Corticosteroids

Question 1

When is cortisol secretion maximal in 24 hours?

Answer 1

6-8 am

Question 2

Why do we give a single dose of prednisone in the morning?

Answer 2

To mimic natural cortisol physiological effect / mimics normal circadian rhythm of cortisol

Question 3

Where is the corticosteroid receptor located in the cell?

Answer 3

Cytoplasm

Question 4

What is the MoA of corticosteroids?

Answer 4

Corticosteroids penetrate cells and bind to a cytoplasmic receptor. The Drug-Receptor complex enters nucleus and binds to Glucocorticoid Response Elements (GRE) on gene.
GRE acting as transcription factor, regulates the transcription leading to mRNA and protein synthesis.

Question 5

What are the major effects of glucocorticoids?

Answer 5

Affect metabolism, inflammation and immune responses–> 1. Reduced synthesis of COX-2, and cytokines IL-1 to IL-6, IL-8, IL-10, IL-13, TNF, IFN
2. Inhibit function of macrophage and antigen presenting cells 3. Increase lymphocyte apoptosis 4. Inhibit neutrophil migration to tissue 5. Inhibit Phospholipase A2 and 6. Decrease capillary permeability

Question 6

Why does prednisone have salt retention as a side effect?

Answer 6

Bc it has mineralocorticoid activity and a major mineralocorticoid is aldosterone.

Question 7

Does dexamethasone have salt retention effect?

Answer 7

No bc there is no mineralocorticoid activity.

Question 8

What is the anti-inflammation potency sequence for corticosteroid?

Answer 8

Cortisol < prednisone < methylprednisolone = triamcinolone < dexamethasone

Question 9

How many days do we use methylprednisolone intensive therapy?

Answer 9

3 - 5 days

Question 10

Which test is used to differentiate primary and secondary adrenal failure?

Answer 10

Dexamethasone suppression test

Question 11

What are the contraindications for corticosteroids?

Answer 11

Peptic ulcer, Heart disease, HTN w/ heart failure, Varicella, TB, Psychosis, Diabetes,
Osteoporosis, Glaucoma (glucocorticoid increases IOP)

Question 12

What is the mechanism of aminoglutethimide?

Answer 12

Inhibits CYP450 (desmolase), which catalyzes the rate-limiting step of conversion of cholesterol to pregnenolone.
Reduces  biosynthesis of all physiologic steroids.

Question 13

Why can antifungal drug ketoconazole, treat Cushing’s syndrome?

Answer 13

Bc inhibits steroid synthesis (p450 dependent) in high dose in human by inhibiting
17-20 lyase, 17 hydroxylase, 11 hydroxylase, and 3β hydroxysteroid dehydrogenase. Note this is all but 21 hydroxylase.

Question 14

Which receptors are blocked by mifepristone?

Answer 14

Antiprogestin activity on glucocorticoid receptors (anti-glucocorticoid)

Question 15

Fludrocortisone mimics cortisol or aldosterone?

Answer 15

Identical structure to cortisol except for addition of a fluorine atom at the 9α position.

Question 16

How many days are required for prednisone to suppress adrenal?

Answer 16

At least two weeks of continuous intake

Question 17

How do we stop prednisone after 2 weeks use?

Answer 17

Tapered slowly to avoid adverse effects

Question 18

What are the side effects of glucocorticoids?

Answer 18

Adrenal suppression, diabetes, Muscle wasting- corticosteroid induced myopathy, osteoporosis, femur head avascular osteonecrosis, peptic ulcer formation, Inhibition of wound healing, Iatrogenic Cushing’s syndrome, Decreased immunity - opportunistic infection, Dermal atrophy (skin thin and firable), and CNS effects i.e. psychosis, anxiety, insomnia, dementia.

Question 19

What are the symptoms of acute and chronic adrenal failure (Addison’s)?

Answer 19

Acute: life threatening, abdominal / flank pain, confusion, LOC, coma, Dehydration, severe weakness,
High fever, low BP, Rapid heart rate, Rapid respiratory rate, Slow, sluggish movement, and excessive sweating on face or palms
Chronic: Hyperpigmentation, ACTH increase, hypotension, hyperkalemia, ↑blood eosinophil count, fasting hypoglycemia

Question 20

How do you treat acute and chronic adrenal failure (adrenal crisis)?

Answer 20

Acute: increase dose of cortisol/hydrocortisone
Chronic: hydrocortisone (corticosteroid replacement) + fludrocortisone (mineralocorticoid replacement)

Question 21

What receptors are in the nucleus (nuclear receptor)?

Answer 21

Thyroid hormone receptor, PPAR, estrogen