Renal Pharmacology 2 (post-transplant)

Question 1

What are the 2 calcinurin inhibitors?

Answer 1

Cyclosporine: small (11aa) cyclic polypeptide, fungal origin
Tacrolimus: macrolide isolated from Streptomyces spp

Question 2

What is calcinurin inhibitors MOA?

Answer 2

1. Bind to cytosolic receptor proteins: Cyclophilin (cyclosporine) & FKBP12 (tacrolimus)
2. Complex binds to and inhibits action of calcineurin
3. Inhibits the transcription of cytokines such as IL-2 that are essential for T-cell activation and proliferation

Question 3

What are some things to know about Cyclosporine administration?

Answer 3

oral or i.v.
• Concentrates in tissues –liver, kidney, spleen, bone marrow
• Metabolized extensively by CYP3A4 in liver
• Long half-life (27 hours)

Question 4

What are side effects of cyclosporin?

Answer 4

• Nephrotoxicity – vasoconstriction, induction TGFβ, fibrosis, tubular atrophy
• Hypertension and fluid retention (50%)
• Hepatic Dysfunction
• Tremor, headache, fatigue
• GI - nausea, vomiting, diarrhea
• Hypertrichosis –excessive hair growth
• Gum Hypertrophy (common)
• Hyperlipidemia
• Hypomagnesemia
• Hypokalemia

Question 5

What are some drugs that interact with cyclosporine?

Answer 5

Nephrotoxic drugs – NSAIDs, aminoglycosides, antimicrobials
Drugs that induce Cyp3A4 – phenytoin, carbamazepine
Drugs that inhibit CYP450 – erythromycin, ketoconazole

Question 6

What are some things to know about tacrolimus administration?

Answer 6

oral or i.v.
• More water soluble
• Metabolized by liver
• Highly variable half-life (4 - 41 hrs)
• Monitor trough blood concentration is essential
• Does not stimulate TGFβ

Question 7

What are the side effects of tacrolimus?

Answer 7

Pleural and pericardial effusions

Cardiomyopathy in children

Question 8

Which calcineurin inhibitor is used more often?

Answer 8

Tacrolimus

Question 9

What is the mTOR inhibitor we need to know?

Answer 9

Sirolimus

Question 10

What is the MOA of Sirolimus?

Answer 10

1. Sirolimus binds to FKBP12
2. complex binds and modulates the activity of mTOR (mammalian target of rapamycin)
3. blocks signal 3: inhibition of cytokine/IL-2 induced cell cycle progression from G1 to S phase

Question 11

What are some things you should know about siroliums administration?

Answer 11

oral

• gut absorption modulated by p-glycoprotein
• metabolized by intestinal and liver CYP450
• very long half life

Question 12

What are some side effects of sirolimus?

Answer 12

• Lymphocele (renal transplant complication can cause ureteric compression)
• Edema, ascites, tachycardia, hypertension
• GI – abdominal pain, nausea, diarrhea

Question 13

What are some overall benefits of sirolimus?

Answer 13

 Potent prophylaxis against acute cellular rejection
 Less vasoconstriction
 Not associated with acute or chronic renal insufficiency

Question 14

What does Mycophenolate mofetil do?

Answer 14

Antiproliferative Agent: Competitive, reversible inhibition of IMPDH, a critical rate-limiting enzyme in de novo purine synthesis &Lymphocytes dependent on de novo pathway vs. salvage pathway utilized by other cell types

Question 15

What are some things to know about mycophenolate mofetil administration?

Answer 15

oral or i.v.
• Metabolized by liver
• Long half-life (18 hrs)

Question 16

What are some side effects of mycophenolate mofetil?

Answer 16

• hypertension, edema, tachycardia
• dyspnea, cough
• dizziness, insomnia, tremor, seizures
• leucopenia, thrombocytopenia, anemia
• opportunistic infections: viral cytomegalovirus, bacterial urinary tract
• lymphoproliferative disease, skin cancer

Question 17

What does azathioprine do?

Answer 17

Antiproliferative Agent: Purine analog Metabolized in the liver to 6-mercaptopurine and then to thiosinosine monophosphate (TIMP). TMP decreases synthesis of DNA precursors and also incorporates into DNA

Blocks CD28 co-stimulation of T-cells

Question 18

What are some alternatives to azathioprine?

Answer 18

Methotrexate

Cyclophosphamide

Question 19

What are some things about azathioprine administration?

Answer 19

oral

• Short half-life (3-5 hrs)

Question 20

What are some side effects of azathioprine?

Answer 20

• bone marrow suppression leucopenia, thrombocytopenia
• hypersensitivity reactions, malaise, dizziness, GI tract, fever, rash, hypotension
• opportunistic infections
• alopecia
• small risks for lymphomas

Question 21

What are the drug interactions with azathioprine?

Answer 21

Allopurinol – decreases 6-mercaptopurine metabolism need to reduce azathioprine dose by 75% if used together

Question 22

What are the anti-CD25- Interleukin-2 Receptor Antibodies?

Answer 22

Basiliximab (Simulect)
Daclizumab (Zenapax)
Alemtuzumab (Campath-
1H)

Question 23

What should you know about Basiliximab (Simulect) administration?

Answer 23

i.v.
• Very long half-life (1 week)
• Given immediately prior to surgery and 4 days following

Question 24

What are the side effects of Basiliximab (Simulect)?

Answer 24

hypersensitivity reactions rarely occur

Question 25

What is Belatacept?

Answer 25

Co-Stimulator Blocker : fusion protein binds CD28 and CD86 molecules and blocks co-stimulatory action with CD28 on T-cell activation

Question 26

What is Belatacept used for?

Answer 26

used for renal transplant in patients that are seropositive for Ebstein-Barr Virus

Question 27

What should you know about Belatacept administration?

Answer 27

IV with a Very long half-life (8-10 days)

Question 28

What are the side effects of Belatacept ?

Answer 28

- hypersensitivity reactions rarely occur | - lymphoproliferative disorder in those with no prior exposure to Ebstein-Barr virus

Question 29

What is Prednisolone?

Answer 29

Corticosteroid

Question 30

How do corticosteroids work?

Answer 30

- Inhibits pro-inflammatory transcription factors such as NF-κB - Activate anti-inflammatory genes by histone acetylation in promoter region of genes - Reduces T-lymphocyte proliferation and increases T-cell apoptosis - Reduces T-cell activation and B-cell proliferation

Question 31

What are side effects of steroids?

Answer 31

```  Acne  Cushingoid facial appearance  Hirsutism  Mood disorders  Hypertension  Glucose intolerance  Cataracts  Osteoporosis  Growth retardation in children ```

Question 32

Advances in transplant immunosuppression have contributed to what?

Answer 32

 decrease in the frequency of acute rejection  increase in graft survival  longevity for renal allograft recipients

Question 33

More choices for immunosuppression post transplant has lead to what?

Answer 33

 more options  different mechanisms of action  more complicated management schemes  increase potential for drug-drug interactions and complex side effect profiles

Question 34

What are induction agents for immunosuppression?

Answer 34

 Monoclonal or polyclonal antibodies |  Administered intravenously immediately following surgery

Question 35

What are the maintenance agents of immunosuppression?

Answer 35

 Prednisolone  Calcineurin Inhibitors: form the cornerstone of immunosuppressive therapy  Anti-proliferative agents: mycophenolate mofetil, azathioprine, sirolimus  Triple agents / withdrawal / avoidance / conversion

Question 36

What are the induction agents we have to know for immunosuppression?

Answer 36

``` Muromonab Anti-thymocyte globulin Basiliximab (Simulect) Daclizumab (Zenapax) Alemtuzumab (Campath-1H) FTY 720 ```

Question 37

What is Muromonab ?

Answer 37

humanized anti-CD3

Question 38

What is Anti-thymocyte globulin (ATGAM)?

Answer 38

deplete circulating lymphocytes

Question 39

What is FTY 720?

Answer 39

sphingosine-1-phosphate receptor (S1P-R) agonist - lymphocyte homing