1. Adrenal Steroids Mineralocorticoids & Glucocorticoids Munir Gharaibeh, MD, PhD, MHPE Faculty of Medicine The Jordan University April 2014

2. Adrenal Gland Cortex Adrenal Gland Cortex Mineralocorticoids Mineralocorticoids (Aldosterone) (Aldosterone) Medulla Glucocorticoids Medulla Glucocorticoids (E, NE) (Cortisol) (E, NE) (Cortisol) Sex hormones Sex hormones (Testosterone, E2, P) (Testosterone, E2, P) November 15 2 Munir Gharaibeh, MD, PhD, MHPE

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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 November 15 4 Munir Gharaibeh, MD, PhD, MHPE

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7. DE Deh. DE Deh. Cholesterol Pregnenolone Progesterone Cholesterol Pregnenolone Progesterone (21) Hyd ’ s (21) Hyd ’ s Aldosterone (18) corticosterone (11) Deoxy- Aldosterone (18) corticosterone (11) Deoxy- corticosterone corticosterone DE= debranching enzyme; side chain cleavage enzyme; desmolase Deh.= 3β-hydroxysteroid dehydrogenase enzyme Hyd ’ s= Hydroxylases November 15 7 Munir Gharaibeh, MD, PhD, MHPE

8. Renin-angiotensin-aldosterone axis Angiotensinogen Angiotensinogen Renin Renin Angiotensin I Angiotensin I ACE ACE Angiotensin II Angiotensin II Aldosterone Aldosterone November 15 8 Munir Gharaibeh, MD, PhD, MHPE

9. Factors/drugs ↑ renin-angiotesin-aldosterone: Factors/drugs ↑ renin-angiotesin-aldosterone: - Volume depletion (hemorrhage, low Na + intake, dehydration, overuse of diuretics…) - Upright posture - K + - ACTH - Vasodilators - Adrenoreceptor antagonists November 15 9 Munir Gharaibeh, MD, PhD, MHPE

10. Factors/drugs ↓ renin-angiotesin-aldosterone: Factors/drugs ↓ renin-angiotesin-aldosterone: - Blood volume expansion - Renin release inhibitors (also known as renin antagonists) Remikerin, Enalkiren, β 1 -blockers Aliskiren, Remikerin, Enalkiren, β 1 -blockers - ACE inhibitors Captopril, Enalapril, Benzopril, fosinopril, Lisinopril, Ramipril… Captopril, Enalapril, Benzopril, fosinopril, Lisinopril, Ramipril … - ARB’s (Angiotensin II receptor blockers) Candesartan, Losartan, Irbesartan, telmesartan… - Aldosterone antagonists Spironolactone, Eplerenone November 15 10 Munir Gharaibeh, MD, PhD, MHPE

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 November 15 11 Munir Gharaibeh, MD, PhD, MHPE

12. Disorders affecting aldosterone release: Disorders affecting aldosterone release: * Hypoaldosteronism...rare * Hyperaldosteronism 1º 2º 1º 2º ↑ Volume ↓ Volume* ↑ Volume ↓ Volume* ↑Na + ↓Renin ↑Na + ↑Renin ↑Ald.* ↑Ald. ↑Ald.* ↑Ald. * Initial defect November 15 12 Munir Gharaibeh, MD, PhD, MHPE

13. Glucocorticoids (Cortisol) Feedback control Feedback controlCRH -ACTH -Cortisol November 15 13 Munir Gharaibeh, MD, PhD, MHPE

14. Glucocorticoids (Cortisol) Circadian rhythm Pt ’ s on cortisol therapy... Cortisol synthesis (from cholesterol) November 15 14 Munir Gharaibeh, MD, PhD, MHPE

15. Glucocorticoids (Cortisol) DE Deh. DE Deh. Cholesterol Pregnenolone Progesterone Cholesterol Pregnenolone Progesterone (17) Hyd ’ s (17) Hyd ’ s Cortisol (11) Deoxy- (21) Hydroxy- Cortisol (11) Deoxy- (21) Hydroxy- corticosterone progesterone corticosterone progesterone DE= debranching enzyme; side chain cleavage enzyme; desmolase Deh.= 3β-hydroxysteroid dehydrogenase enzyme Hyd ’ s= Hydroxylases November 15 15 Munir Gharaibeh, MD, PhD, MHPE

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 November 15 16 Munir Gharaibeh, MD, PhD, MHPE

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. November 15 17 Munir Gharaibeh, MD, PhD, MHPE

18. Steroid synthesis inhibitors - Amphenone B An inhibitor of different hydroxylases but very toxic. The therapeutic use of amphenone B is limited by its severe CNS depression, GIT upset and many skin disorders 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 November 15 18 Munir Gharaibeh, MD, PhD, MHPE

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) November 15 19 Munir Gharaibeh, MD, PhD, MHPE

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 November 15 20 Munir Gharaibeh, MD, PhD, MHPE

21. Effects of Glucocorticoids - Antiinflammatory effect: major mechanism: major mechanism: Phospholipids Phospholipids Pospholipase A2 Pospholipase A2 Arachidonic acid Arachidonic acid Lipoxygenase Cyclooxygenase Lipoxygenase Cyclooxygenase Leukotreines PG’s (SRS-A) (SRS-A) November 15 21 Munir Gharaibeh, MD, PhD, MHPE

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… November 15 22 Munir Gharaibeh, MD, PhD, MHPE

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) November 15 23 Munir Gharaibeh, MD, PhD, MHPE

24. Effects of glucocorticoids Antiallergic effect: Supress allergic response ↓ histamine release ↓ eosinophils CNS effects: EuphoriaPsychosis November 15 24 Munir Gharaibeh, MD, PhD, MHPE

25. Glucocorticoids Glucocorticoids dosage forms: 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 Structure activity relationship: Major objective: Good antiinflammatory effect, less or no aldosterone-like activity Metabolism: Metabolism: In the liver by reduction and conjugation (90-95%); little hydroxylation reactions (5%) November 15 25 Munir Gharaibeh, MD, PhD, MHPE

26. Glucocorticoid preparations Short-acting Half-life AIA Ald.-like Corisol 10 1 1 Cortisone 10 0.8 1 Corticosterone 10 0.3 30 Fludrocortisone 10 10 150 November 15 26 Munir Gharaibeh, MD, PhD, MHPE

27. Glucocorticoid preparations Intermediate-acting Half-life AIA Ald.-like Prednisone 20 4 0.8 Prednisolone 20 5 0.8 Methylprednisolone 20 6 - Triamcinolone 20 6 - Beclomethasone 20 6 - November 15 27 Munir Gharaibeh, MD, PhD, MHPE

28. Glucocorticoid preparations Long-acting: Half-life AIA Ald.-like Long-acting: Half-life AIA Ald.-like Betamethasone 50 25 - Dexamethasone 50 30 - ** Plasma half-life; Nuclear half-life November 15 28 Munir Gharaibeh, MD, PhD, MHPE

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 November 15 29 Munir Gharaibeh, MD, PhD, MHPE

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) November 15 30 Munir Gharaibeh, MD, PhD, MHPE

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… November 15 31 Munir Gharaibeh, MD, PhD, MHPE

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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 November 15 33 Munir Gharaibeh, MD, PhD, MHPE