Adrenal Steroids Mineralocorticoids & Glucocorticoids. Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The Jordan University April 2014
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1 Adrenal Steroids Mineralocorticoids & Glucocorticoids Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The Jordan University April 2014
2 Medulla (E, NE) Adrenal Gland Cortex Mineralocorticoids (Aldosterone) Glucocorticoids (Cortisol) Sex hormones (Testosterone, E2, P) 2
3 3
4 Mineralocorticoids (Aldosterone) Control of synthesis and release: - Angiotensin III. - Angiotensin II - K + (the most sensitive stimulator of aldosterone) - ACTH - ECF or blood volume. - Metabolic acidosis 4
5 5
6 6
7 DE Deh. Cholesterol Pregnenolone Progesterone (21) Hyd s Aldosterone (18) corticosterone (11) Deoxy- corticosterone DE= debranching enzyme; side chain cleavage enzyme; desmolase Deh.= 3β-hydroxysteroid dehydrogenase enzyme Hyd s= Hydroxylases 7
8 Renin-angiotensin-aldosterone axis Angiotensinogen Renin Angiotensin I ACE Angiotensin II Aldosterone 8
9 Factors/drugs renin-angiotesin-aldosterone: - Volume depletion (hemorrhage, low Na + intake, dehydration, overuse of diuretics ) - Upright posture - K + - ACTH - Vasodilators - Adrenoreceptor antagonists 9
10 Factors/drugs renin-angiotesin-aldosterone: - Blood volume expansion - Renin release inhibitors (also known as renin antagonists) Aliskiren, Remikerin, Enalkiren, β 1 -blockers - ACE inhibitors Captopril, Enalapril, Benzopril, fosinopril, Lisinopril, Ramipril - ARB s (Angiotensin II receptor blockers) Candesartan, Losartan, Irbesartan, telmesartan - Aldosterone antagonists Spironolactone, Eplerenone 10
11 Effects of Aldosterone Receptor-mediated Acts on distal convoluted tubules in the kidney - reabsorption of Na + hypertension - excretion of K + & H + hypokalemia & metabolic alkalosis - EC volume - BP 11
12 Disorders affecting aldosterone release: * Hypoaldosteronism...rare * Hyperaldosteronism 1º 2º Volume Volume* Na + Renin Na + Renin Ald.* Ald. * Initial defect 12
13 Glucocorticoids (Cortisol) Feedback control CRH - ACTH Cortisol - 13
14 Glucocorticoids (Cortisol) Circadian rhythm Pt s on cortisol therapy... Cortisol synthesis (from cholesterol) 14
15 Glucocorticoids (Cortisol) DE Deh. Cholesterol Pregnenolone Progesterone (17) Hyd s Cortisol (11) Deoxy- (21) Hydroxy- corticosterone progesterone DE= debranching enzyme; side chain cleavage enzyme; desmolase Deh.= 3β-hydroxysteroid dehydrogenase enzyme Hyd s= Hydroxylases 15
16 Steroid synthesis inhibitors - o,p -DDD (Mitotane) Causes selective atrophy of Zona Fasciculata and Zona Reticularis Useful in R x of adrenal Ca when radiotherapy or surgery are not feasible and in certain cases of breast cancer - Aminoglutethimide Selective desmolase inhibitor and non selective aromatase inhibitor, same uses as mitotane 16
17 Steroid synthesis inhibitors: - Trilostane: Competitive inhibitor of 3β-hydroxysteroid dehydrogenase enzyme. Effective in Cushing s syndrome and breast cancer. - Ketoconazole: An antifungal agent An inhibitor of different hydroxylases. Inhibits steroidogenesis in adrenals and testes. Effective in Cushing s syndrome and Ca of prostate. 17
18 Steroid synthesis inhibitors - Amphenone B An inhibitor of different hydroxylases but very toxic. The therapeutic use of amphenone B is limited by its toxicity : antithyroid effect, severe CNS depression, GIT upset and many skin disorders - Metyrapone (Metopirone) 11β-hydroxylase inhibitor Effective as a diagnostic tool (metyrapone test) and in the management of Cushing s syndrome 18
19 Effects of Glucocorticoids - On proteins: Catabolism anabolism Osteoporosis; steroid myopathy; delayed wound healing; delayed peptic ulcer healing - On CHO: Diabetogenic: gluconeogenesis; peripheral utilization of glucose) 19
20 Effects of Glucocorticoids - On lipids: lipolysis Fat redistribution - On electrolytes: Aldosterone-like effect Ca ++ absorption from intestine Ca ++ excretion by kidney Uric acid excretion 20
21 Effects of Glucocorticoids - Antiinflammatory effect: major mechanism: Phospholipids Pospholipase A2 Arachidonic acid Lipoxygenase Cyclooxygenase Leukotreines (SRS-A) PG s 21
22 Effects of Glucocorticoids Other possible mechanisms: - Inhibition of neutrophil and macrophage function. - Inhibition of platelet activation factor (PAF) - Inhibition of tissue necrosis factor or receptor (TNF; TNR) - Inhibition of nitric oxide reductase 22
23 Effects of Glucocorticoids Immunosuppressant effect: initial processing of Ag Ab formation effectiveness of T-lymphocytes lymphocyte induction & proliferation lymphoid tissue including leukemic lymphocytes (antileukemic effect) 23
24 Effects of glucocorticoids Antiallergic effect: Supress allergic response histamine release eosinophils CNS effects: Euphoria Psychosis 24
25 Glucocorticoids Glucocorticoids dosage forms: Available in all dosage forms Available in many preparations Structure activity relationship: Major objective: Good antiinflammatory effect, less or no aldosterone-like activity Metabolism: In the liver by reduction and conjugation (90-95%); little hydroxylation reactions (5%) 25
26 Glucocorticoid preparations Short-acting Half-life AIA Ald.-like Corisol Cortisone Corticosterone Fludrocortisone
27 Glucocorticoid preparations Intermediate-acting Half-life AIA Ald.-like Prednisone Prednisolone Methylprednisolone Triamcinolone Beclomethasone
28 Glucocorticoid preparations Long-acting: Half-life AIA Ald.-like Betamethasone Dexamethasone ** Plasma half-life; Nuclear half-life 28
29 Clinical uses to Glucocorticoids - Adrenal insufficiency (acute; chronic, Addisonian crisis, Addison s disease...) - Inflammatory conditions (rheumatoid arthritis, SLE, arteritis, dermatomyositis, cerebral edema, ulcerative colitis, rheumatic carditis, active chronic hepatitis, proctitis, acute gout...) - Allergic reactions (hay fever, eczema, dermatitis), bronchial asthma, status asthmaticus 29
30 Clinical uses to Glucocorticoids - Immunosuppression: (organ transplantation, hemolytic anemia, leukemias, many tumors...) - Hypercalcemia associated with Vit. D intoxication or sarcoidosis or hyperparathyroidism or cancer...) - Many eye, ear, and skin diseases (allergic or inflammatory) 30
31 Side effects of Glucocorticoids - Suppression of hypothalamic-pituitary-adrenal axis (major and most dangerous side effect) - Cushing s syndrome - Salt & water retention, edema, BP, obesity - Peptic ulcer disease and GIT ulcerations - Osteoporosis - Diabetes mellitus - incidence of viral and fungal infections - wound healing and skin atrophy and myopathy - Suppression of growth of children - Cataract 31
32 32
33 Strategies in the use of Glucocorticoids - Use a short-acting steroid. - Use the minimal possible dose. - 2/3rd of the dose in morning and 1/3rd in evening. - Use alternate day therapy which is associated with less suppression to growth of children and to the hypothalamic-pituitary-adrenal axis and fewer side effects 33
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