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  2. 2. Adrenal hormones
  3. 3. The Adrenal Gland
  4. 4. <ul><li>Manufactures steroid hormones (corticosteroids) </li></ul><ul><li>Cortex divided into three layers </li></ul><ul><ul><li>Zona glomerulosa (produces mineralocorticoids) </li></ul></ul><ul><ul><li>Zona fasciculata (produces glucocorticoids) </li></ul></ul><ul><ul><li>Zona reticularis (produces androgens) </li></ul></ul>Adrenal cortex
  5. 6. Stressors
  6. 10. Therapeutic uses ACTH <ul><li>Testing the integrity of HPA axis , i.e. Inj. cosyntropin (250mcg) is administered intravenously leads to increase in plasma cortisol level > 20 mcg after 30 minutes [ in normal adrenal gland ] ; response absent in HPA suppression </li></ul><ul><li>Secondary adrenocortical insufficiency due to hypopituitarism </li></ul><ul><li>Better response in multiple sclerosis & infantile spasm </li></ul>
  7. 11. ACTH release <ul><li>Regulated partly: by </li></ul><ul><li>Corticotropin releasing factor [ CRF ] from hypothalamus </li></ul><ul><li>The level of glucocorticoids in the blood [negative feed back control ] </li></ul>
  8. 13. CRF release <ul><li>Controlled by: </li></ul><ul><li>Level of gluco-corticoids in the blood </li></ul><ul><li>Level of ACTH in the blood </li></ul><ul><li>Natural stimuli from CNS , i.e. opioid peptides exert tonic inhibitory control & severe heat, cold, injury or infection activate the release. </li></ul>
  9. 14. Terms <ul><li>Steroid: A group of compound, having a common structure based on the steroid nucleus, which consists of three “six-member carbon rings” and one five member carbon ring” </li></ul><ul><li>For examples: the male and female sex hormones [ androgen and estrogens ], the hormones of the adrenal cortex. </li></ul>
  10. 15. Continued <ul><li>Steroid card: A card that must be carried by the patient taking long term steroid medication, particularly if high doses are used </li></ul><ul><li>Card states that in emergency treatment with steroids must not be sudden stopped, since this may precipitate an “addisonian crisis” </li></ul>
  11. 16. Continued <ul><li>#.Cushing’s syndrome: Abnormal bodily condition, caused by excess cortico-steroids [cortisol] usually from adrenal or pituitary hyper function </li></ul><ul><li>Signs & symptoms: Moon faces, obesity, easy bruising , slow wound healing and hypokalemia </li></ul><ul><li>Adreno-genital syndrome </li></ul>
  12. 17. Corticosteroids <ul><li># Two major groups [ physiologic & pharmacologic ] </li></ul><ul><li>Glucocorticoids: metabolism, catabolism, immune responses & inflammation </li></ul><ul><li>Mineralocorticoids: regulate sodium & potassium reabsorption in CT of kidneys </li></ul>
  13. 18. Continued <ul><li>#. Others: Androgenic & estrogenic steroids are also synthesized in the adrenal gland </li></ul><ul><li>#. Normal rate of secretion of: </li></ul><ul><li>Hydrocortisone ~ 10 mg/day [mainly half of this in the few in the morning hours] </li></ul><ul><li>Aldosterone: 0.125 mg daily </li></ul>
  14. 19. Adrenal Cortex: Steroid Hormone Production Cholesterol Pregnenolone Progesterone 17- α - Hydroxy pregnenolone 17- Hydroxy progesterone Dehydro-epi androsterone Andro-stenedione Estrone Estriol TESTOSTERONE ESTRADIOL Aromatase Aromatase Corticosterone Corticosteroids Aldosterone
  15. 20. Control of Cortisol Secretion: Feedback Loops <ul><li>External stimuli </li></ul><ul><li>Hypothalamic </li></ul><ul><li>Anterior Pituitary </li></ul><ul><li>Adrenal cortex </li></ul><ul><li>Tissues </li></ul>The control pathway for cortisol
  16. 21. Corticosteroids <ul><li>Short acting: Cortisone, hydrocortisone & fludrocortisone [ 8-12 hours ] </li></ul><ul><li>Intermediate acting: prednisone, prednisolone, methylprednisolone triamcinolone [ 12-36 hours ] </li></ul><ul><li>Long acting: dexamethasone, betamethasone, etc. [ 36-72 hours ] </li></ul>
  17. 23. Circadian rhythm of cortisol secretion
  18. 24. <ul><li>Corticosteroid enter the cell & bind to cytosolic receptors that transport the steroid into the nucleus </li></ul><ul><li>The steroid-receptor complex alters gene expression by binding to GREs or equivalent MC-specific elements </li></ul><ul><li>Tissue specific response to steroids are made possible by the presence in each tissue of different protein regulators that controls the interaction between the hormone-receptor complex and particular response elements. </li></ul>Mechanism of action:
  19. 27. Effects of Glucocorticoids
  20. 28. Effects of Glucocorticoids [ moon facies and buffalo hump ]
  21. 29. <ul><li>Catabolic effects: </li></ul><ul><li>Catabolism of muscle protein [ also wasting of lymphoid & connective tissue, fat & skin ] </li></ul><ul><li>Osteoporosis </li></ul><ul><li>Growth retardation in children </li></ul>Effects of Glucocorticoids
  22. 30. Corticosteroids : Actions Involution of lymphoid tissue (species dependent) Decrease in peripheral lymphocytes, monocytes, eosinophils Increase in peripheral neutrophils, platelets, RBCs Decreased Clotting Time Decreased phagocyte competence Hematopoietic system Decreased calcium and iron absorption Facilitation of fat absorption Increased acid, pepsin, and trypsin Structural alteration of mucin Gastrointestinal Tract Required for normal sensitivity of adrenergic receptors Autonomic Nervous System Euphoria and behavioral changes Maintenance of alpha rhythm Lower Seizure Threshold Central Nervous System Parturition induced during the latter part of pregnancy in ruminants and horses Less reliable in dogs and cats Teratogenesis during early pregnancy. Reproductive Tract
  23. 31. Increased reabsorption of water, sodium, chloride Increased excretion of potassium , calcium Increased extracellular fluid Kidneys Positive inotropic effect Increased blood pressure (increased blood volume) Cardiovascular system Atrophy and thinning (chronic excess) Calcinosis Cutis Skin Weakness (excess and deficiency) Muscle atrophy (chronic excess ) Skeletal Muscle &quot;Stabilization&quot; of liposomal membranes Inhibition of macrophage response to migration inhibition factor Lymphocyte sensitization blocked Cellular response to inflammatory mediators blocked Inhibition of fibroblast proliferation Cells Inhibition of collagen synthesis by fibroblasts Acceleration of Bone resorption Antagonism of Vitamin D Bone
  24. 32. Continued <ul><li>Immune suppressive effects: </li></ul><ul><li>Inhibit mechanism of cell-mediated immunologic function [lymphocytes] </li></ul><ul><li>For examples: </li></ul><ul><li>In treatment of lymphocytic leukemia </li></ul><ul><li>Delay rejection reaction in patient with organ transplants [ not in normal immunity ] </li></ul>
  25. 33. Important Drugs <ul><li>A. Cortisol [hydrocortisone]: endogenous </li></ul><ul><li>In the adrenal cortex from 17- hydroxy-pregnenolone </li></ul><ul><li>Secretion of cortisone is regulated by ACTH and varies during the day [ circadian ], with the peak occurring in the morning & the trough around mid night </li></ul>
  26. 34. Continued <ul><li>In the plasma, Cortisol is 95% bound to CBG </li></ul><ul><li>Well absorbed and distributed and cleared by liver </li></ul><ul><li>Cortisol is readily absorbed across inflamed skin & mucous membranes </li></ul><ul><li>Salt-retaining effect: HTN with a cortisol-secreting adrenal or a pituitary ACTH-secreting tumor [ Cushing's syndrome ] </li></ul>
  27. 35. Continued <ul><li>B. Synthetic glucocorticoids : prednisone & active metabolites [ prednisolone, dexamethasone, & triamcinolone ] with longer half-life </li></ul><ul><li>Less salt-retaining effect </li></ul><ul><li>Better tissue penetration [topical activity] </li></ul><ul><li>Beclomethasone and budesonide: readily penetrate the airway mucosa with less systemic side effect. </li></ul>
  28. 36. Therapeutic Uses <ul><li>A. As a replacement therapy in : </li></ul><ul><li>Acute adrenal insufficiency </li></ul><ul><li>Chronic adrenal insufficiency </li></ul><ul><li>Congenital adrenal hyperplasia syndrome </li></ul><ul><li>Hypopituitarism </li></ul>
  29. 37. B. Pharmacotherapy <ul><li>1. Intensive short term therapy: </li></ul><ul><li>The conditions [ Anaphylaxis, status asthmaticus, circulatory collapse, acute necrotising vascultits, hyperthermia [central], acute hypercalcemia of vitamin D intoxication ]: </li></ul><ul><li>Hydrocortisone [ 100-200 mg ], 8 hourly or 100-200 mg/day of Prednisolone for 2-3 days. </li></ul>
  30. 38. Continued <ul><li>2. Prolonged high suppressive therapy: </li></ul><ul><li>In conditions [ acute rheumatic fever, ulcerative colitis, coelic disease, hepatic necrosis, chronic hepatitis, hemolytic anemia, all, desseminated Hodgkin’s disease, nephritic syndrome, acute homograph rejection & collagen diseases, etc ] </li></ul><ul><li>Prednisolone [ 100-200 mg ]/day for 7-14 days </li></ul>
  31. 39. Continued <ul><li>In Rheumatoid arthritis: low dose chronic palliative with 2-10 mg/ day </li></ul><ul><li>In chronic suppression of pituitary ACTH: dexamethasone or betamethasone [ 0.75 mg at bed time ] </li></ul><ul><li>Topical application: interstitial keratitis, spring catarrh </li></ul><ul><li>Skin: inflammatory dermatoses, psoriasis </li></ul>
  32. 40. Continued <ul><li>In OA and tendonitis: Intra-articular route </li></ul><ul><li>Bell’s palsy, acute infective polyneuritis, complete heart block </li></ul><ul><li>Life saving in cerebral edema due to neoplasm: dexamethasone 5 mg, 8 hourly </li></ul><ul><li>Bronchial asthma (adjuvant bronchodilator) & other lung diseases.( pulmonary edema, aspiration pneumonitis following drowning) In preterm delivery for lung maturation of fetus & thus to avoid respiratory distress syndrome. </li></ul>
  33. 41. <ul><li>Infective diseases: sever form of tuberculosis, lepra reaction, bacterial meningitis & pneumocystis carinii in AIDS patient. </li></ul><ul><li>Malignancies: important component of cancer chemotherapy. </li></ul><ul><li>In organ transplant </li></ul>Therapeutic Uses:
  34. 42. Deflazacort <ul><li>Tissue selective synthetic corticosteroid </li></ul><ul><li>Potent anti-inflammatory action </li></ul><ul><li>Less effect on calcium & glucose metabolism </li></ul><ul><li>No osteoporosis </li></ul>
  35. 43. The adverse effects <ul><li>Cushing’s habitus [ prolonged use ] </li></ul><ul><li>hyperglycemia, hyperlipidemia, pituitary adrenal suppression </li></ul><ul><li>Muscular weakness, osteoporosis, myopathy, compression fracture of vertebrae </li></ul><ul><li>Peptic ulcer, gut bleeding, intestinal perforation, pancreatitis </li></ul>
  36. 44. Continued <ul><li>Suceptibility to infection & delayed wound healing </li></ul><ul><li>Glaucoma, post- subcapsular cataract </li></ul><ul><li>Growth retardation in children [ dexamethasone & betamethasone ] </li></ul><ul><li>Hypertension, edema </li></ul>
  37. 45. Continued <ul><li>Others: Hirsutism, baldness, S/C tissue atrophy & coagulation disorder [ thrombo-embolism, etc ] </li></ul>
  38. 47. Precautions <ul><li>A. Pre medication: </li></ul><ul><li>Enquire about history of peptic ulcer </li></ul><ul><li>Watch for anemia, diabetes & infections </li></ul><ul><li>B. During drug therapy: </li></ul><ul><li>Prescribe the drug with food </li></ul><ul><li>Urine test for sugar </li></ul><ul><li>Not to stop drug abruptly </li></ul>
  39. 48. Continued <ul><li>Keep record of weight & blood pressure </li></ul><ul><li>Increase the dose of drug in infection or during pregnancy </li></ul><ul><li>Treat infection with proper antibiotic. </li></ul><ul><li>C. While stopping the medication: </li></ul><ul><li>Taper therapy </li></ul>
  40. 49. Contraindication <ul><li>A. Relative contra-indications: in </li></ul><ul><li>Diabetes mellitus; peptic ulcer </li></ul><ul><li>Pregnancy; osteoporosis </li></ul><ul><li>Tuberculosis & other infection </li></ul><ul><li>Epilepsy </li></ul><ul><li>Renal failure & congestive cardiac failure </li></ul><ul><li>B. The absolute contra-indications: </li></ul><ul><li>Cushing’s syndrome </li></ul><ul><li>Herpes ocular infections </li></ul>
  41. 50. Complications after abrupt corticosteroid withdrawal : <ul><li>Not to be stopped abruptly, if the patient is on hydrocortisone [>25 mg/day ] or for > 2-3 weeks </li></ul><ul><li>It refers to severe adrenal crisis & death of patient due to suppression of HPA axis. </li></ul>
  42. 51. Methods of withdrawal: <ul><li>Use short acting steroids with lowest possible doses form </li></ul><ul><li>Prescribe the whole daily dose of the drugs at once in the morning </li></ul><ul><li>Switch to alternate day therapy if possible </li></ul>
  43. 52. Mineralo-corticosteroids : <ul><li>Aldosterone: is regulated by ACTH & by the renin-angiotensinogen system </li></ul><ul><li>Effects: regulates blood volume & blood pressure </li></ul><ul><li>Glucocorticoidal activity [ little] </li></ul><ul><li>Mechanism of action: similar to glucocorticoids </li></ul>
  44. 53. Continued <ul><li>Deoxycorticosterone: laboratory </li></ul><ul><li>Fludrocortisone: Significant gluco-corticoid activity with long duration of action </li></ul><ul><li>Use: Replacement therapy: after adrenalectomy, etc. </li></ul>
  45. 54. Corticosteroid Antagonists <ul><li>A. Receptor antagonists: </li></ul><ul><li>Spironolactone: inhibits and an antagonist of aldosterone [diuretics ] </li></ul><ul><li>Mefepristone inhibits glucosteroid receptors & progesterone receptors [ sex hormones ] </li></ul><ul><li>Used in treatment of Cushing’s syndrome </li></ul>
  46. 55. Continued <ul><li>Eplerenone : </li></ul><ul><li>A new Aldosterone antagonist, which unlike spironolactone does not produce gynecomastia </li></ul>
  47. 56. Continued <ul><li>B. Synthesis inhibitors: Metyrapone, Amino-glutethimide, & ketaconazole </li></ul><ul><li>Aminoglutethimide: In advanced breast cancer to suppress adrenal secretion of estrogen steroids </li></ul><ul><li>Ketoconazole: inhibits the P459 enzyme, reduces steroidal level are desirable [ hirsutism, breast cancer ] </li></ul>
  48. 57. Continued <ul><li>Metyrapone: inhibits the normal synthesis of cortisol, some extent. </li></ul><ul><li>Uses: In diagnosis of adrenal function [ a normal response to test dose of metyrapone is evidence that the adrenal cortex is functioning ] </li></ul><ul><li>Trilostante: inhibits 3-beta-hydroxysteroid dehydrogenase [ stops pregnenolone to progesterone ] </li></ul>
  49. 58. Continued <ul><li>Anastrozole: New selective non-steroidal aromatase inhibitor </li></ul><ul><li>Uses: in postmenopausal breast cancer </li></ul>
  50. 59. Next Class on … FEMALE SEX HORMONES: ESTROGENS
  51. 60. THANK YOU