Adrenocorticosteroids & Adrenocortical Antagonists

1. Adrenocorticosteroids&Adrenocortical Antagonists Dr. Shereen Ayoub Faculty of Medicine 2009

3. Adrenal Gland • Adrenal cortex – mineralocorticoids, glucocorticoids, adrenal androgens (androstenedione & dehydroepiadrosterone) • Adrenal medulla – catecholamines (Epinephrine and Norepinephrine)

4. Adrenal Cortex • Outer zone (zona glomerulosa) – secretes mineralocorticoids - Aldosterone: under control of Renin-angiotensin system • Inner zone (zona fasciculata and reticularis) – secrete glucocorticoids and adrenal androgens

7. Anterior pituitary • Anterior pituitary: connected to the hypothalamus by hypothalmoanterior pituitary portal vessels. • The anterior pituitary produces six peptide hormones: • prolactin, growth hormone (GH), • thyroid stimulating hormone (TSH), • adrenocorticotropic hormone (ACTH), • follicle-stimulating hormone (FSH), • luteinizing hormone (LH).

9. Adrenocorticosteroids • Bind to specific intracellular cytoplasmic receptors target tissue • Production is diurnal • Peak early in the morning • Smaller peak in the late afternoon

10. Adrenocorticosteroids • Glucocorticoids • Natural – e.g. cortisone and hydrocortisone • Semi-synthetic and synthetic – e.g. prednisolone, fludrocortisone, triamcinolone, dexamethasone, fluocinonide • Preparations available: systemic, topical, inhalation, ophthalmic, otic, nasal • Discontinuation/withdrawal of therapy should be gradual after long-term use

11. Classification of Adrenocorticosteroids I. Short to medium-acting glucocorticoids: a. Hydrocortisone (cortisol) b. Cortisone c. Prednisone d. Prednisolone e. Methylprednisolone f. Meprednisone

12. 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

13. 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

14. 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)

15. 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)

16. 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

17. 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

18. Pharmacokinetics: • Absorption: • Well absorbed from all sites of administration. • Plasma Protein binding: • 90% to globulin. • Half life (t1/2): • 1- 1.5 hr. • Metabolism and Excretion: • Excreted in urine after glycosylation with glucuronic acid.

19. 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,t ½ 15-20mins , excreted in the urine as tetrahydroaldosterone and 3-oxo-glucoronide 2. Deoxycortisone: as precursor of aldosterone 3. Fludrocortisone – most widely used; both mineralocorticoid and glucocorticoid activity

20. Therapeutic uses of adrenal corticosteroids • Replacement for primary adrenocortical insufficiency (Addison’s disease9 • Hydrocortisone , 2/3 in am, 1/3 in pm • Fludrocortisone- synthetic mineralocorticoid • Replacement for secondary or tertiary adrenocortical insufficiency • Lacking ACTH or CRH, but you still treat with hydrocortisone • Synthesis of mineralocorticoids is less impaired

21. Addison’s Disease • Disease in which patients lack cortisol from zona fasiculata, and thus lacks negative feedback that suppresses ACTH production • Result: overproduction of ACTH • Skin color will darken • JFK had Addison’s disease and was treated with cortisol injections

23. Therapeutic uses of adrenal corticosteroids • Diagnosis of Cushing’s syndrome • Hypersecretion of glucocorticoids that results either from excessive release of ACTH or adrenal tumor • Dexamethasone suppression test is used to diagnose the cause • Suppresses cortisol release in pituitary dependent Cushings, but not when it is released from adrenal tumors

24. Therapeutic uses of adrenal corticosteroids • Replacement therapy for congenital adrenal hyperplasia • Group of diseases resulting from an enzyme defect in the synthesis of one or more of the adrenal steroid hormones • Leads to virilization in females due to overproduction of adrenal androgens • Treatment: give enough steroids to normalize the patient’s hormone levels of CRH and ACTH • Relief of inflammatory symptoms • Arthritis, asthma, skin conditions, allergies, etc • Acceleration of lung maturation in premature infants • Beclomethasone IM given to mother 48 hours prior to birth , followed by a second dose 24 hours before delivery

25. 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 • Ocular disease – 0.1% dexamethasone • Contraindication: herpes simplex keratitis (clouding of the cornea) , glaucoma

26. 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

27. Side effects of long term usage • 1. Hyperglycemia-can be managed with diet and/or insulin • 2. Fluid and electrolyte disturbances- hypertension, edema • 3. Increased susceptibility to infection • 4. Myopathy — can be severe, recovery may be slow or incomplete • 5. Osteoporosis — Ca2+ uptake, all ages, related to dosage and duration, ribs/vertebrae, Ca2+, vitamin D therapy 30-50% of chronic • 6. Osteonecrosis – mainly femoral head, joint pain/stiffness, progressive 7. Cataracts – especially children, may not resolve with cessation • 8. Behavioral disturbances — nervousness, insomnia • 9. Iatrogenic adrenal insufficiency — prolonged suppression of the hypothalamic-pituitary axis

28. Therapeutic considerations • 1. Contraindications — peptic ulcer, osteoporosis, hypertension, infection, psychosis • 2. Alternate day therapy- decreases the prolonged suppression • 3. Relief of symptoms — glucocorticoids do not cure • 4. Especially useful for: • a. Diseases that occur in episodes (e.g. rheumatoid arthritis) • b. Topical applications

29. 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

30. Corticosteroid Withdrawal Should Be Gradual • Most frequent side effect- flare-up or the underlying disease • Sudden cessation leads to acute adrenal insufficiency, due to the prolonged suppression of the HPA axis • Need weeks/months/year to have full recovery of the HPA axis • Normal withdrawal symptoms- fever, muscle and joint pain, and malaise

31. Antagonists of Adrenocortical Agents • Synthetic inhibitors and glucocorticoid antagonists 1. Metyrapone – inhibits 11-hydroxylation, interfering with cortisol and corticosterone synthesis - used in tests of adrenal function - treat hypercorticotism (cushing syndrome in pregnancy)

32. 2. Aminoglutethimide • blocks the conversion of cholesterol to pregnanelolone and causes a reduction in the synthesis of all hormonally active steroids • Used in treatment of breast Cancer and Cushing’s syndrome due to adrenocortical Cancer (malignancese of adrenal cortex) • enhances metabolism of dexamethasone

33. 3. Ketoconazole an antifungal imidazole derivative; potent, non-selective inhibitor of adrenal and gonadal steroid synthesis; used in Cushing’s syndrome 4.Mifepristone (RU 486) 11β-aminophenyl-substituted 19-norsteroid; has strong anti-progestin activity; blocks glucocorticoid receptor 5. Trilostane 3β-17 hydroxysteroid dehydrogenase inhibitor that interferes with the synthesis of adrenal and gonadal hormones, comparable to aminogluthemide

34. B. Mineralocorticoid Antagonists 1. Spirinolactone – diagnosis of aldosteronism; preparing for surgery to reduce the incidence of arrhythmias; hirsutism in women; K-sparing diuretic 2. Eplerenone: aldosterone antagonist in clinical trials to treat hypertension 3. Drospirenone – progestin in a new oral contraceptive, antagonizes the effect of aldosterone

35. In practice (Goodman and Gilman): • 1. For any disease, in any patient, the appropriate dose to achieve a given therapeutic effect must be determined by trial and error and be reevaluated from time to time as the stage and the activity of the disease change. • 2. A single dose of corticosteroid, even a large one is virtually without harmful effects. • 3. A few days of corticorticosteroid therapy, in the absence of specific contraindications, is unlikely to produce harmful results except at the most extreme dosages. • 4. As corticosteroid therapy is prolonged over periods of weeks or months, and to the extent that the dose exceeds the equivalent of substitution therapy, the incidence of disabling and potentially lethal effects increases. • 5. Except in adrenal insufficiency, the administration of corticosteroids is neither specific nor curative therapy, but only palliative by virtue of their antiinflammatory and immunosuppressive effects. • 6. sudden stop of prolonged, high-dose corticosteroid therapy is associated with a significant risk of adrenal insufficiency of sufficient severity to be threatening to life.