Adverse Effects of Glucocorticoids

Question 1

What are 4 main categories of adverse effects of long term glucocorticoid Tx?

Answer 1

1. Fluid/electrolyte imbalances
2. Metabolic Changes
3. Immune Suppression
4. Myopathy

Question 2

How are AE mediated by fluid/electrolyte imbalances?

Answer 2

1. Glucocorticoid excess can stimulate mineralocorticoid actions.

• Direct stimulation of MR by some steroids
• Some evidence of effects (HTN, edema) that are not mediated by MR.

Question 3

How are AE mediated by metabolic changes?

Answer 3

1. Hyperglycemia/ glucosuria

- can be managed w/ diet and insulin.

Question 4

How are AE mediated by immune suppression?

Answer 4

1. Increased susceptibility to infection w/ chronic steroid use.
2. Increased risk of peptic ulcer, esp. in conjunction w/ NSAIDs.

Question 5

How are AE mediated by Myopathy?

Answer 5

1. Can occur w/ both acute, high-dose therapy and chronic therapy.
2. Proximal limb muscle weakness.
3. Can be severe enough to require termination of Tx, and recovery can be slow and incomplete.
4. Mechanism unknown, more common w/ fluorinated glucocorticoids (dexamethasone, triamcinolone)
5. Twice as common in women.

Question 6

What is a frequent and serious complication of glucocorticoid therapy?

Answer 6

1. Glucocorticoid-induced Osteoporosis.
2. 30-50% of all chronically treated patients will develop fractures.
3. Ribs and vertebra are most frequent sites of fractures.

Question 7

How do glucocorticoids decrease bone density?

Answer 7

1. Inhibition of bone formation
   - Suppression of osteoblasts, stimulation of osteoclasts.
2. Suppression of sex steroid hormone synthesis
   - Androgens are especially important here, but androgen/estrogen therapy to maintain bone mass has not been shown effective.
3. Decreased GI absorption of Ca.
   - Compensatory increase in PTH, which promotes bone resorption.
   - Does NOT appear to involve effects on calcitriol synthesis.

Question 8

When does bone loss begin while on glucocorticoids therapy?

Answer 8

1. first 6 months.
2. Pt should have baseline bone density scan upon initiation of therapy.
3. Maintain high Ca intake: 1500 mg/day + Vit D (600 IU/d)
4. Prolonged use of loop diuretics may aggravate fracture risk.

Question 9

What can prevent bone loss?

Answer 9

1. Bisphosphates

• Pyrophosphate analogs, bind Ca in bones and prevent resorption.
• Fosamax (Alendronate) and Actonel (Risendronate) approved for glucocorticoid-induced osteoporosis.

Question 10

What two drugs are approved for Tx of glucocorticoid induced osteoporosis?

Answer 10

1. Fosamax (Alendronate)

2. Actonel (Risendronate)

Question 11

What characterizes Osteonecrosis?

Answer 11

1. Typically affects Femoral Head, Humoral Head and Distal Femur.
2. Relatively common complication of chronic therapy
   - unknown cause
3. Should be considered in patients complaining of joint pain in hip, shoulder, knee.
4. Can occur w/ high doses for short periods.
   - progresses to joint replacement.

Question 12

What characterizes Cataracts (posterior sub-capsular)?

Answer 12

1. Well-established complication of glucocorticoid therapy.
2. Children especially susceptible
3. Cataracts may not regress upon cessation of therapy.
4. Patients on chronic therapy should have regular eye exams.

Question 13

What characterizes behavioral changes?

Answer 13

1. Many forms: nervousness, insomnia, mood, even psychosis.
2. Suicidal tendencies
3. Previous psychiatric illness does not preclude, or predict glucocorticoid induced psychiatric disorders.

Question 14

Can glucocorticoids retard growth in children?

Answer 14

YES

1. effects on growth have been demonstrated w/ low-to-moderate chronic glucocorticoid treatment.
2. Oral steroids are of greatest concern.
   - Use in CAH requires careful monitoring to establish and maintain normal cortisol levels.

Question 15

Why is use of steroids in chronic asthma children a common concern?

Answer 15

1. Inhaled glucocorticoids now shown to cause an initial slowing in growth of prepubertal children.
   - 1.2 cm height deficit in adults
   - slowing is only first 2 years and not cumulative w/ continued use.
2. Cromolyns can be used in place of steroids
   - Also antileukotrienes (Montelukast-sigulair)
3. Use of oral steroids for severe chronic asthma should be adjusted to Minimal Effective Dose.
   - Use of non-steroidal agens can also be included.
   - Cromolyn Na, Nedocromil, Montelukast.

Question 16

Why can sudden withdrawal from glucocorticoid therapy be life-threatening?

Answer 16

1. Acute adrenal insufficiency can occur due to suppression of hypothalamic-pituitary-adrenal axis.
2. Recovery typically takes weeks-months; in some cases up to a year.
   - Patients that have been treated w/ supraphysiological levels of glucocorticoids for 2-4 weeks in previous year may have some level of HPA suppression.
3. Patients are unable to handle stressful situations: surgery,injury, illness.
   - Can experience severe hypotension, NVD, severe pain in lower back and legs.

Question 17

At termination of treatment what is done to the dosing of glucocorticoids?

Answer 17

1. Usually reduced slowly over 1-2 weeks or longer depending on length of treatment.
2. Signs of adrenal insufficiency should be noted:
   - NV, malaise
3. Withdrawal symptoms can also occur.
   - Similar symptoms: fever, muscle, joint pain.
   - rarely, increased intracranial pressure.

Question 18

What is Cushing’s syndrome also called?

Answer 18

Hypercortisolism.

Question 19

What is the Incidence of Cushing’s syndrome?

Answer 19

1. Rare disease

2. 0.7-2.4 cases/million/yr (200-700 cases/yr in US)

Question 20

What is the Etiology of Cushing’s syndrome?

Answer 20

1. Pituitary adenomas are most common cause.
2. Ectopic ACTH syndrome
3. Adrenal Tumors
4. Familial Cushing’s syndrome
5. Drug-induced hypercortisolism- common.

Question 21

What is characteristic of Pituitary adenomas as a cause of cushings syndrome?

Answer 21

Most common cause

1. benign tumors which secrete ACTH.
2. 5-fold more common in women than in men.

Question 22

What is characteristic of Ectopic ACTH syndrome as a cause of Cushings syndrome?

Answer 22

1. ACTH release from non-pituitary tumors.
2. Most commonly lung small-cell carcinoma, carcinoid tumors.
3. 3-fold more common in men
4. Also thymomas, pancreatic islet cell tumors, thyroid carcinomas.

Question 23

What is characteristic of Adrenal Tumors as a cause of Cushing’s syndrome?

Answer 23

1. Non-cancerous adrenal adenomas
   - Typical onset after age 40
2. Rarely, adrenocortical carcinomas

Question 24

What is characteristic of Familial Cushing’s Syndrome?

Answer 24

1. Inherited tendency to develop endocrine gland tumors that secrete cortisol.
2. May be more common than realized in Type 2 DM, obesity, hypertension.

Question 25

What is characteristic of Drug-Induced Hypercortisolism

Answer 25

1. Common 2. Steroid suppression of immune system in transplants. 3. Treatment of severe asthma

Question 26

What are the symptoms of Cushing's?

Answer 26

1. Upper body obesity, rounded (moon) face, thin arms and legs. 2. Children have slowed growth rates. 3. Easily bruised skin; purple stretch marks on abdomen, thighs; weak bones --> rib and spinal fx. 4. Fatigue, weakness, hypertension, hyperglycemia, irritability, anxiety, depression. 5. Hisutism, menstrual irregularity, loss of libido (both)

Question 27

How is Cushing's Diagnosed?

Answer 27

1. Urinary cortisol test: levels >50-100 ug/day 2. CRH stimulation test - CRH increases ACTH and cortisol levels in pituitary adenomas, but not in ectopic and adrenal tumors.

Question 28

How is Hypercortisolism primarily treated?

Answer 28

Surgically - Pituitary tumors, adrenal adenomas, ectopic sources. - Pharmacotherapy can be used in interim or when surgery is not possible.

Question 29

What is first choice agent for treatment of Hypercortisolism?

Answer 29

1. Ketoconazole - Inhibits CYP17 --> prevents/decreases cortisol and androgen. - At higher doses blocks CYP11A1 and 11B1 - 11A1 is needed for all steroids (P450scc) - 11B1 is last step for cortisol synth.

Question 30

What is the dosing for Ketoconazole?

Answer 30

2-3/ day 200-400mg - Monitor serum cortisol or 24hr urinary cortisol for effectiveness. - NOT approved for tx of hypercortisolism (off-label)

Question 31

What is Ketoconazole usually used for?

Answer 31

Treat fungal infections usually systemically.

Question 32

What is the second choice for Hypercortisolism treatment?

Answer 32

1. Metyrapone (Metopirone) - Used mainly in Europe - Inhibits CYP11B1 (cortisol synth) - Can cause increase in androgen, leading to masculinization - Can cause increase in aldosterone leading to salt retention and hypertension. - HIGH doses can block aldosterone synth and cause hypotension.

Question 33

What is the protocol when Metyrapone is combined with ketoconazole for a synergistic effect?

Answer 33

Dosing 3-4 times a day 500mg.

Question 34

What is the third choice for the treatment of hypercortisolism?

Answer 34

1. Mitotane -Adrenocorticolytic drug- mitochondrial toxin -Is a congener of DDT (long banned pesticide) -Causes atrophy of zona fasiculata and reticularis (GC and sex steroid synth) -Mechanism of action unknown - probably a mitochondrial toxin. normally used exclusively in Adrenal Carcinoma. - used when surgery or radiation is not feasible - dosed at bedtime (nausea) - ONLY one that "CURES" --> adrenotoxic

Question 35

What are AE of Ketoconazole?

Answer 35

1. HA, sedation, N/V 2. Inhibition of androgen synthesis in men leads to gynecomastia, decreased libido, impotence. 3. Hepatotoxicity - Monitor biweekly at first, monthly therafter. 4. Teratogenic in animals.

Question 36

What are AE of Metyrapone?

Answer 36

1. Dizziness, HA, sedation, abdominal discomfort, NV | 2. CNS depression.

Question 37

What is a common AE that Ketoconazole and Metyrapone have?

Answer 37

1. Broad P450 Inhibitors. | 2. MANY interactions w/ other drugs metabolized by P450s.

Question 38

What are AE of Mitotane?

Answer 38

1. GI disturbances (anorexia, NV) 80% 2. CNS effects (depression, lethargy) 40% 3. Sequesters into fat - very long lasting effects. 4. Strong inducer of CYP3A4

Question 39

How is Mifepristone used for hypercortisolism?

Answer 39

1. Glucocorticoid receptor antagonist. 2. Blocks effects of cortisol 3. Best known for use in medical abortions (Cat X in preg) 4. Indicated for pts w/ Cushing's syndrome and T2DM or hyperglycemia and who are not candidates for surgery. - Decreases insulin usage, diabetic sx.

Question 40

What are the AE of Mifepristone?

Answer 40

1. Nausea | 2. Peripheral edema, dizziness, loss of appetite.

Question 41

How is Pasireotide used for hypercortisolism?

Answer 41

1. Somatostatin analog that also lowers cortisol levels. 2. Administered s.c. BID APPROVED for hypercortisolism. 3. Often used w/ Cabergoline (DA receptor agonist) 4. Also decreases BP and LDL 5. Significant incidence of hyperglycemia (73%) and new onset diabetes, diarrhea, nausea.