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IC 1.0 > Adrenal Pharmacology > Flashcards

Adrenal Pharmacology Flashcards

1
Q

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

A
  • glomerulosa (aldosterone)
  • fasciculata (cortisol)
  • reticularis (sex steroids)
  • medulla (catecholamines)
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2
Q

What is Addison disease?

A
  • primary adrenal insufficiency, most often due to autoimmune destruction of the adrenal gland
  • but can be due to a pituitary or hypothalamic issue
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3
Q

List several causes of Addison disease.

A
  • 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)
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4
Q

Acute Adrenal Insufficiency

A
  • acute onset deficiency which presents as weakness and shock
  • often due to withdrawal of glucocorticoids, treatment of Cushing syndrome, or Waterhouse-Friderichsen syndrome
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5
Q

What is Waterhouse-Friderichsen syndrome?

A

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

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6
Q

What is secondary adrenal insufficiency?

A

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

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7
Q

How is a diagnosis of adrenal insufficiency made?

A
  • a finding of low morning cortisol levels

- unresponsive to CRH or ACTH stimulation

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8
Q

How do primary Addison disease present?

A
  • 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
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9
Q

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

A
  • 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
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10
Q

How are acute and chronic adrenal insufficiency treated?

A
  • 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
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11
Q

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

A
  • 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
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12
Q

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

A

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

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13
Q

All glucocorticoid receptors share what features?

A

they interact with promoters and regulate the transcription of target genes

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14
Q

What are the physiologic effects of cortisol?

A

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

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15
Q

What are the physiologic effects of glucocorticoids?

A
  • 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
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16
Q

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

A

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

17
Q

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

A
  • 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
18
Q

Fludrocortisone

A
  • 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
19
Q

What are the side effects of exogenous steroids?

A
  • immunosuppression
  • hypertension
  • weight gain and redistribution of body fat
  • osteoporosis
  • insomnia
  • mood swings
  • peptic ulcers
  • thinning of skin
  • retarded growth in children
20
Q

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

A

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

21
Q

Cushing’s Disease

A
  • 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
22
Q

How does cortisol cause immune suppression?

A
  • inhibits phospholipase A2, limiting the production of arachidonic acid metabolites
  • it inhibits IL-2
  • it inhibits mast cell degranulation
23
Q

What does cortisol induce hypertension with hypokalemia and metabolic acidosis?

A
  • 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
24
Q

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

A

there would be a decline in cortisol production

25
Q

What is the late evening salivary cortisol level used for?

A
  • 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
26
Q

Ketoconazole

A
  • 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
27
Q

Mitotane

A
  • 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
28
Q

Mifepristone

A
  • 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
29
Q

Primary Aldosteronism

A
  • 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)
30
Q

What is secondary hyperaldosteronism?

A
  • excess aldosterone due to increased plasma-renin activity

- most often due to renal artery stenosis

31
Q

How is primary hyperaldosteronism treated?

A
  • removal of adenoma if present
  • dietary salt restriction
  • use of an aldosterone receptor blockade (spironolactone or eplerenone)
32
Q

Spironolcatone

A
  • 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)
33
Q

Eplerenone

A
  • 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
34
Q

Congenital Adrenal Hyperplasia

A
  • 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
35
Q

21-Hydroxylase Deficiency

A
  • 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

IC 1.0 (24 decks)

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