Adrenal steroids and Immunopharmacology

Question 1

Explain the layers of adrenal cortex and the synthesis of aldosterone and cortisol.

Answer 1

Cortex layers from superficial to deeper: zona glomerulosa, fasiculata, reticularis

Aldosterone (GLOMERULOSA): cholesterol -> pregnenolone -> deoxycorticosterone -> aldosterone

Cortisol (FASICULATA AND RETICULARIS): cholesterol -> pregnenolone -> deoxycortisol -> cortisol

Question 2

Where are adrenal steroids inactivated and by what steps?

Answer 2

Liver

• Reduction of A ring
• Sulfate conjugation
• Glucuronide conjugation

Question 3

What are the adrenal steroid synthesis inhibitors?

Answer 3

Metyrapone

Question 4

What are the adrenal steroid antagonists?

Answer 4

Mifepristone
Sprionolactone
Eplerenone
Drospirenone

Question 5

Which drug is used to see if your adrenal-pituitary axis is functioning. Why?

Answer 5

Metyrapone
- It blocks 11beta-hydroxylation so you end up with 11-deoxycortisol, which gets excreted out at 17-hydroxycorticoids. Since 11-doxycortisol does NOT inhibit the pituitary, ACTH levels as well as 17-hydroxycorticoids should increase if everything is working.

Question 6

What does Mifepristone do?

Answer 6

Competitive antagonist for progesterone to terminate pregnancy
Competitive antagonist for glucocorticoid to treat Cushing’s

Question 7

Spironolactone and Eplerenone are competitive antagonists at ______ receptors and are used to treat ______

Answer 7

mineralocorticoid receptors,

used as a diuretic to treat hypertension, cardiac hypertrophy and heart failure

Question 8

What is drospirenone used for?

Answer 8

“PAM (think Pam from The Office draws/dros)

• *Progesterone receptor AGONIST
• Used with estrogen to suppress ovulation
• Used with estrogen for hormone replacement in post-menopausal women
• *Androgen receptor antagonist
• *Mineralocorticoid receptor antagonist
• Diuretic
• Antagonists salt retaining effects of estrogen

Question 9

Adrenal steroids/glucocorticoids are contraindicated in those with _______

Answer 9

Tuberculosis

Question 10

What are the anti-flammatory properties of adrenocortical steroids/glucocorticoids? (NOT therapeutic uses)

Answer 10

Inhibit immune system
Inhibits AA release -> decreased prostaglandin and leukotriene synthesis
Inhibit induction of COX-2
Decrease capillary permeability

Question 11

Therapeutic uses of adrenocortical steroids?

Answer 11

Adrenal insufficiency
Autoimmune conditions - Rheumatoid arthritis
Osteoarthritis
Allergic diseases
Cerebral edema

Question 12

What are the cytotoxic agents in immunosuppressant drugs?

Answer 12

MCAM - Malignant cells are mean
Methotrexate
Cyclophosphamide
Azathiaprine
Mycophenolate Mofetil

Question 13

How does azathiaprine work? Therapeutic use? How is it administered? Side effect?

Answer 13

Is metabolized to 6-mercaptopurine -> inhibits purine biosynthesis and inhibits DNA synthesis

Blocks salvage AND de-novo pathway

Inhibits rejection of transplanted organs, treat some autoimmune diseases like RA

Orally active

Bone marrow suppression (major), GI and hepatic toxicity

Question 14

How does cyclophosphamide work? How does it compare to

Answer 14

Alkylating agent that cross links DNA -> kills replicating and unreplicating cells, mostly B cells so it affects humoral immunity.

NOT effective in graft rejection

Bone marrow suppression is a major side effect

Question 15

How does methotrexate work? Therapeutic use? Side effects?

Answer 15

Inhibits FH2 -> FH4 (dihydrofolate -> tetrahydrofolate) by inhibiting the enzyme dihydrofolate reductase.

Inhibits folate dependent steps in purine synthesis -> inhibits DNA synthesis.

Treats autoimmune diseases

Hepatic toxicity is a side effect

Question 16

How does mycophenolate mofetil work? What does it treat? Special consideration?

Answer 16

Inhibits IMPDH (IMP->GMP), which is required for de novo purine synthesis. Has NO effect on salvage pathway.

Lymphocytes have no salvage pathway so this drug is SELECTIVE for lymphocytes. Inhibits their proliferation and expression of surface adhesion molecules.

Treats autoimmune; RA and refractory psoriasis

NOT TO BE USED WITH PREGNANCY: associated with pregnancy loss and congenital malformations

Question 17

Cyclosporine is what kind of molecule? How does cyclosporine work?

Answer 17

Lipophilic peptide antibiotic
Enters the T cell, binds cyclophilln, complex inactivates calcineurin (phosphatase) so NFAT is NOT dephosphorylated/active and T cell cannot produce cytokines/IL-2

Question 18

What is cyclosporine’s therapeutic use? Side effects?

Answer 18

Prevent rejection of transplanted organs.
*More effective than other agents and has less side effects

Nephrotoxicity is a major side effect (25-40% of pts taking a high dose) but is reversible if you stop the drug/lower dose

Question 19

How does tacrolimus differ from cyclosporine?

Answer 19

Same mechanism of action; but binds to FKBP instead of cyclophillin.

Spectrum of action is the same but 50-100 times more potent

Less nephro/hepatotoxicity

Question 20

How does sirolimus work?

Answer 20

Inhibits T cell activation and proliferation downstream of IL-2

Normally IL-2 binds to receptor, activates mTOR -> phosphorylation of cyclic kinases for cell progression.

Sirolimus enters cell, binds FKBP, inactivates mTOR, prevent downstream activation of factors responsible for cell cycle progression (inhibits G1->S)

Question 21

What are the therapeutic uses for sirolimus?

Answer 21

Same as cyclosporine; prevention of graft rejection

Used to coat cardiac stents

Question 22

What drug is used to coat cardiac stents?

Answer 22

Sirolimus