1. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Chapter 60 Drugs for Disorders of the Adrenal Cortex

2. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenal Cortex Hormones  Affect multiple processes  Maintenance of glucose availability  Regulation of water and electrolyte balance  Development of sex characteristics  Life-preserving responses to stress 2

3. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Physiology of the Adrenocortical Hormones  Three classes of steroid hormones produced by the adrenal cortex:  Glucocorticoids  Mineralocorticoids  Androgens  Two most familiar forms of adrenocortical dysfunction:  Adrenal hormone excess Cushing’s syndrome  Adrenal hormone deficiency Addison’s disease 3

4. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Glucocorticoids: Physiologic Effects  Occur at low levels of glucocorticoids  Carbohydrate metabolism  Protein metabolism  Fat metabolism  Cardiovascular system  Skeletal muscle  Central nervous system  Stress  Respiratory system in neonates 4

5. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Mineralocorticoids  Influence renal processing of sodium, potassium, and hydrogen  Aldosterone  Promotes sodium and potassium hemostasis  Maintains intravascular volume  Has harmful cardiovascular effects at high levels  Regulated by renin-angiotensin-aldosterone system (RAAS) 5

6. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenal Androgens  Androstenedione  Minimal physiologic effects at normal levels  Overproduction seen in congenital adrenal hyperplasia 6

7. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenal Hormone Excess  Cushing’s syndrome  Causes Hypersecretion of adrenocorticotropic hormone (ACTH) Hypersecretion of glucocorticoids Administration of glucocorticoids in large doses  Clinical presentation Obesity Hyperglycemia Glycosuria Hypertension Fluid and electrolyte disturbances 7

8. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenal Hormone Excess  Cushing’s syndrome (Cont.)  Treatment Carcinoma/adenoma: Surgical removal of adrenal gland Replacement therapy with glucocorticoids and mineralocorticoids for bilateral adrenalectomy Drugs used as adjuncts to surgical treatment Ketoconazole [Nizoral] 8

9. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Primary Hyperaldosteronism  Excessive secretion of aldosterone  Causes  Hypokalemia, metabolic alkalosis, hypertension  Treatment  Based on underlying cause  Surgery or aldosterone antagonist (spironolactone) 9

10. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenal Hormone Insufficiency  General therapeutic considerations  Replacement therapy with glucocorticoids Should mimic normal patterns of corticosteroid secretion ⅔ in the morning and ⅓ in the afternoon Doses much smaller for endocrine disorders than for nonendocrine disorders Dosage is increased in times of stress 10

11. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenal Hormone Insufficiency  Addison’s disease (primary adrenocortical insufficiency)  Clinical presentation and causes Weakness and hypotension Emaciation Hypoglycemia, hyperkalemia, hyponatremia Increased pigmentation of skin and mucous membranes  Treatment Replacement therapy with adrenocorticoids Hydrocortisone is drug of choice  Both glucocorticoid and mineralocorticoid 11

12. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenal Hormone Insufficiency  Addison’s disease (Cont.)  Secondary adrenocortical insufficiency results from decreased secretion of ACTH  Tertiary insufficiency results from decreased secretion of corticotropin-releasing hormone (CRH)  In both cases, adrenal secretion of glucocorticoids is diminished, whereas secretion of mineralocorticoids is usually normal  Treatment consists of replacement therapy with a glucocorticoid (for example, hydrocortisone) 12

13. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenal Hormone Insufficiency  Acute adrenal insufficiency (adrenal crisis)  Can lead to death  Clinical presentation  Hypotension  Dehydration  Weakness  Lethargy  Gastrointestinal (GI) symptoms (vomiting and diarrhea)  Causes  Adrenal failure  Pituitary failure  Inadequate doses of corticosteroids or abrupt withdrawal 13

14. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenal Hormone Insufficiency  Acute adrenal insufficiency (Cont.)  Treatment Rapid replacement of fluid, salt, and glucocorticoids (hydrocortisone) Glucose : Normal saline with dextrose 14

15. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Adrenal Hormone Insufficiency  Congenital adrenal hyperplasia  Clinical presentation and causes  Treatment: Glucocorticoids – Hydrocortisone, dexamethasone, prednisone  Screening 15

16. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Agents for Replacement Therapy in Adrenocortical Insufficiency  Replacement therapy with corticosteroids is required  Glucocorticoid is always required  Some patients also require a mineralocorticoid  Principal glucocorticoids used are hydrocortisone, dexamethasone, and prednisone  Fludrocortisone is the only mineralocorticoid available 16

17. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Hydrocortisone  Synthetic steroid with a structure identical to that of cortisol  Therapeutic uses  Adrenal insufficiency  Allergic reactions to inflammation  Cancer  Adverse effects of high-dose therapy  Adrenal suppression  Cushing’s syndrome 17

18. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Prednisone and Dexamethasone  Preferred drugs for oral therapy of chronic adrenal insufficiency.  Cortisone is a prodrug that undergoes conversion to hydrocortisone (its active form) in the body. The drug has both glucocorticoid and mineralocorticoid activity. 18

19. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Fludrocortisone [Florinef]  Potent mineralocorticoid  Therapeutic uses  Addison’s disease  Primary hypoaldosteronism  Congenital adrenal hyperplasia  Adverse effects  Hypertension  Edema  Cardiac enlargement  Hypokalemia 19

20. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Diagnostic Testing of Adrenocortical Function  ACTH is used primarily for diagnostic tests  Cosyntropin Synthetic polypeptide whose structure corresponds to the first 24 amino acids of ACTH 250-mcg dose of cosyntropin is injected intramuscularly (IM) or intravenously (IV) Plasma cortisol is measured just before injection and then 30 or 60 minutes later Cortisol level rises above 20 mcg/dL: Adrenal response is considered normal, and primary adrenal insufficiency can be ruled out Cortisol level fails to rise significantly: A diagnosis of primary adrenal insufficiency can be made 20

21. Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Dexamethasone  Synthetic steroid  Primarily glucocorticoid properties; very little mineralocorticoid activity  Overnight dexamethasone test to diagnose Cushing’s syndrome  Prolonged dexamethasone suppression test 21