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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
What is the tx of drug induced cushings syndrome?
Removal of the cause (tapering the medication)
26
When are medications used in Cushings?
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
27
What are examples of pharmacotx of Cushing'S?
1. Steroidogenesis Inhibitors - Ketoconazole - Metyrapone - Mitotane 2. Inhibitors of ACTH Secretion - Pasireotide
28
MOA of ketoconazole in Cushing's
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
29
What is the DOC for cushings?
Ketoconazole - effective and adverse effect profile not as bad as others
30
Why is ketoconazole the DOC for Cushings?
Effective and a/e profile not as bad as others
31
Dose of ketoconazole
Start low and titrate based on lab results Typical 200-400 mg TID
32
S/e's of Ketoconazole
GI Upset Gynecomastia Headache Sedation Impotence Increased liver function tests Decreased libidio
33
What are some DI's of ketoconazole?
MANY - CYP 1A2, 2c9, 3A4 - CCB's, cyclosporine, carbamzapine, benzo's, aminoglycosides, protese inhibitors ,PPI, tacrolimus, warfarin
34
Metyrapone MOA
Inhibits the enzyme 11 β-hydroxylase (11-Deoxycortisol --> Cortisol)
35
Metyrapone Uses:
--> if experiencing dose-limiting SEs with ketoconazole (minimize the adverse effects of each – used with ketoconazole) --> as adjunct therapy --> as a diagnostic agent
36
Dose of metyrapone:
Wide range
37
AE's of Metyrapone
significant androgenic AE’s (hirsutism and acne) N/V, abdominal discomfort, headache, dizziness, allergic rash
38
Mitotane MOA
Decreases the synthesis of cortisol by inhibiting the11-hydoxylation of 11-desoxycortisol and 11-desoxycorticosterone Deoxycortisol --> Cortisol deoxycorticosteorne --> corticosterone (aldosterone pathway)
39
Mitotane Indication
Inoperable adrenal carcinoma
40
Mitotane Use
Use: in combination with irradiation, other steroidogenic inhibitors
41
Mitotane Initiation and Dosage
Initiate dosing in hospital b/c: 1) greatly ↓’s cortisol synthesis 2) AE’s
42
MItotane Importaant Clinical Guideline
May have to administer glucocorticoids at the same time
43
Mitotane s/e's
GI: anorexia, N/V/D (80%) Depression, lethargy, somnolence (40-80%) Hypercholesterolemia, rash, hepatotoxicity
44
Are steroidogenic inhibitors used as monotherapy?
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
Pasireotide MOA
Binds to somatostatin receptors. This results in inhibition of ACTH secretion in ACTH-producing adenomas
46
Pasireotide Indication
Surgery not an option or failure of surgery
47
Pasireotide Dose
0.6 to 0.9mg BID subcutaneous injection
48
Pasireotide Billing/Avilability for Patient
Must be enrolled in the Access Program to receive - Private Insurance is important (no public coverage)
49
Pasireotide s/e
hepatotoxicity, CV events (bradycardia; QT-prolongation), hyperglycemia, gall-bladder events
50
Pasireotide Drug Interactions
Caution with antiarrhythmics and drugs that prolong QT interval
51
Other agents for Cushing's
Cyproheptadine Bromocriptine Cabergoline Valproic acid Octreotide Rosiglitazone Tretinoin
52
Aside from cortisol-lowering therapy, pt's may also require......
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
Patient Education
- 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
Addison's disease is also know as.....
Primary Adrenal Insufficiency
55
Define Addison's Disease
A rare disorder in which the adrenal glands cannot synthesize enough glucocorticoids and mineralocorticoids
56
Result of Addison's Disease. When do sx appear?
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
When is Addison's disease usually diagnosed?
Is most commonly first diagnosed in 3rd to 4th decade of life (can be present in infants/kids as well)
58
What causes primary adrenal insufficiency (addisons)?
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
What are some causes of secondary adrenal insufficieny?
Most commonly occurs in those taking chronically administered exogenous corticosteroids --> symptoms occur as a result of abrupt withdrawal of these corticosteroids 2. Other causes: Pituitary, hypothalamic tumours Surgical removal of pituitary Medications
60
What are the categories of Addisons?
Gluco Deficiency Mineralo Deficiency Other
61
What are the signs and symptoms of gluco defieciency?
Fatigue (Most common) Weight Loss Loss of appetite Nauseau, vomitting, abdominal pain Muscle/joint pain Hypotension Depression, others
62
What are the signs of a mineralo deficiency?
Dehydration Postural Hypotension Hypotension
63
What are some other signs of adrenal insufficiency?
- Skin hyperpigmentation - Salt craving Dry/itchy skin Decreased axillary and pubic hair Decreased libidio
64
Lab values of that are often out of range in adrenal insufficiency
Hyponatremia Hyperkalemeia Normochromic Anemia
65
Hyperpigmentation Onset
- Often precedes other sx's by months to years
66
Hyperpigmentation Cause
Caused by high levels of ACTH that bind to the melanocortin 1 receptor on the surface of dermal melanocytes
67
Where is hyperpigmentation most common?
Most prominent on sun-exposed areas, knuckles, elbows, knees, mucous membranes
68
Diagnosis of adrenal insufficiency:
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
What is the treatment of chronic adrenal insufficiency?
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
What is an important consideration in dosing of corticosteroids in adrenal insufficiency? Counselling tip?
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
Is treatment with androgens necessary for adrenal insufficiency? If so, when? Is there a/e?
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
What is an acute adrenal crisis? What are the major causes?
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
Signs and symptoms of acute adrenal crisis? Tx?
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
Treatment of Acute Adrenal Crisis?
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
In a follow up, a pharmacist should monitor for _________ or ___________ treatment? Signs of each?
Signs of undertreatment: Symptom recurrence Nonspecific symptoms (i.e. malaise) Signs of overtreatment: Weight gain Hyperglycemia, hypertension Osteopenia
76
A patient should be couinselled and educated on:
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
T/F: Patients require long-term monitoring/follow-up
True

PHARM 253 Exam 1 (8 decks)

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