Adrenal Pharmacology

Question 1

What are the layers of the adrenal glands and their major output?

Answer 1

• glomerulosa (aldosterone)
• fasciculata (cortisol)
• reticularis (sex steroids)
• medulla (catecholamines)

Question 2

What is Addison disease?

Answer 2

• primary adrenal insufficiency, most often due to autoimmune destruction of the adrenal gland
• but can be due to a pituitary or hypothalamic issue

Question 3

List several causes of Addison disease.

Answer 3

• autoimmune destruction is most common in the US
• infection, particularly from TB and AIDS, is most common in the developing world
• metastatic carcinoma, typically from the lung
• adrenoleukodystrophy (build up of LCFA in the gland)

Question 4

Acute Adrenal Insufficiency

Answer 4

• acute onset deficiency which presents as weakness and shock
• often due to withdrawal of glucocorticoids, treatment of Cushing syndrome, or Waterhouse-Friderichsen syndrome

Question 5

What is Waterhouse-Friderichsen syndrome?

Answer 5

a hemorrhagic necrosis of the adrenal glands due to sepsis and DIC, most often in young children with Neisseria meningitidis infection

Question 6

What is secondary adrenal insufficiency?

Answer 6

adrenal insufficiency due to adrenal gland atrophy secondary to an ACTH deficiency

Question 7

How is a diagnosis of adrenal insufficiency made?

Answer 7

• a finding of low morning cortisol levels

- unresponsive to CRH or ACTH stimulation

Question 8

How do primary Addison disease present?

Answer 8

• vague, progressive symptoms of weakness, fatigue, nausea, vomiting, weight loss, and MSK pains
• lack of aldosterone contributes to hyponatremia, hyperkalemia, and low blood volume
• lack of cortisol contributes to hypotension because its absence lowers a1-receptor expression
• lack of sex hormones leads to a loss of axillary and pubic hair in women
• high compensatory ACTH is often shunted toward MSH (another POMC derivative), leading to hyperpigmentation of skin creases and areas exposed to light/pressure

Question 9

How do primary, secondary, and tertiary Addision disease differ?

Answer 9

• primary: excess ACTH leads to hyper pigmentation and low aldosterone leads to a hyperkalemia
• secondary: there is no excess ACTH or lack of aldosterone so no hyperpigmentation or hyperkalemia; instead ACTH levels are low and don’t respond to a metyrapone stimulation test
• tertiary: there is no excess ACTH or lack of aldosterone so no hyperpigmentation or hyperkalemia; instead, ACTH levels are low but respond to a CRH stimulation test

Question 10

How are acute and chronic adrenal insufficiency treated?

Answer 10

• acute: IV fluids and high-dose glucocorticoids
• chronic: oral glucocorticoid replacement, mineralocorticoid replacement if primary adrenal insufficiency, and patient education
• patients with chronic need to know to increase dosage during periods of stress and surgery and provided with an injectable form for instances when vomiting precludes oral replacement therapy

Question 11

Compare hydrocortison, prednisone, fludrocortisone, and dexamethasone for the treatment of adrenal insufficiency.

Answer 11

• hydrocortison: 1:1 anti-inflammatory to mineralocorticoid activity but requires twice daily dosing
• prednisone: mildly favors anti-inflammatory activity and requires just once daily dosing
• fludrocortisone: heavily favors mineralocorticoid activity
• dexamethasone: heavily favors anti-inflammatory activity

Question 12

How does treatment for adrenal insufficiency change during periods of illness or before surgery?

Answer 12

when the patient is ill or anticipating surgery, he or she should double the current dose for three days

Question 13

All glucocorticoid receptors share what features?

Answer 13

they interact with promoters and regulate the transcription of target genes

Question 14

What are the physiologic effects of cortisol?

Answer 14

vasoconstriction via up regulation and activation of a1-receptors, increasing blood pressure

Question 15

What are the physiologic effects of glucocorticoids?

Answer 15

• works to keep serum glucose high
• does so by stimulating gluconeogenesis and glycogen synthesis
• inhibits uptake of glucose into the muscle
• stimulates hormone sensitive lipase and induces lipolysis

Question 16

Which steroid mimics the diurnal rhythm of endogenous steroids the best?

Answer 16

hydrocortisone because of its 12 hour half life and twice daily dosing

Question 17

Which steroid replacement therapies are long-acting? Who are these most beneficial for? What is the downside?

Answer 17

• dexamethasone and prednisone
• best for patients that are non-compliant
• problem is they have greater inter-individual variability and the best dose is often difficult to predict

Question 18

Fludrocortisone

Answer 18

• a potent steroid with mainly mineralocorticoid effects
• generally given to individuals with primary adrenal insufficiency, who have little or no aldosterone
• improves sodium retention in the kidneys
• most common side effect is hypokalemia

Question 19

What are the side effects of exogenous steroids?

Answer 19

• immunosuppression
• hypertension
• weight gain and redistribution of body fat
• osteoporosis
• insomnia
• mood swings
• peptic ulcers
• thinning of skin
• retarded growth in children

Question 20

If glucocorticoids are meant to induce lean, linear growth, why do they have many catabolic side effects?

Answer 20

because at super physiologic levels they become catabolic with decreased muscle mass, weakness, thinning of skin, and osteoporosis

Question 21

Cushing’s Disease

Answer 21

• an excess of cortisol, either endogenous or exogenous
• presents with muscle weakness and thin extremities, moon facies, buffalo hump, truncal obesity, abdominal striae, hypertension with hypokalemia and metabolic alkalosis, osteoporosis, and immune suppression
• diagnosis is made on the basis of increased 24-hours urine cortisol, increased late night salivary cortisol, and no response to a low-dose dexamethasone suppression test

Question 22

How does cortisol cause immune suppression?

Answer 22

• inhibits phospholipase A2, limiting the production of arachidonic acid metabolites
• it inhibits IL-2
• it inhibits mast cell degranulation

Question 23

What does cortisol induce hypertension with hypokalemia and metabolic acidosis?

Answer 23

• because at high concentration, it can cross react with mineralocorticoid receptors and function like aldosterone
• additionally, it increases the sensitivity of peripheral vessels to catecholamines, increasing tone

Question 24

How would a normal individual respond to a low dose dexamethasone suppression test?

Answer 24

there would be a decline in cortisol production

Question 25

What is the late evening salivary cortisol level used for?

Answer 25

- to help diagnose Cushing's syndrome - normal evening nadir in serum cortisol is unaffected in obese and depressed patients but levels will be elevated in those with Cushing's syndrome

Question 26

Ketoconazole

Answer 26

- a nonselective inhibitor of adrenal and gonadal steroids, which functions by blocking enzymes in the cortisol pathway - can cause headaches, sedation, and nausea - also have potential hepatotoxicity in larger doses or those with pre-existing hepatic disease

Question 27

Mitotane

Answer 27

- a nonselective cytotoxic agent of the adrenal cortex - reserved for patients with adrenal carcinoma - severe toxicity is common and is likely to present with diarrhea, nausea, vomiting, and depression

Question 28

Mifepristone

Answer 28

- a glucocorticoid receptor antagonist which is rapidly effective for treating diabetes related to Cushing's disease - improves metabolic status quickly and in most patients - side effects include profound hypokalemia and QT prolongation

Question 29

Primary Aldosteronism

Answer 29

- an excess of aldosterone - often due to bilateral adrenal hyperplasia, adrenal adenoma, or carcinoma - presents with asymptomatic hypertension and unprovoked or easily provoked hypokalemia - some patients complain of a hypokalemic alkalosis with fatigue, muscle weakness, paresthesia, and orthostatic hypotension - best screening test is plasma aldosterone and plasma renin activity (PA/PRA > 20 indicates primary aldosteronism while <10 indicates a secondary aldosteronism) - confirm the diagnosis with a 24-hour urine aldosterone in the setting a high sodium diet (should be low but is elevated) - can also confirm with a salt loading test: measure PA/PRA before and after 2L saline, normally PA would be suppressed - can differentiate from extrarenal loss of potassium if you find excess potassium in the urine of a hypokalemic patient, and this indicates mineralocorticoid excess - differentiate between an adenoma and adrenal hyperplasia using imaging or venous sampling (unilateral gradient points to adenoma)

Question 30

What is secondary hyperaldosteronism?

Answer 30

- excess aldosterone due to increased plasma-renin activity | - most often due to renal artery stenosis

Question 31

How is primary hyperaldosteronism treated?

Answer 31

- removal of adenoma if present - dietary salt restriction - use of an aldosterone receptor blockade (spironolactone or eplerenone)

Question 32

Spironolcatone

Answer 32

- a mineralocorticoid (aldosterone) antagonist - used in the treatment of hyperaldosteronism to limit potassium loss and lower blood pressure - slow onset (2-3 days) - may cause a hyperkalemia and gynecomastia (by activating a steroid receptor in the breast tissue)

Question 33

Eplerenone

Answer 33

- a mineralocorticoid (aldosterone) antagonist - used in the treatment of hyperaldosteronism to limit potassium loss and lower blood pressure - slow onset (2-3 days) - may cause a hyperkalemia but doesn't cause gynecomastia

Question 34

Congenital Adrenal Hyperplasia

Answer 34

- a group of AR disorders that result from a deficiency of an enzyme required for synthesis of cortisol in the adrenal cortex - in all cases, low cortisol increases ACTH production, which stimulates adrenal hyperplasia - most cases are due to a 21-hydroxylase deficiency - 11-hydroxylase and 17-hydroxylase deficiencies are also described

Question 35

21-Hydroxylase Deficiency

Answer 35

- a congenital adrenal hyperplasia (autosomal recessive) in which there is a full or partial blockade of glucocorticoid and mineralocorticoid production - instead those precursors are shunted into the androgen pathway, causing androgen excess - presents as hyponatremia and hyperkalemia with life-threatening hypotension, some hyperpigmentation, rapid somatic growth, advanced bone age, and premature epiphyseal fusion and short stature, and acne - precocious puberty in males or ambiguous genitalia with enlarged clitoris, partially fused labia major, and urogenital sinus in women - treated with glucocorticoids to reduce ACTH levels, suppressing androgen synthesis - don't use glucocorticoids in asymptomatic children or those with non-classic CAH - add a mineralocorticoid in the salt-wasting form