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

2. 2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

3. 3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Physiology of the Adrenocortical Hormones  Three classes of steroid hormones from the adrenal cortex: 1. Glucocorticoids 2. Mineralocorticoids 3. Androgens  Two most familiar forms of adrenocortical dysfunction: 1. Adrenal hormone excess Cushing’s syndrome Cushing’s syndrome 2. Adrenal hormone deficiency Addison’s disease Addison’s disease

4. 4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Glucocorticoids: Physiologic Effects  Physiologic effects (occur at low levels)  Carbohydrate metabolism  Protein metabolism  Fat metabolism  Cardiovascular system  Skeletal muscle  Central nervous system  Stress  Respiratory system in neonates

5. 5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig. 60–2. Negative feedback regulation of glucocorticoid synthesis and secretion.

6. 6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Mineralocorticoids   Influence renal processing of sodium, potassium, and hydrogen   Aldosterone   Promotes sodium and potassium hemostasis   Maintains intravascular volume   Harmful cardiovascular effects with high levels   Regulated by renin-angiotensin-aldosterone system (RAAS)

7. 7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adrenal Androgens   Androstenedione   Minimal physiologic effects at normal levels   In excess (congenital adrenal hyperplasia)

8. 8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adrenal Hormone Excess  Cushing’s syndrome  Causes Hypersecretion of adrenocorticotropic hormone (ACTH) Hypersecretion of adrenocorticotropic hormone (ACTH) Hypersecretion of glucocorticoids Hypersecretion of glucocorticoids Administering glucocorticoids in large doses Administering glucocorticoids in large doses  Clinical presentation Obesity Obesity Hyperglycemia Hyperglycemia Glycosuria Glycosuria Hypertension Hypertension Fluid and electrolyte disturbances Fluid and electrolyte disturbances

9. 9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adrenal Hormone Excess  Cushing’s syndrome (cont’d)  Treatment Carcinoma/adenoma: surgical removal of adrenal gland Carcinoma/adenoma: surgical removal of adrenal gland Replacement therapy with glucocorticoids and mineralocorticoids for bilateral adrenalectomy Replacement therapy with glucocorticoids and mineralocorticoids for bilateral adrenalectomy Drugs are adjunct for surgical treatment Drugs are adjunct for surgical treatment

10. 10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Primary Hyperaldosteronism  Excessive secretion of aldosterone  Causes  Hypokalemia, metabolic alkalosis, hypertension  Treatment  Based on underlying cause  Surgery or aldosterone antagonist (spironolactone)

11. 11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adrenal Hormone Insufficiency  General therapeutic considerations  Replacement therapy with glucocorticoids Should mimic normal patterns of corticosteroid secretion Should mimic normal patterns of corticosteroid secretion 2/3 in the morning and 1/3 in the afternoon 2/3 in the morning and 1/3 in the afternoon Doses for endocrine disorders are much smaller than for nonendocrine disorders Doses for endocrine disorders are much smaller than for nonendocrine disorders Increase dosage in times of stress Increase dosage in times of stress

12. 12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adrenal Hormone Insufficiency  Addison’s disease (primary adrenocortical insufficiency)  Clinical presentation and causes Weakness and hypotension Weakness and hypotension Emaciation Emaciation Hypoglycemia, hyperkalemia, hyponatremia Hypoglycemia, hyperkalemia, hyponatremia Increased pigmentation of skin and mucous membranes Increased pigmentation of skin and mucous membranes  Treatment Replacement therapy with adrenocorticoids Replacement therapy with adrenocorticoids Hydrocortisone is the drug of choice Hydrocortisone is the drug of choice  Both glucocorticoid and mineralocorticoid

13. 13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adrenal Hormone Insufficiency  Secondary adrenocortical insufficiency results from decreased secretion of ACTH  Tertiary insufficiency results from decreased secretion of 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 (eg, hydrocortisone)

14. 14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adrenal Hormone Insufficiency  Acute adrenal insufficiency (adrenal crisis)  Can lead to death  Clinical presentation  Hypotension  Dehydration  Weakness  Lethargy  GI symptoms (vomiting and diarrhea)  Causes  Adrenal failure  Pituitary failure  Inadequate doses of corticosteroids or abrupt withdrawal

15. 15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adrenal Hormone Insufficiency  Acute adrenal insufficiency (cont’d)  Treatment Rapid replacement of fluid, salt, and glucocorticoids (hydrocortisone) Rapid replacement of fluid, salt, and glucocorticoids (hydrocortisone) Glucose : normal saline with dextrose Glucose : normal saline with dextrose

16. 16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Adrenal Hormone Insufficiency  Congenital adrenal hyperplasia  Clinical presentation and causes  Treatment—glucocorticoids employed— hydrocortisone, dexamethasone, prednisone  Screening

17. 17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Agents for Replacement Therapy in Adrenocortical Insufficiency  Require replacement therapy with corticosteroids  Glucocorticoid is always required  Some patients require a mineralocorticoid as well  The principal glucocorticoids employed are hydrocortisone, dexamethasone, and prednisone  Fludrocortisone is the only mineralocorticoid available

18. 18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Hydrocortisone  Synthetic steroid with structure identical to cortisol  Therapeutic uses  Adrenal insufficiency  Allergic reactions to inflammation  Cancer  Adverse effects of high-dose therapy  Adrenal suppression  Cushing’s syndrome

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

20. 20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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 Synthetic polypeptide whose structure corresponds to the first 24 amino acids of ACTH

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