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PHAR 253 > Cushing's Syndrome > Flashcards

Cushing's Syndrome Flashcards

1
Q

What are the 2 major hormones produced by the adrenal glands

A

Cortisol and Aldosterone

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2
Q

What zone of the adrenal gland is cortisol produced in

A

Zona Fasciculata

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3
Q

What zone of the adrenal gland is aldosterone produced in

A

Zona Glomerulosa

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4
Q

What system controls secretion of aldosterone

A

RAAS
also controlled by potassium and adrenocorticotropic hormone (ACTH) to a lesser extent

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5
Q

What is the role of aldosterone in the body

A

Maintain appropriate balance of salt and water while helping to control blood pressure

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6
Q

What stimulates the release of aldosterone

A

drop in blood pressure, salt depletion, and CNS excitation

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7
Q

What are the actions of aldosterone, and what result does this produce

A

it maintains electrolyte (K, Mg, Na) and volume homeostasis, by increasing Na and water retention, and increasing K excretion in the ducts of kidneys
Result - expanded plasma volume, increased B, hypokalemia

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8
Q

What is the primary androgen produced by the adrenal cortex

A

DHEA

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9
Q

What is the role of androgens in the body

A
  • bone density
  • sexual desire and function
  • sex and body maturation
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10
Q

What is the main cause of Cushing’s Syndrome

A

Persistent exposure to excessive glucocorticoids - primarily exogenous use

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11
Q

What is the incidence of Cushing’s Syndrome in steroid users

A

about 10%

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12
Q

Does Cushing’s more commonly affect women or men? at what age would it start to present?

A
  • More common in women
  • Symptoms start to present themselves after 45 years of age
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13
Q

Describe the difference between ACTH dependent and ACTH independent causes of Cushing’s Syndrome

A

ACTH dependent:
- a benign pituitary tumor over-producing ACTH
- a non-pituitary tumor producing ACTH
ACTH independent:
- adrenal gland tumors

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14
Q

What is the clinical name for a pituitary tumor that over produces ACTH

A

Cushing’s disease

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15
Q

In regard to endogenous causes of Cushing’s, what percent are ACTH dependent and independent

A

80% dependent
20% independent

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16
Q

Why is diagnosis of Cushing’s typically difficult

A

wide variety of symptoms mimicking other conditions

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17
Q

If Cushing’s is suspected, what is the 2 step process to confirm a diagnosis

A
  1. Establish if hypercortisolism is present
  2. Establish the cause of hypercortisolism
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18
Q

What tests do we perform to determine if hypercortisolism is present

A
  • urinary free cortisol
  • midnight serum cortisol (taken from saliva)
  • low-dose dexamethasone suppression test (via a specialist)
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19
Q

Once we know a person has hypercortisolism, what tests to we run to determine the cause

A
  • high dose dexamethasone suppression test (via a specialist)
  • plasma ACTH via radioimmunoassay
  • CRH stimulation test
  • Metyrapone stimulation test
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20
Q

What are the clinical features of Cushing’s Syndrome

A

Listed from most to least common:
- obesity/weight gain
- facial redness
- facial rounding
- decreased libido (along with erectile dysfunction)
- thin skin and striae
- irregular periods
- hypertension
- facial hair growth (women)
- depression/emotional lability
- easy bruising
- glucose intolerance
- weakness

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21
Q

What specific signs of Cushing’s could help in distinguishing it from obesity

A
  • Protein wasting: thin skin, unusual bruising, muscle weakness)
  • Suddenly appearing red striae
  • Children: decreased linear growth
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22
Q

What are the 4 goals of treatment for Cushing’s

A
  • remove the source of hypercortisolism
  • restore cortisol secretion to normal
  • reverse clinical features
  • prevent dependency on medications
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23
Q

What is the 5 year survival rate of untreated Cushing’s

A

50%

24
Q

How long does it take for most signs and symptoms to resolve after treatment

A

within 2-12 months

25
Q

What is the primary treatment option for a pituitary adenoma

A

Surgical (transsphenoidal) resection
- may require glucocorticoid replacement therapy after surgery if there is HPA- axis suppression

26
Q

If transsphenoidal resection fails to cure someone of Cushing’s, what are the next 4 options

A
  1. Repeat the surgery
  2. Medication therapy
  3. Radiation therapy
  4. Bilateral adrenalectomy
27
Q

What are the treatment options for adenomas and carcinomas on the adrenal glands

A
  • surgical resection: more successful for adenomas than carcinomas
  • if there are metastases you can try radiation or chemo
28
Q

What makes surgical resection of an ectopic ACTH tumor so difficult, and what percentage of surgeries typically result in a cure

A

There are often multiple tumor sites, only 10-30% are completely cured with surgical resection.

29
Q

If surgical resection of an ectopic ACTH tumor does not completely remove the tumor, what is required as the next step of treatment

A

Post-op medication

30
Q

How do we treat drug induced Cushing’s Syndrome

A

removal of the cause

31
Q

What are the 4 reasons for using medications in treatment for Cushing’s

A
  1. To decrease cortisol levels pre-surgery
  2. As adjunct treatment after unsuccessful surgery or radiation
  3. non-resectable tumors
  4. to help treat severe symptoms
32
Q

What are the 3 steroidogenesis inhibitors we use for Cushing’s

A

Ketoconazole
Metyrapone
Mitotane

33
Q

What is Pasireotide

A

Inhibitor of ACTH secretion

34
Q

What is the mechanism of action of ketoconazole

A

Blocks the synthesis of cortisol in the adrenal gland via inhibition of 11 beta and 17 alpha hydroxylase

35
Q

Why is ketoconazole the drug of choice for Cushing’s

A

Effective and it’s adverse effect profile is not as bad as other medications

36
Q

What is the dose of ketoconazole for Cushing’s

A

Typical dose is 200-400mg. Start low and titrate based on lab results

37
Q

What are the side effects of ketoconazole

A
  • GI upset
  • gynecomastia
  • headache
  • sedation
  • impotence
  • increased LFT’s
  • decreased libido
38
Q

What enzymes does ketoconazole interact with

A

1A2
2C9
3A4

39
Q

What medications does ketoconazole interact with

A

CCBs
cyclosporine
carbamazepine
benzodiazepines
aminoglycosides
protease inhibitors
PPIs
Tacrolimus
Warfarin

40
Q

What is metyrapones mechanism of action

A

Inhibits 11 beta hydroxylase, preventing the conversion of 11 deoxycortisol to cortisol

41
Q

What are the 3 uses of metyrapone in regard to Cushing’s

A
  1. If experiencing dose-limiting side effects with ketoconazole (used in combo with keto if need to lower keto dose due to s/e’s)
  2. As adjunct therapy
  3. As a diagnostic agent
42
Q

True or false: There’s a wide dosing range for metyrapone

A

True

43
Q

What are the adverse effects of metyrapone

A
  • androgenic (hirsutism and acne)
  • N/V, abdominal discomfort
  • headache
  • dizziness
  • allergic rash
44
Q

What is the mechanism of action of Mitotane

A

Decreases the synthesis of cortisol by inhibiting the hydroxylation of 11 desoxycortisol and 11 desoxycorticosterone

45
Q

What is the indication for the use of mitotane

A

inoperable adrenal carcinoma

46
Q

How do we use mitotane? (alone?,combo?,with what?)

A

Used in combination with irradiation and other steroidogenic inhibitors

47
Q

Why do we use mitotane only in the hospital?

A
  1. Greatly decreases cortisol synthesis
  2. large adverse effect profile
  3. high risk of toxicity, patient needs to be monitored
48
Q

What are the side effects of mitotane

A
  • GI: anorexia, N/V/D (80%)
  • depression, lethargy, somnolence (40-80%)
  • hypercholesterolemia, rash, hepatotoxicity
49
Q

Are steroidogenic inhibitors effective as monotherapy long term?

A

No, they are often combined with one another if not providing adequate response on their own

50
Q

What is the mechanism of action of Pasireotide (Signifor)

A

binds to somatostatin receptors. resulting in inhibition of ACTH secretion in ACTH-producing adenomas

51
Q

What is the indication of pasireotide

A

when surgery isn’t an option or surgery has failed

52
Q

What is the dose and route of administration of pasireotide

A

0.6 - 0.9mg BID subcutaneous injection

53
Q

Why is pasireotide only available through the special access program

A

it has some severe side effects:
- hepatotoxicity
- CV events
- hyperglycemia
- gall bladder events

54
Q

What drugs does pasireotide interact with

A

antiarrhythmics and drugs that prolong QT interval

55
Q

What are 8 other medications that Cushing’s patients might need to be on, aside from cortisol lowering drugs

A
  1. antihypertensives
  2. spironolactone
  3. anticoagulants
  4. calcium regulators
  5. antidepressants
  6. growth hormones (for children)
  7. thyroid supplements
  8. antihyperglycemics
56
Q

What is the purpose of spironolactone in patients with Cushing’s

A

mineralocorticoid levels can also rise, spironolactone is an aldosterone antagonist and would keep these levels stable

57
Q
A

PHAR 253 (3 decks)

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