Adrenal steroids and Immunopharmacology Flashcards
Explain the layers of adrenal cortex and the synthesis of aldosterone and cortisol.
Cortex layers from superficial to deeper: zona glomerulosa, fasiculata, reticularis
Aldosterone (GLOMERULOSA): cholesterol -> pregnenolone -> deoxycorticosterone -> aldosterone
Cortisol (FASICULATA AND RETICULARIS): cholesterol -> pregnenolone -> deoxycortisol -> cortisol
Where are adrenal steroids inactivated and by what steps?
Liver
- Reduction of A ring
- Sulfate conjugation
- Glucuronide conjugation
What are the adrenal steroid synthesis inhibitors?
Metyrapone
What are the adrenal steroid antagonists?
Mifepristone
Sprionolactone
Eplerenone
Drospirenone
Which drug is used to see if your adrenal-pituitary axis is functioning. Why?
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.
What does Mifepristone do?
Competitive antagonist for progesterone to terminate pregnancy
Competitive antagonist for glucocorticoid to treat Cushing’s
Spironolactone and Eplerenone are competitive antagonists at ______ receptors and are used to treat ______
mineralocorticoid receptors,
used as a diuretic to treat hypertension, cardiac hypertrophy and heart failure
What is drospirenone used for?
“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
Adrenal steroids/glucocorticoids are contraindicated in those with _______
Tuberculosis
What are the anti-flammatory properties of adrenocortical steroids/glucocorticoids? (NOT therapeutic uses)
Inhibit immune system
Inhibits AA release -> decreased prostaglandin and leukotriene synthesis
Inhibit induction of COX-2
Decrease capillary permeability
Therapeutic uses of adrenocortical steroids?
Adrenal insufficiency Autoimmune conditions - Rheumatoid arthritis Osteoarthritis Allergic diseases Cerebral edema
What are the cytotoxic agents in immunosuppressant drugs?
MCAM - Malignant cells are mean Methotrexate Cyclophosphamide Azathiaprine Mycophenolate Mofetil
How does azathiaprine work? Therapeutic use? How is it administered? Side effect?
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
How does cyclophosphamide work? How does it compare to
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
How does methotrexate work? Therapeutic use? Side effects?
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
How does mycophenolate mofetil work? What does it treat? Special consideration?
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
Cyclosporine is what kind of molecule? How does cyclosporine work?
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
What is cyclosporine’s therapeutic use? Side effects?
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
How does tacrolimus differ from cyclosporine?
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
How does sirolimus work?
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)
What are the therapeutic uses for sirolimus?
Same as cyclosporine; prevention of graft rejection
Used to coat cardiac stents
What drug is used to coat cardiac stents?
Sirolimus
