Renal Pharmacology 2 (post-transplant) Flashcards Preview

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Flashcards in Renal Pharmacology 2 (post-transplant) Deck (39):
1

What are the 2 calcinurin inhibitors?

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

2

What is calcinurin inhibitors MOA?

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

3

What are some things to know about Cyclosporine administration?

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

4

What are side effects of cyclosporin?

• 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

5

What are some drugs that interact with cyclosporine?

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

6

What are some things to know about tacrolimus administration?

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

7

What are the side effects of tacrolimus?

Pleural and pericardial effusions
Cardiomyopathy in children

8

Which calcineurin inhibitor is used more often?

Tacrolimus

9

What is the mTOR inhibitor we need to know?

Sirolimus

10

What is the MOA of Sirolimus?

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

11

What are some things you should know about siroliums administration?

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

12

What are some side effects of sirolimus?

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

13

What are some overall benefits of sirolimus?

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

14

What does Mycophenolate mofetil do?

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

15

What are some things to know about mycophenolate mofetil administration?

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

16

What are some side effects of mycophenolate mofetil?

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

17

What does azathioprine do?

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

18

What are some alternatives to azathioprine?

Methotrexate
Cyclophosphamide

19

What are some things about azathioprine administration?

oral
• Short half-life (3-5 hrs)

20

What are some side effects of azathioprine?

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

21

What are the drug interactions with azathioprine?

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

22

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

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

23

What should you know about Basiliximab (Simulect) administration?

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

24

What are the side effects of Basiliximab (Simulect)?

hypersensitivity reactions rarely occur

25

What is Belatacept?

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

26

What is Belatacept used for?

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

27

What should you know about Belatacept administration?

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

28

What are the side effects of Belatacept ?

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

29

What is Prednisolone?

Corticosteroid

30

How do corticosteroids work?

- 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

31

What are side effects of steroids?

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

32

Advances in transplant immunosuppression have contributed to what?

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

33

More choices for immunosuppression post transplant has lead to what?

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

34

What are induction agents for immunosuppression?

 Monoclonal or polyclonal antibodies
 Administered intravenously immediately following surgery

35

What are the maintenance agents of immunosuppression?

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

36

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

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

37

What is Muromonab ?

humanized anti-CD3

38

What is Anti-thymocyte globulin (ATGAM)?

deplete circulating lymphocytes

39

What is FTY 720?

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