Adrenal Disorders PDF

Adrenal Disorders SCOTT HANES, PHARMD ASSOCIATE PROFESSOR PHARMACY PRACTICE Learning Objectives Describe the physiologic function of the hypothalamic pituitary adrenal axis (HPA) Identify hormones and mediators prod...

Adrenal Disorders SCOTT HANES, PHARMD ASSOCIATE PROFESSOR PHARMACY PRACTICE Learning Objectives Describe the physiologic function of the hypothalamic pituitary adrenal axis (HPA) Identify hormones and mediators produced by the adrenal glands Describe how aldosterone concentrations are regulated Differentiate primary vs. secondary adrenal insufficiency based on clinical presentation and hypothalamus and pituitary function Recognize adrenal disorders based on clinical presentation including electrolyte disorders Identify the most common causes of adrenal disorders Adrenal Gland Disorders Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59  Physiology Total Gland ○ Adrenal Medulla  10%  Secretes catecholamines ○ Adrenal Cortex  90%  Secretes three types of hormones ○ Aldosterone ○ Glucocorticoids ○ Androgens Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59 Image from: Uptodate.com Adrenal Cortex Hormones Zona glomerulosa (15%) ○ Aldosterone (mineralocorticoid) production  Sodium and potassium homeostasis Zona fasciculata (60%) ○ Glucocorticoid production (mainly cortisol)  Regulates lipid, carbohydrate, protein metabolism Zona reticularis (25%) ○ Androgen production (testosterone and estradiol)  Influence reproductive system/gender characteristics Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59 HPA Axis Hypothalamic corticotropin-releasing hormone (CRH) is released CRH stimulates release of (ACTH; aka corticotropin) from anterior pituitary ACTH stimulates adrenal cortex to release cortisol Cortisol circulates Adequate [cortisol] then as free and bound “turns off” production via (cortisol binding globulin negative feedback at –CGB) hypothalamus/anterior pituitary Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59 Image from: Harrison’s Principles of Internal Medicine. Chapter 406  Summary of Secretion Regulation Hormone Pituitary secretion Pituitary secretion stimulus inhibition ACTH CRH Cortisol (Neg feedback) GH GHRH GH, IGF-1, somatostatin TSH TRH Thyroid (Neg feedback) Prolactin TRH (minor) Dopamine (major) Lutenizing hormone GnRH Testosterone, estrogen, somatostatin Follicle-stimulating GnRH Testosterone, estrogen hormone Mineralocorticoid Production Controlled by the RAA system AT II receptors abundant in zona glomerulosa Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59 Image from: Harrison’s Principles of Internal Medicine. Chapter 406 Adrenal Gland Disorders Hyperfunction Hypofunction Excess production of Insufficient production adrenal hormones of adrenal hormones Cushing’s Syndrome Addison’s Disease (too much cortisol) ○ (Primary adrenal Hyperaldosteronism insufficiency) (too much aldosterone) ○ Secondary adrenal ○ Primary insufficiency ○ Secondary Hypoaldosteronism (too little aldosterone) Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59  **Cushing’s Syndrome** Hypercortisolism Epidemiology ○ 1-2 cases per 1,000,000 ○ But mild cortisol excess may be more common ○ More common in women (8:1)  Ectopic ACTH syndrome more common in men (3:1) Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59 Harrison’s Principles of Internal Medicine. Chapter 406 Etiology/Risk Factors-Cushing’s ACTH Dependent (80%) ACTH Independent (20%) Iatrogenic Cushing’s Disease ○ Due to exogenous ○ ACTH producing pituitary administration of adenoma glucocorticoids  microadenoma>>>macro Adrenocortical Ectopic ACTH adenoma syndrome Adrenocortical ○ ACTH secretion by non- carcinoma pituitary tumors Other rare causes Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59 Harrison’s Principles of Internal Medicine. Chapter 406 ACTH Secretion Cushing ○ Variable, random ○ Normal to high ACTH ○ Stress response impaired Ectopic ○ Variable, random ○ High ACTH ACTH independent ○ Low ACTH ○ HPA axis intact Glucocorticoid administration do not suppress  Clinical Presentation Clinical presentation as a continuum from mild to severe Milder (earlier in disease) presentations more difficult to diagnose ○ Manifestations may be treated as isolated conditions Severe (prolonged disease duration) presentations easier to diagnose Requires combination of ○ clinical effects followed by ○ diagnostic screening ○ diagnosing etiology (ACTH dependent/independent) Clinical Presentation Central obesity ○ Weight gain ○ Adipose redistribution  Facial rounding  Buffalo hump  Abdomen Hypertension (↑CHD risk) ○ Na/H2O retention ○ ↓ NO synthesis ○ ↑Endothelin, ATII Glucose intolerance (↑CHD risk) ○ Protein catabolism ○ Cortisol insulin suppression ○ Gluconeogenesis Muscular weakness/wasting ○ Protein catabolism Osteoporosis ○ Cortisol inhibits VitD3 actions and formation in kidney; RANKL, OPG ○ Back pain/spinal compression Andronergic ○ Amenorrhea ○ Hirsutism in females ○ Acne, papules Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59 Harrison’s Principles of Internal Medicine. Chapter 406 Clinical Presentation Fibroblast/collagen synthesis inhibition ○ Thin skin ○ Central striae (purple/red)  Fat deposition stretches skin ○ Easy bruising Psychiatric changes ○ Labile mood ○ Poor concentration, memory, sleep ○ Depression/anxiety Immune suppression ○ Inhibits Th1 cytokines, CD4 T-lymphocytes  Treatment Removal of source of hypercortisolism Surgery ○ Treatment of choice for tumors (transphenoidal resection) ○ Steroids are used afterwards Radiation (2nd line after surgery) Adrenalectomy (3rd line) ○ requires lifelong replacement of cortisol/mineralocorticoid ○ Stimulates ACTH excess (Nelson’s syndrome) Drug therapy ○ Adjunctive therapy (surrounding surgery), inoperable cases as palliative therapy, refractory disease ○ 1. Steroidogenesis inhibitors ○ 2. Adrenolytic agents ○ 3. Neuromodulators of ACTH release ○ 4. Glucocorticoid-receptor antagonist Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59 Harrison’s Principles of Internal Medicine. Chapter 406 **Addison’s Disease** AKA Primary Adrenal Insufficiency ○ Etiology at adrenal gland 2 in 10,000 people Pathophysiology: ○ Destruction of all layers of adrenal cortex  ↓ levels of aldosterone, cortisol, androgens ○ 90% destruction before symptomatic ○ Compensatory ↑ CRH, ACTH Etiology: ○ Developing countries  Tuberculosis ○ Developed countries  Autoimmune dysfunction – antibodies to adrenal cortex or 21-hydroxylase  common to have other autoimmune disorders (thyroid)  Acute: thrombosis, hemorrhage, sepsis Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59  **Secondary/Tertiary Adrenal Insufficiency** Pathophysiology: ○ Reduced glucocorticoid production due to decreased ACTH levels (adrenal glands normal) ○ Mineralocorticoid pathway is unaffected – not ACTH dependent Etiology: ○ Exogenous steroid use (oral/IV, inhaled, intranasal, topical) – suppressing HPA axis – when discontinued abruptly ○ Mirtazapine and progestins (megestrol and medroxyprogesterone) ○ Radiation therapy ○ Hypopituitarism Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59 Clinical Presentation Addison’s Disease Secondary Hyperpigmentation (tan look) ○ Especially on skin contact areas May be pale ○ ACTH induces melanocytes Weight loss Aldosterone secretion Dehydration (loss of aldosterone) ○ Hyponatremia is preserved  Salt craving ○ Hyperkalemia Dehydration & ○ Elevated BUN ○ Hypotension hypotension is less Hypoglycemia ○ ↓gluconeogenesis prominent N/V, abd pain Weakness Na and K normal or Myalgia Malaise mild changes Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59  Hyperpigmentation Adrenal Crisis Acute adrenocortical insufficiency Etiology: ○ Abrupt withdrawal of chronic glucocorticoids ○ Major stress  Surgery  Infections  Trauma Signs/Symptoms: ○ Hypotension and shock ○ Myalgias ○ Malaise ○ Anorexia ○ Vomiting ○ Fever Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 5 9 Treatment Addison’s disease ○ Goal of therapy:  Use the lowest effective dose of steroids to achieve a mimic of the normal adrenal rhythm ○ 67% of dose should be in the AM and 33% 6-8 hrs later ○ Stress management: 5-10mg hydrocortisone before vigorous exercise; double daily dose during illness ○ Can add fludrocortisone for mineralcorticoid loss Secondary adrenal insufficiency ○ Steroids but supplemental mineralcorticoid not usually needed Adrenal crisis IV steroids Pharmacotherapy: A Pathophysiologic Approach, 9e. Chapter 59 Questions?