PR 12.09 Pharmacology of Transplant

Question 1

Name 2 examples of Calcineurin inhibitors

Answer 1

Cyclosporine A (Sandimmune®), Tacrolimus (Prograf®)

Question 2

Describe the MOA for Calcineurin inhibitors

Answer 2

Inhibit the phosphatase calcineurin, thus preventing the expression of IL-2 and proliferation of T lymphocytes.

Question 3

Describe the ADME and Side effects of Calcineurin inhibitors

Answer 3

3. Side Effects: Nephrotoxicity, Hepatotoxicity, HTN, Neurotoxicity, Hyperglycemia/Diabetes.
4. ADME: IV or oral. Low oral bioavailability and variable pharmacokinetic because metabolized by CYP3A4; important to monitor serm levels. Majority is excreted in feces.

Question 4

Name 2 examples of mTOR inhibitors (lymphocyte signaling inhibitors)

Answer 4

Sirolimus (Rapamune®), Everolimus (Afinitor®)

Question 5

Describe the MOA for mTOR inhibitors

Answer 5

Binds FKBP and inhibits mTOR, thus preventing IL-2 receptor signaling and translation effects.

Question 6

Describe the ADME and Side effects of mTOR inhibitors

Answer 6

3. Side Effects: Hyperlipidemia, MYELOSUPPRESSION (leukopenia and thrombocytopenia), and Heptatotoxicity. No neprhotoxicity.
4. ADME: IV or oral (low oral availability). CYP3A metabolizd and transported by P-glycoprotein. SUPER long half-life means it is difficult to achieve steady-state. Majority excreted in feces.

Question 7

Name 2 examples of Antimetabolites and describe their general MOA.

Answer 7

Azathioprine (Imuran®) and Mycophenolate Mofetil (CellCept®) [aka Mycophenolic acid]

2. MOA: lower the number of NT’s available

Question 8

What is the specific MOA for Azathioprine?

Answer 8

Inhibits de novo sytnehsis of NT’s. Converted to active form (Mercaptopurine)

Question 9

What is the specific MOA for Mycophenolate Mofetil?

Answer 9

primarily inhibits lymphocyte production by inhibiting IMP dehydrogenase

Question 10

Describe the side effects and ADME of Antimetabolites

Answer 10

3. Side Effects: (More commonly seen with azathioprine) Bone marrow suprression (leukopenia), Hepatotoxicity, Alopecia, GI toxicity.
4. ADME: Good oral bioavailability. Mercaptopruine is toxic, and inactivated by xanthine oxidase (need to give 1/3 lower doses in patients taking inhibitors of this such as allopurinol), Mycophenolic acid is less toxic and has longer half life.

Question 11

Name 2 examples of T-lymphocyte depletes used as biologics for transplant pharmacology

Answer 11

1. Antithymocyte globulin-rabbit/equine (Thymoglobulin/Atgam)
2. Muromonab (Orthoclone OKT3®)

Question 12

Describe the MOA and side effects for Thymoglobulin/Atgam

Answer 12

(a) MOA: Polyclonal antibtodies that target and deplet T-lymphocytges.
(b) Side Effects: Leukopenia, Cross-reaction with other tissue antigens, Infection risk, Cyokine release syndrome, Malignancy risk.

Question 13

Describe the MOA and side effects for Muomonab

Answer 13

(a) MOA: anti-CD3 antibody (part of the T cell receptor complex). CD3 presenting cells rapidly removed from the blood.
(b) Side Effects: Cytokine release syndrome, Infection risk, Short term usefulness due to antibodies to the drug.

Question 14

What is a common IL-2 antagonist used as a Biologic in transplant pharmacology?

Answer 14

1. Basiliximab (Simulect®)

Question 15

Describe the MOA and any prevalence of Side effects for Basiliximab

Answer 15

(a) MOA: Receptor antogonist for Anti-CD25 receptor of IL-2 receptors found on activated T cells.
(b) Side Effects: Doesn’t cause T-cell depletion/reduced side effects and longer half life so its replacing Muromonab.

Question 16

What is a Glucocorticoid used in transplant pharmacology? General mechanism?

Answer 16

Prednisone. Suppress prolif at multiple steps?

Question 17

What is a common combination of drugs used in maintenance therapy?

Answer 17

2 or more drugs with different MOA

Commonly: Tacrolimus, Mycophenolate mofetil, and Prednisone

Question 18

What is a common combination of drugs used in the treatment of established agents and the rationale?

Answer 18

B. Treatment of establisehd rejection therefore requires the use of agents directs against Activated T cells.

1. Glucocorticoids in high doses (pulse therapy)
2. Polyclonal antilymphocyte antibodies
3. Muromonab-CD3