Immunosuppressive drugs

Question 1

If a patient complains of hirsutism and gingival hyperplasia, which drug was she on? What’s another calcineurin inhibitor you can prescribe her?

Answer 1

She was on Cyclosporine but you can switch her to Tacrolimus, and avoid excessive hair and gingival growth.

Question 2

To what molecule does Tacrolimus bind?

Answer 2

FK Binding protein: necessary for the protease function of calcineurin.

Question 3

Does Cyclosporine directly inhibit calcineurin?

Answer 3

No. It binds to cyclophillin, a molecule necessary for the function of calcineurin.

Question 4

Calcineurin activates what transcription factor? What does this TF cause the transcription of?

Answer 4

NFAT causes IL-2 transcription.

Question 5

What is the main toxicity of Tacrolimus?

Answer 5

Neurotoxicity. Confusion.

Question 6

What are the 2 terms for excessive hair growth in women?

Answer 6

Hirsutism and hypertrichosis

Question 7

What drug inhibits mTOR? To what molecule does it bind?

Answer 7

Sirolimus binds FK binding protein, preventing mTOR activation by Il-2.

Question 8

What 2 drugs bind FK binding protein? What do each do?

Answer 8

Sirolimus - inhibits mTOR (T-cell proliferation, B-cell doesn’t differentiate to plasma cell)

Tacrolimus - inhibits calcineurin, causing decreased transcription of Il-2

Question 9

Describe the potential synergism between cyclosporine and sirolimus.

Answer 9

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.

Question 10

What is the main toxicity associated with Sirolimus?

Answer 10

Hepatotoxicity and hyperlipidemia

Question 11

Which of the following drugs is a substrate for metabolism via CYP3A4?

Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate mofetil

Answer 11

Cyclosporing
Tacrolimus
Sirolimus

NOT mycophenolate mofetil

Question 12

Which of the following drugs are substrates for metabolism by the P-gp receptor?

Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate mofetil

Answer 12

Cyclosporine and Sirolimus

Question 13

What drug specifically targets T-cells with CD3 on them?

Answer 13

Thymoglobulin

Question 14

If you get a transplant, what drug is pretty much guaranteed to be on our regimen, regardless of which organ is being replaced>

Answer 14

Cyclosporine - chart page 35 of sweat man’s notes

Question 15

What class of immunosuppressants is the most dangerous when pregnant and breastfeeding?

Answer 15

Cell cycle inhibitors

Question 16

What classes of drugs are most likely to be used during INDUCTION of immune suppression? (aka.. initial depletion of immunity)

Answer 16

T-cell depletion by Thymoglobulin

Biological agents like Basiliximab

Question 17

What classes of drugs are generally used for maintenance of immune suppression, post-transplantation?

Answer 17

Cell Cycle inhibitors like azathioprine or prednisone

Calcineurin inhibitors like cyclosporin and tacrolimus

Question 18

How does prednisone work?

Answer 18

Cell cycle inhibitor via inhibition of transcription.

Used for maintenance therapy post-transplant.

Question 19

DOes prednisone cause bone marrow depletion?

Answer 19

NO.

Don’t know why… he mentioned it in class.

Question 20

Define the “first” and “second” phases of T-cell activation according to sweatman.

Answer 20

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

Question 21

Why do immunosuppressive drug therapies vary between individuals and even ethnicities?

Answer 21

Different metabolism abilities and reactions to drug combinations.

Question 22

T/F: There is a standard regimen used for INDUCTION of immunosuppressive therapy.

Answer 22

FALSE. Always an individualized regimen.

Question 23

How many drugs are simultaneously prescribed in maintenance therapies? What are their mechanisms, usually?

Answer 23

Triple-drug therapy:

Calcineurin inhibitor (cyclosporine/tacrolimus)
Anti-proliferative cell cycle inhibitor (Azothioprine)
Steriod (Corticosteroids)

Question 24

What drugs inhibit the first phase of T-cell activation? What class of drugs are these?

Answer 24

Cyclosporine, Tacrolimus: Calcineurin inhibitors

Question 25

The action of Sirolimus is before or after the production of Il-2?

Answer 25

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)

Question 26

Which of the cell cycle inhibiting drugs blocks the synthesis of guanine?

Answer 26

Mycophenolate mofetil - Inhibits the enzyme inosine monophosphate dehydrogenase. –> no more GMP, so no more DNA synthesis.

Question 27

Why does Mycophenolate mofetil only target B and T cell populations?

Answer 27

B and T cells (lymphocytes) have no guanine salvage pathway. Block guanine, block DNA synthesis.

Question 28

Which drugs that we talked about are also anti-neoplastic agents?

Answer 28

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)

Question 29

Which cell cycle inhibitor undergoes extensive metabolic conversion to a # of products?

Answer 29

Azathioprine

Question 30

MOA of Azathioprine?

Answer 30

Produces a metabolite (6 thioguanine triphosphate) that blocks T-cell co-stimulation and promotes apoptosis in Il-2 stimulated T-cells.

Question 31

People on immunosuppressants are at the greatest risk of developing what form of cancer?

Answer 31

Melanoma - stay out of UV light!

Question 32

What drug has the greatest effect in suppressing humoral immunity? (B-cells)

Answer 32

Cyclophosphamide

Question 33

MOA of Cyclophosphamide?

Answer 33

Alkylating agent that causes x-links between DNA strands or within the same DNA strand.

Question 34

Which drug causes the accumulations of adenosine? how does it do this?

Answer 34

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

Question 35

Explain the significance of Adenosine Receptor Occupancy on monocytes and macrophages.

Answer 35

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

Question 36

What phase of the cell cycle does methotrexate cause cells to freeze in?

Answer 36

S phase - most purine synthesis going on due to DNA replication

Question 37

Name the primary toxicities of Methotrexate.

Answer 37

Hematologic toxicity

Teratogenic

Acute diarrhea