrenal or a pituitary tumor • Baseline cortisol levels are determined • Dexamethasone 0.5mg every 6hrs x 48 hrs. • Dexamethasone 2 mg every 6 hrs. x 48 hrs. Toxicity: • Withdrawal of therapy: ssx: fever, myalgias, arthralgias, malaise, pseudomotor cerebri ( ↑ICP, papilledema) • Continued use at supraphysiologic doses ssx: fluid and electrolyte abnormalities, hypertension, hyperglycemia, increased susceptibility to infection, myopathy, behavioral disturbances, cataracts, growth arrest and fat redistribution, acne, hirsutism, striae, ecchymoses, osteonecrosis, peptic ulcer • Adrenal suppression - >2 wks. Contraindications: peptic ulcer, heart disease or Hpn with CHF, infections, psychoses, diabetes, osteoporosis, glaucoma or herpes simplex infection Supplemental measures: • • • • • • Diet rich in potassium and low in sodium Caloric mgt to prevent obesity High protein intake Appropriate antacid therapy Calcium and vit D, physical therapy Alendronate biphosphonate Antagonists of Adrenocortical Agents A. Synthetic inhibitors and glucocorticoid antagonists 1. Metyrapone – inhibits 11-hydroxylation, interfering with cortisol and corticosterone synthesis (0.25g BID to 1g QID) - used in tests of adrenal function (300-500mg q 4hrs. X 6doses, ffed by urine collection - treat hypercorticotism: 4 g/day 2. Aminoglutethimide – blocks the conversion of cholesterol to pregnanelolone and causes a reduction in the synthesis of all hormonally active steroids; breast Ca and Cushing’s syndrome due to adrenocortical Ca: 250 mg every 6hrs. - enhances metabolism of dexamethasone 3. Ketoconazole – an antifungal imidazole derivative; potent, non-selective inhibitor of adrenal and gonadal steroid synthesis; tx of Cushing’s syndrome (2001200mg/d) 4. Mifepristone (RU 486) – 11β-aminophenyl-substituted 19-norsteroid; has strong anti-progestin activity; blocks glucocorticoid receptor 5. Mitotane – adrenal Ca; 12 g/daily results in reduction in tumor mass; caution: adverse effects (80%) 6. Trilostane - 3β-17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones - comparable to aminogluthemide B. Mineralocorticoid Antagonists 1. Spirinolactone – diagnosis of aldosteronism (400-500mg/day fro 4-8 days); preparing for surgery (30040mg/day x 2 wks to reduce the incidence of arrhythmias); hirsutism in women (androgen antagonist 50-200mg/d x 2-6 mos); diuretic 2. Eplerenone – in clinical trials 3. Drospirenone – progestin in a new oral contraceptive, antagonizes the effect of aldosterone Classification of Adrenocorticosteroids I. Short to medium-acting glucocorticoids: a. Hydrocortisone (cortisol) b. Cortisone c. Prednisone d. Prednisolone e. Methylprednisolone f. Meprednisone II. Intermediate-acting glucocorticoids a. Triamcinolone b. Paramethasone c. Fluprednisolone III. Long-acting glucocorticoids a. Betamethasone b. Dexamathasone IV. Mineralocorticoids a. Fludrocortisone b. desoxycorticosterone acetate Addison described : . general languor and debility . remarkable feebleness of the heart's action . irritability of the stomach . peculiar change of the color of the skin Thank You