Immunosuppressive drugs Flashcards
If a patient complains of hirsutism and gingival hyperplasia, which drug was she on? What’s another calcineurin inhibitor you can prescribe her?
She was on Cyclosporine but you can switch her to Tacrolimus, and avoid excessive hair and gingival growth.
To what molecule does Tacrolimus bind?
FK Binding protein: necessary for the protease function of calcineurin.
Does Cyclosporine directly inhibit calcineurin?
No. It binds to cyclophillin, a molecule necessary for the function of calcineurin.
Calcineurin activates what transcription factor? What does this TF cause the transcription of?
NFAT causes IL-2 transcription.
What is the main toxicity of Tacrolimus?
Neurotoxicity. Confusion.
What are the 2 terms for excessive hair growth in women?
Hirsutism and hypertrichosis
What drug inhibits mTOR? To what molecule does it bind?
Sirolimus binds FK binding protein, preventing mTOR activation by Il-2.
What 2 drugs bind FK binding protein? What do each do?
Sirolimus - inhibits mTOR (T-cell proliferation, B-cell doesn’t differentiate to plasma cell)
Tacrolimus - inhibits calcineurin, causing decreased transcription of Il-2
Describe the potential synergism between cyclosporine and sirolimus.
Cyclosporine inhibits the transcription of Il-2 genes by blocking calcineurin activation of NFAT.
Sirolimus blocks Il-2 stimulation of mTOR by binding FK binding protein.
They are essentially two sequential steps in the pathway of T-cell differentiation and proliferation, so they act synergistically to one another. Less Il-2 produced as a result of cyclosporine means less mTOR to inhibit.
What is the main toxicity associated with Sirolimus?
Hepatotoxicity and hyperlipidemia
Which of the following drugs is a substrate for metabolism via CYP3A4?
Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate mofetil
Cyclosporing
Tacrolimus
Sirolimus
NOT mycophenolate mofetil
Which of the following drugs are substrates for metabolism by the P-gp receptor?
Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate mofetil
Cyclosporine and Sirolimus
What drug specifically targets T-cells with CD3 on them?
Thymoglobulin
If you get a transplant, what drug is pretty much guaranteed to be on our regimen, regardless of which organ is being replaced>
Cyclosporine - chart page 35 of sweat man’s notes
What class of immunosuppressants is the most dangerous when pregnant and breastfeeding?
Cell cycle inhibitors
What classes of drugs are most likely to be used during INDUCTION of immune suppression? (aka.. initial depletion of immunity)
T-cell depletion by Thymoglobulin
Biological agents like Basiliximab
What classes of drugs are generally used for maintenance of immune suppression, post-transplantation?
Cell Cycle inhibitors like azathioprine or prednisone
Calcineurin inhibitors like cyclosporin and tacrolimus
How does prednisone work?
Cell cycle inhibitor via inhibition of transcription.
Used for maintenance therapy post-transplant.
DOes prednisone cause bone marrow depletion?
NO.
Don’t know why… he mentioned it in class.
Define the “first” and “second” phases of T-cell activation according to sweatman.
T-Cell activation:
Phase 1: Antigen presentation via MHC and secondary stimulation via B7/CD28 interaction and the gene transcription of Il-2 as a result.
Phase 2: Proliferation and clonal expansion induced by intracellular production of Il-2
Why do immunosuppressive drug therapies vary between individuals and even ethnicities?
Different metabolism abilities and reactions to drug combinations.
T/F: There is a standard regimen used for INDUCTION of immunosuppressive therapy.
FALSE. Always an individualized regimen.
How many drugs are simultaneously prescribed in maintenance therapies? What are their mechanisms, usually?
Triple-drug therapy:
Calcineurin inhibitor (cyclosporine/tacrolimus)
Anti-proliferative cell cycle inhibitor (Azothioprine)
Steriod (Corticosteroids)
What drugs inhibit the first phase of T-cell activation? What class of drugs are these?
Cyclosporine, Tacrolimus: Calcineurin inhibitors
The action of Sirolimus is before or after the production of Il-2?
AFTER! It prevents the interaction of FK binding protein and Il-2 that activates mTOR, and subsequently cell proliferation and clonal expansion (2nd phase of T-cell)
Which of the cell cycle inhibiting drugs blocks the synthesis of guanine?
Mycophenolate mofetil - Inhibits the enzyme inosine monophosphate dehydrogenase. –> no more GMP, so no more DNA synthesis.
Why does Mycophenolate mofetil only target B and T cell populations?
B and T cells (lymphocytes) have no guanine salvage pathway. Block guanine, block DNA synthesis.
Which drugs that we talked about are also anti-neoplastic agents?
Azathioprine
Methotrexate
Cyclophosphamide
Mycophenolate mofetil
ALL THE CELL CYCLE INHIBITORS (they target host cells, so it makes sense that they would be involved in cancer treatment)
Which cell cycle inhibitor undergoes extensive metabolic conversion to a # of products?
Azathioprine
MOA of Azathioprine?
Produces a metabolite (6 thioguanine triphosphate) that blocks T-cell co-stimulation and promotes apoptosis in Il-2 stimulated T-cells.
People on immunosuppressants are at the greatest risk of developing what form of cancer?
Melanoma - stay out of UV light!
What drug has the greatest effect in suppressing humoral immunity? (B-cells)
Cyclophosphamide
MOA of Cyclophosphamide?
Alkylating agent that causes x-links between DNA strands or within the same DNA strand.
Which drug causes the accumulations of adenosine? how does it do this?
Methotrexate.
- It’s usually a DHFR inhibitor, and the pathways for de novo purine synthesis and Folate synthesis overlap.
- Buildup of AICAR causes buildup of adenosine, which has anti-inflammatory properties
Explain the significance of Adenosine Receptor Occupancy on monocytes and macrophages.
A high adenosine receptor occupancy on MACs and monocytes decreases the expression of inflammatory cytokines Il-12 and TNF-a, while increasing expression of anti-inflammatory Il-10 and VEGF.
GREAT FIGURE ON PAGE 30 OF HANDOUT
What phase of the cell cycle does methotrexate cause cells to freeze in?
S phase - most purine synthesis going on due to DNA replication
Name the primary toxicities of Methotrexate.
Hematologic toxicity
Teratogenic
Acute diarrhea
