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PHARM 253 Exam 1 > Cushing's and Addison's > Flashcards

Cushing's and Addison's Flashcards

1
Q

What is the function of the adrenal glands?

A

Produce hormones that react to stressors (illness/injury), regulate how fats, proteins and CHO are converted to energy, regulate BP, help control BG, and help control kidney function

Stress Response
metabolism
Blood Glucose, Blood Pressure
Kidney Function

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2
Q

What hormones are produced by the adrenal glands?

A

The 2 major hormones produced are cortisol and aldosterone; others are androgens and adrenaline

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3
Q

Where is adrenaline produced in the adrenals?

A

Adrenal Medulla

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4
Q

What is cortisol?

A

The “stress hormone”
Is secreted in higher levels in response to stress, and in normal release, it helps restore homeostasis after stress

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5
Q

What are some of the actions of cortisol?

A

Has many actions which may or may not be beneficial in excess ranging from immunosuppressive properties, to anti-inflammatory activity, to actions on BG and bone

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6
Q

What is the major mineralcorticoid secreted by the adrenals?

A

ALDOSTERONE

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7
Q

What controls aldosterone secretion? How is it’s release stimulated?

A

Secretion is mainly controlled by the RAAS; less so by potassium, then ACTH (decreasing importance)

It’s release is stimulated by: bp lowering, salt depletion, & CNS excitation

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8
Q

What is the main functions of aldosterone?

A

Helps maintain the right balance of salt and water while helping control BP

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9
Q

What are the actions of aldosterone and its result?

A

It maintains electrolyte (potassium, magnesium, sodium) and volume homeostasis

↑’s Na & H2O retention and K+ excretion in dct’s of kidney

Result: expanded plasma volume, elevated BP, hypokalemia

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10
Q

The adrenal are a ________ production site for ___________

A

Secondary site for androgen synthesis (primary site is the testes and ovaries)

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11
Q

What is the main androgen produced by the adrenal glands? When is it released?

A

Primarily DHEA (Dehydroepiandrosterone)

Release is increased with puberty, decreased with aging

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12
Q

What are androgens responsiblefor?

A
  • Androgens help with bone density, sexual desire and function, sex and body maturation amongst others
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13
Q

What is cushing’s syndrome?

A

A disorder caused by persistent exposure to excessive glucocorticoids (exogenous or endogenous) – orally or body production

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14
Q

What is the primary cause of Cushings? The rate of incidence is highest in……

A
  • Exogenous corticosteroid usage
  • Women > Men
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15
Q

What is the etyiology of Cushings?

A

Cushings results from the effects of excess cortisol levels originating from:

  1. Endogenous overproduction

A. ACTH dependent; 80% (main)
… a benign pituitary tumour over-producing ACTH (Cushing’s Disease)
… by an ectopic ACTH source (e.g. non-pituitary tumour in the lungs – may or may not be cancerous)

B. ACTH independent; 20%
… by adrenal gland tumours

  1. Exogenous administration of corticosteroids
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16
Q

How is Cushings diagnosed?

A

Often difficult and delayed because it mimics other conditions
Based on clinical history and testing of HPA axis
Must know their medical history

A 2-step process if Cushing’s Syndrome is suspected:

  1. Establish if hypercortisolism is present
    Urinary free cortisol
    Midnight serum cortisol [ ] or salivary cortisol [ ]
    Low-Dose dexamethasone suppression test
  2. Establish the cause
    High-dose dexamethasone suppression test
    Plasma ACTH via radioimmunoassay
    CRH stimulation test
    Metyrapone stimulation test
    Others…..
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17
Q

What are some clinical features of cushings?

A

Obesity/Weight Gain
Facial Plethora
Rounded Face/Buffalo Hump
Decreased Libidio
Thin Skin
Decreased linear growth in children
Menstrual Irregularity
HTN
Hirutism (excess hair growth)
Depression
Muscle Weakness
Osteosoporosis
Poor Skin Healing (Skin Ulcers)

(progressive obesity and skin changes, acne, straie, fatigue, erectile ndysfunction)

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18
Q

What are some signs that may help distinguish Cushings from obesity?

A

Protein wasting:
Thin skin
Unusual bruising
Muscle weakness

Suddenly appearing red striae

Children: decreased linear growth especially evident

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19
Q

What are the tx goals of Cushings?

A

Remove the source of hypercortisolism
Restore cortisol secretion to normal
Reverse clinical features
Prevent dependency on medications

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20
Q

What is the prognosis of cushings? When will sx resolve?

A

Left untreated –> high morbidity and mortality (5yr survival rate of 50%)

With appropriate tx, most signs and sx’s will resolve within 2-12 months (20yr survival rate of 87%)

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21
Q

Overall, what is the main purpose of treatment of Cushings?

A

Treatment is aimed at removing the cause

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22
Q

What is the tx of a pituitary adenoma? What may pt’s need afterwards? What if it fails?

A

Surgical (transphenoidal) resection

Patients may require glucocorticoid-replacement therapy post-surgery if there is HPA axis suppression

When patients are not cured by transsphenoidal resection, the following options are available:

a) repeat the transsphenoidal surgery
b) medication therapy
c) radiation therapy
d) bilateral adrenalectomy

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23
Q

What is the tx of adrenal tumours? Which has more favourable outcomes: adenomas and carcinomas? What if metasteses?

A

Surgical resection

Adenomas (benign) have a favorable outcome; carcinomas do not (malignant)

If there are metastases – can try radiation, chemotherapy

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24
Q

What is the tx of ectopic ACTH syndrome?

A

Multiple tumour sites often exist; therefore 10-30% are cured with surgical removal and remaining 70-90% require post-op medication

Hypercortisolism can be controlled with pharmacologic therapy

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25
Q

What is the tx of drug induced cushings syndrome?

A

Removal of the cause (tapering the medication)

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26
Q

When are medications used in Cushings?

A

Medications are used:
To ↓ cortisol levels pre-surgery
As adjunct tx after unsuccessful surgery or radiation
For non-resectable tumours
To help treat severe sx’s

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27
Q

What are examples of pharmacotx of Cushing’S?

A
  1. Steroidogenesis Inhibitors
    - Ketoconazole
    - Metyrapone
    - Mitotane
  2. Inhibitors of ACTH Secretion
    - Pasireotide
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28
Q

MOA of ketoconazole in Cushing’s

A

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

11 Beta –> 11-deoxycortisol - cortisol

17 Alpha –> progesteron –> 17 hydroxyprogesterone

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29
Q

What is the DOC for cushings?

A

Ketoconazole - effective and adverse effect profile not as bad as others

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30
Q

Why is ketoconazole the DOC for Cushings?

A

Effective and a/e profile not as bad as others

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31
Q

Dose of ketoconazole

A

Start low and titrate based on lab results

Typical 200-400 mg TID

32
Q

S/e’s of Ketoconazole

A

GI Upset
Gynecomastia
Headache
Sedation
Impotence
Increased liver function tests
Decreased libidio

33
Q

What are some DI’s of ketoconazole?

A

MANY

  • CYP 1A2, 2c9, 3A4
  • CCB’s, cyclosporine, carbamzapine, benzo’s, aminoglycosides, protese inhibitors ,PPI, tacrolimus, warfarin
34
Q

Metyrapone MOA

A

Inhibits the enzyme 11 β-hydroxylase (11-Deoxycortisol –> Cortisol)

35
Q

Metyrapone Uses:

A

–> if experiencing dose-limiting SEs with ketoconazole (minimize the adverse effects of each – used with ketoconazole)
–> as adjunct therapy
–> as a diagnostic agent

36
Q

Dose of metyrapone:

A

Wide range

37
Q

AE’s of Metyrapone

A

significant androgenic AE’s (hirsutism and acne)
N/V, abdominal discomfort, headache, dizziness, allergic rash

38
Q

Mitotane MOA

A

Decreases the synthesis of cortisol by inhibiting the11-hydoxylation of 11-desoxycortisol and 11-desoxycorticosterone

Deoxycortisol –> Cortisol

deoxycorticosteorne –> corticosterone (aldosterone pathway)

39
Q

Mitotane Indication

A

Inoperable adrenal carcinoma

40
Q

Mitotane Use

A

Use: in combination with irradiation, other steroidogenic inhibitors

41
Q

Mitotane Initiation and Dosage

A

Initiate dosing in hospital b/c:
1) greatly ↓’s cortisol synthesis
2) AE’s

42
Q

MItotane Importaant Clinical Guideline

A

May have to administer glucocorticoids at the same time

43
Q

Mitotane s/e’s

A

GI: anorexia, N/V/D (80%)

Depression, lethargy, somnolence (40-80%)

Hypercholesterolemia, rash, hepatotoxicity

44
Q

Are steroidogenic inhibitors used as monotherapy?

A

No

Not usually effective as monotherapy long-term (why you may see ketoconazole and mytyropone being used together)

Are often combined with one another if not providing adequate response on their own

45
Q

Pasireotide MOA

A

Binds to somatostatin receptors. This results in inhibition of ACTH secretion in ACTH-producing adenomas

46
Q

Pasireotide Indication

A

Surgery not an option or failure of surgery

47
Q

Pasireotide Dose

A

0.6 to 0.9mg BID subcutaneous injection

48
Q

Pasireotide Billing/Avilability for Patient

A

Must be enrolled in the Access Program to receive

  • Private Insurance is important (no public coverage)
49
Q

Pasireotide s/e

A

hepatotoxicity, CV events (bradycardia; QT-prolongation), hyperglycemia, gall-bladder events

50
Q

Pasireotide Drug Interactions

A

Caution with antiarrhythmics and drugs that prolong QT interval

51
Q

Other agents for Cushing’s

A

Cyproheptadine
Bromocriptine
Cabergoline
Valproic acid
Octreotide
Rosiglitazone
Tretinoin

52
Q

Aside from cortisol-lowering therapy, pt’s may also require……

A

Antihypertensives

Spironolactone: can also get high amounts of mineralocorticoid production, and spironolactone is an aldosterone antagonist

Anticoagulants
Calcium Regulators
Antidepressants –> affects mood
Growth Hormones (children)

Thyroid Supplements –> affects other autoimmune systems

Antihyperglycemic medications –> BG goes up

53
Q

Patient Education

A
  • Be supportive
  • Reinforce cortisol level lab work.
  • Monitor for cortisol insufficiency and resolevement of hypercortiolism
  • Ensure proper corticosteroid counselling if on temporary glucocorticoids
  • Be sure patients are aware of signs of adrenal crisis
  • FOLLOW UP IS NECESSARY
54
Q

Addison’s disease is also know as…..

A

Primary Adrenal Insufficiency

55
Q

Define Addison’s Disease

A

A rare disorder in which the adrenal glands cannot synthesize enough glucocorticoids and mineralocorticoids

56
Q

Result of Addison’s Disease. When do sx appear?

A

Destruction of all 3 zones of the adrenal glands

Signs & Sx’s appear when ≥90% of the adrenal cortex is destroyed, and are a result of deficiencies in cortisol, aldosterone, and androgens

57
Q

When is Addison’s disease usually diagnosed?

A

Is most commonly first diagnosed in 3rd to 4th decade of life (can be present in infants/kids as well)

58
Q

What causes primary adrenal insufficiency (addisons)?

A

Autoimmune-mediated destruction of the adrenal cortex (North America)

Infectious diseases: (other parts of the world)
*TB, HIV, CMV, fungal infections

Tumours

Hemorrhage (bleeding into the adrenals)

Injury to adrenal glands

59
Q

What are some causes of secondary adrenal insufficieny?

A

Most commonly occurs in those taking chronically administered exogenous corticosteroids
–> symptoms occur as a result of abrupt withdrawal of these corticosteroids

  1. Other causes:
    Pituitary, hypothalamic tumours
    Surgical removal of pituitary
    Medications
60
Q

What are the categories of Addisons?

A

Gluco Deficiency
Mineralo Deficiency
Other

61
Q

What are the signs and symptoms of gluco defieciency?

A

Fatigue (Most common)
Weight Loss
Loss of appetite
Nauseau, vomitting, abdominal pain
Muscle/joint pain
Hypotension
Depression, others

62
Q

What are the signs of a mineralo deficiency?

A

Dehydration
Postural Hypotension
Hypotension

63
Q

What are some other signs of adrenal insufficiency?

A
  • Skin hyperpigmentation
  • Salt craving
    Dry/itchy skin
    Decreased axillary and pubic hair
    Decreased libidio
64
Q

Lab values of that are often out of range in adrenal insufficiency

A

Hyponatremia
Hyperkalemeia
Normochromic Anemia

65
Q

Hyperpigmentation Onset

A
  • Often precedes other sx’s by months to years
66
Q

Hyperpigmentation Cause

A

Caused by high levels of ACTH that bind to the melanocortin 1 receptor on the surface of dermal melanocytes

67
Q

Where is hyperpigmentation most common?

A

Most prominent on sun-exposed areas, knuckles, elbows, knees, mucous membranes

68
Q

Diagnosis of adrenal insufficiency:

A
  1. Clinical presentation (signs and symptoms)
    Patients complain of persistent vague sx’s, especially in presence of other autoimmune dx
    Usually presents gradually with nonspecific symptoms; up to 25% present with adrenal crisis
  2. Lab tests
    >90% present with biochemical abnormalities:
    Hyponatremia, hyperkalemia, ↑ BUN, hypoglycemia, mild anemia, elevated plasma creatinine, neutropenia….
  3. Cortisol levels
    Short ACTH Stimulation Test (cosyntropin test)
  4. Medical Imaging
69
Q

What is the treatment of chronic adrenal insufficiency?

A

Requires daily glucocorticoid and mineralocorticoid replacement

  1. Glucocorticoids:
    DOC: HC, cortisone, prednisone, dexamethasone
    E.g. HC 15-30mg/d
    E.g. Cortisone acetate 20-35mg/d
    Dose adjustments based on patient well-being, BP, weight
    A ↓ in hyperpigmentation is a good marker (good markers for that’s the correct dose)
    Dosed 2-3x per day with majority of dose in the am
  2. Mineralocorticoids:
    Fludricortisone 0.05 to 0.1mg qd (range 0.05 to 0.2mg/d)
    Titrate dose based on BP, Na and K levels
70
Q

What is an important consideration in dosing of corticosteroids in adrenal insufficiency? Counselling tip?

A

Strenuous activities or events require the use of supplemental glucocorticoid dosing (double or triple the dose)

Examples:
Strenuous exercise: Add 5-10mg HC
Minor febrile illness or trauma: Double dose until recovery
Emergency self-treatment necessary: HC 75mg-300mg/d IM in divided doses→ seek care ASAP

It is important to always have extra glucocorticoid (oral or IM HC) doses on hand

71
Q

Is treatment with androgens necessary for adrenal insufficiency? If so, when? Is there a/e?

A

Adrenal cortex is the primary source of DHEA & androgens in WOMEN

If low libido is also present despite CS replacement, a trial of DHEA could be considered
Treatment: DHEA 25-50mg/d
Can be compounded

AE’s: sweat odour, acne, hirsutism, itchy scalp

72
Q

What is an acute adrenal crisis? What are the major causes?

A

A true emergency – can be precipitated by anything that increase’s adrenal requirements (especially if an underlying deficiency)

Most occur with abrupt steroid withdrawal, or lack of appropriate stress-dosing (not taking enough)

73
Q

Signs and symptoms of acute adrenal crisis? Tx?

A

Signs and sx’s are indicative of gluco & mineralo- deficiency:

Profound N/V, anorexia
Tachycardia Severe dehydration
Severe fever Hypoglycemia
Biochemical changes Deteriorating mental status
Hypotension, shock unresponsive to vasopressors

If suspected, treatment is initiated with empiric glucocorticoid & supportive therapy ASAP

74
Q

Treatment of Acute Adrenal Crisis?

A

Requires prompt administration of IV glucocorticoids and fluid resuscitation

Parenteral glucocorticoids for gluco deficiency

HC is 1st choice due to combined gluco and mineralo activity
Eg. 300mg HC IV over 24h x2-3d, then dose decrease over the next week eventually to daily oral replacement doses

Fluid replacement (5% dextrose / normal saline) given at a rate to support blood pressure

Fludricortisone is initiated when patient able to eat/drink and HC dose is decreased (dose 0.05 to 0.1mg/d)

75
Q

In a follow up, a pharmacist should monitor for _________ or ___________ treatment? Signs of each?

A

Signs of undertreatment:
Symptom recurrence
Nonspecific symptoms (i.e. malaise)

Signs of overtreatment:
Weight gain
Hyperglycemia, hypertension
Osteopenia

76
Q

A patient should be couinselled and educated on:

A

Seriousness of disease
Importance of adherence
Medication effects/ SE”s (under and over tx)
Have extra meds, glucocorticoid injection on hand
Recognizing worsening of condition
Importance of wearing a Medic Alert bracelet

77
Q

T/F: Patients require long-term monitoring/follow-up

A

True

PHARM 253 Exam 1 (8 decks)

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