Kidney Transplantation (Pharmacology)

Which medication is the costimulatory signal inhibitor?

Belatacept

MOA of Belatacept?

binds costimulatory ligands (CD80 and CD86) on APC (antigen presenting cells) which prevents interaction with CD28 on T Cells → inhibited initiation of costimulatory signal that activates calcineurin which would have activated and proliferated T cells

ID where Belatacept functions in the CD4 T cell activating pathway:

Between APC’s MHC’s II and T cell’s TCR (A)

Which medication are the calcineurin inhibitors?

cyclosporine and tacrolimus

Which cytoplasmic immunophilin does cyclosporine target?

cyclophilin

Which cytoplasmic immunophilin does tacrolimus target?

FKBP12 (FK-binding protein-12)

T/F - cyclosporine and tacrolimus both target calcineurin

F - although they are both calcineurin inhibitors, they both target different proteins that, when bound to the drugs, inhibit calcineurin action

What is the function of the drug-immunophilin complex formed by cyclosporin and tacrolimus respectively?

inhibits action of calcineurin (protein phsophatase) that activates nuclear factor of activated T cells (NFAT) which inhibits transcription of cytokines like IL-2 further down the pathway

What are DDIs with cyclosporine and tacrolimus?

drugs that induce or inhibit CYP3A4 function

Which medication(s) increase cyclosporine levels?

methylprednisolone

Which medication(s) decrease cyclosporine levels?

phenytoin, carbamazepine, mycophenolic

Which medications increase tacrolimus levels?

corticosteroids

What are common adverse effects from medications like cyclosporine and tacrolimus (CSA)?

nephrotoxicity, hypertension

Which corticosteroids used in kidney transplants?

methylprednisolone and prednisone

MOA of corticosteroids?

block cytokine activation and interfere with cell migration, recognition, and cytotoxic effector mechanisms

Which medications interact with prednisone?

barbiturates, phenytoin, and rifampin induce CYP3A4 (hepatic metabolism) → decreasing prednison effect

What type of injury can cyclosporine cause to allograft injury?

hemodynamically mediated kidney injury: renal vasoconstriction (mainly of afferent ateriole) → decrease renal blood flow and GFR (Nephrotoxicity seen in both calcineurin inhibitors)

The antigen of ATG and RATG is ______

lymphocyte receptors

MOA of antithymocyte globulin (ATG and RATG)

lymphocyte depletion (T cells > B cells)

antigen of alemtuzumab is _______

CD52

MOA of alemtuzumab

depleting both T and B lymphocytes

antigen of rituximab is _____

CD20

MOA of rituximab

depleting B cells

Which are the depleting antibodies?

ATG, RATH, alemtuzumab, rituximab

What are the non-depleting antibodies?

basiliximab

Antigen of basiliximab is ______

alpha-chain (CD25) of IL-2 receptor

MOA of basiliximab

prevents Il-2 mediated activation and proliferation of T cells

Which of the depleting antibodies are selective?

rituximab (B cell depletion only)

Which of the depleting antibodies mainly deplete T cells more than B cells?

ATG, RATG (antithymocyte globulin),

what are the mTOR Inhibitors?

sirolimus (also called rapamycin) and everolimus (derivative of sirolimus)

Which medications target FKBP12?

Tacrolimus and sirolimus

Do Tacrolimus and sirolimus have the same effect since they both bind to FKBP12?

No, tacrolimus binding leads to inhibition of calcineurin effect, sirolimus binding leads to mTOR inhibition

After sirolimus and FKBP12 form a complex, what is its effect?

drug-FKBP12 complex inhibiting mTOR (mammalian target of rapamycin) and inhibiting cell response to IL-2 and progression of cell cycle

After tacrolimus and FKBP12 form a complex, what is its effect?

drug-FKB12 complex inhibits calcineurin which inhibits activation of nuclear factor of activate T cells (NFAT), which inhibits transcription of cytokines (IL-2)

What is mycophenolate mofetil (MMF)?

prodrug of mycophenolic acid

MOA of MMF?

inhibits inosine monophosphate dehydrogenase (IMPDH) which decreases nucleotide synthesis and diminishes DNA polymerase activity, ultimately reducing lymphocyte proliferation

What is Azathioprine?

prodrug of 6-MP

Which medication disrupts DNA synthesis?

Azathioprine and MMF

______ disrupts DNA de novo synthesis

1. coritocosteroids

2. azathioprine

3. cyclosporine

4. sirolimus

azathioprine

____ is a mTOR inhibitor

1. CS

2. tacrolimus

3. cyclosporine

4. mycophenolate mofetil

5. sirolimus

sirolimus

_____ is a calcineurin inhibitor

1. CS

2. azathioprine

3. cyclosporine

4. mycophenolate mofetil

5. tacrolimus

cyclosporine, tacrolimus

cyclosporine and tacrolimus are metabolized by ______

1. CYP2C9

2. CYP3A4

3. CYP2D6

4. CYP7A4

CYP3A4

Belatacept interfere with the costimulatory signal between CD80/CD86 and _____

1. CD40

2. CD28

3. CD70

4. CD20

CD28

____ is a non-depleting antibody

1. Alemtuzumab

2. Basiliximab

3. antithymocytes globuline ATG

4. antithymocyte globulin RATG

basiliximab

basiliximab is an antibody against ______

1. CD52

2. CD25

3. CD28

4. CD20

CD25

Alemtuzumab is an antibody against _______

1. CD52

2. CD25

3. CD28

4. CD20

CD52