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Flashcards in Immunosuppressive Agents Deck (35):

What is the receptor which glucocorticoids bind and what is complexed to it?

Steroid receptor in the cytosol, which is complexed to hsp90 and other stabilizing proteins


What does the steroid receptor bind to? What does this do?

Glucocorticoid response elements - which bind in the promotor or enhancer regions of appropriate response genes and modulates transcription


What are two primary transcription factors that GRE modifies? What is the net result?

Two inflammatory factors:
1. AP1
2. NF-kappaB

Net result is anti-growth, anti-inflammation, and immunosuppression


What is the most commonly prescribed glucocorticoid and its active form?

Prednisone is most prescribed. It is a pro-drug which is easily activated in the liver to active form prednisolone (unless liver disease)


When and how much of steroids are typically used?

Primarily used in the "induction" stage of solid organ or hematopoietic stem cell transplants at HIGH doses

Used in low doses in another regimen during the "maintenance" stage


What is a common ocular side effect of glucocorticoids?



What is a common vascular side effect of glucocorticoids?

Atherosclerosis (due to hyperlipidemia / hyperglycemia)


What is a common musculoskeletal side effect of glucocorticoids?

Osteoporosis from inhibition of osteoblast function


What is a common neurological side effect of glucocorticoids?

Insomnia -> euphoria -> depression


What is the generalized effect of immunophilin binding? What drug classes are included in this?

Inhibitory effects on T-cell activation by selective block of IL-2 and other cytokines in T-helper cells

Calcineurin inhibitors


What are the calcineurin inhibitors and how do they work in general?

1. Tacrolimus
2. Cyclosporin A

They work by having their protein - drug complex bind and inhibit calcineurin, a phosphatase which is required to activate NF-AT. NF-AT is responsible for increasing translation of IL-2 and other cytokines for T-cell proliferation.


What are the drug targets of tacrolimus and cyclosporin A?

Tacrolimus - FK-binding proteins
Cyclosporin A - cyclophilins


How is the distribution of the calcineurin inhibitors and how are they metabolized?

Very lipid-soluble so they get everywhere, with a relatively long halflife

Metabolized via Cytochrome P450 CYP3A4 -> remember this because Tacrolimus is a macrolide


What drugs increase and decrease cyclosporine / tacrolimus levels?

Increase: CYP substrates i.e. azole antifungals, macrolides, grapefruit juice

Decrease: CYP inducers i.e. phenytoin, rifampin, carbamezepine


What is the most significant and common side effect of calcineurin inhibitors and how does this relate to drugs which can / can't be taken with them?

Nephrotoxicity -> manifests as azotemia (high BUN) and hyperkalemia

Drugs cannot take: NSAIDs, aminoglycosides, ACE-inhibitors, amphotericin B, acyclovir (other nephrotoxic drugs)


What is an early side effect of calcineurin inhibitors and what should be used to treat it?

Hypertension -> due to sodium retention and vasoconstriction

Use calcium channel blockers because ace-inhibitors are nephrotoxic and diuretics can precipitate gout


What cancer does calcineurin inhibitor pre-dispose you to?

non-Hodgkin's lymphoma


What is the non-calcineurin-inhibiting immunophilin and how does it work?

Sirolimus (rapamycin) - binds FKBP12 (similar to tacrolimus) but rather inhibits mTOR (mammalian target of rapamycin), a protein responsible for downstream signalling of IL-2. This will keep the cell arrested at G1 phase.


Can sirolimus be used with tacrolimus?

Yes, even though they both bind FKBPs, they are present in such large amounts that they do not become a rate-limiting step


How is sirolimus metabolized and why might it be preferable to tacrolimus / cyclosporin?

Metabolized via CYP3A4 (it is a macrolide after all)

Might be preferable because it is not nephrotoxic on its own


What is azathioprine?

The nitroimidazole derivative of 6-mercaptopurine (6-MP) with good bioavailability


What is the mechanism of action of azathioprine?

Suppression of intracellular inosine synthesis, thereby decreasing RNA production via inhibition of purines

This lowers the B and T lymphocyte numbers


What is the drug interaction of note with azathioprine and why?

Since it is metabolized by xanthine oxidase, the gout drug allopurinol which inhibits xanthine oxidase can cause bone marrow aplasia (due to 6-MP buildup)


What is the methotrexate mechanism of action and what is its worst drug interaction?

Irreversible inhibition of dihydrofolate reductase, decreasing pyrimidine production.

Major interaction with other folate-depleting drugs: TMP/SMX or probenecid


What is methotrexate indicated for?

Rheumatoid arthritis and psoriasis + graft-versus host disease. Used for lots of chemotherapy.


What drug is used in episodes of renal or other solid organ transplant rejection and how does it work?

Mycophenolate mofentil

Inhibits inosine monophosphate dehydrogenase, part of the de novo purine production pathway which makes guanine, needed for lymphocyte proliferation


Why is mycophenolate really juicy?

It is easily hydrolyzed / glucuronated so it is not very toxic (just GI distress), and only decreases GTP pools in lymphocytes / monocytes but not neutrophils (bacterial infection less likely)


What is the pro-drug inhibitor of pyrmidine synthesis?



Why is the mechanism of action of cyclophosphamide and when is it used?

It's an alkylating agent which interferes with nucleic acids / enzyme macromolecules

Used for severe, life-threatening autoimmune diseases and induction phase of immunosuppression


Why can we not used cyclophosphamide with tricyclic antidepressants?

TCA's will decrease bladder emptying, leading to prolonged bladder exposure to "acrolein", the toxic metabolite of cyclophosphamide


In what way is drug metabolism of cyclophosphamide opposite of tacrolimus/sirolimus/cyclosporine?

Microsomal inducers will actually increase the action -> the drug is activated in the liver.

Microsomal blockers will decrease the action -> accumulation of unactivated drug


Cyclophosphamide reduces plasma pseudocholinesterase activity. What drug should it NEVER be used with?



Define the following endings for antibodies:

-imab or -ximab - chimeric antibodies
-omab - mouse monoclonal antibody
-zumab - humanized monoclonal antibody
-umab - human monoclonal antibody


What is the polyclonal antibody used to "induce" immunosuppression?

anti-thymocyte globulin "ATG" -> polyclonal antibodies against thymus cells


What is adalimumab?

Humira - recombinant monoclonal antibody to TNF