Renal Pharmacology Part 2 Flashcards Preview

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Flashcards in Renal Pharmacology Part 2 Deck (40):
1

What types of T cells are most significant in kidney transplant rejection?

Memory T cells

2

What are the three signal approaches to immunosuppression?

  • Calcineurin
    • Cyclosporine, Tacrolimus
  • mTOR
    • Sirolimus
  • Cell Cycle
    • Azathioprine

3

What type of drug is cyclosporine?

How is it metabolized?

What is it's half life?

Calcineurin inhibitor (binds to cyclophlin)

Metabolized by CYP3A4 in liver

Long half life (27 hours)

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4

How does Cyclosporine lead to nephrotoxicity?

What are its other side effects?

Nephrotoxicity - vasoconstriction, induction of TGF-ß, fibrosis, and tubular atrophy

  • Other SE
    • HTN
    • Hepatic dysfunction
    • Hypertrichosis (excessive hair growth)
    • GI
    • Gum hypertrophy
    • Hyperlipidemia

5

What are drug interaction that occur with cyclosporine?

Nephrotoxic drugs - NSAIDs, aminoglycosides

Drugs that induce CYP3A4 - phenytoin, carbamazepine

Drugs that inhibit CYP450 - erythromycin, ketoconazole

6

What is tacrolimus?

How is the same as cyclosporine?

How is it different?

  • Tacrolimus - calcineurin inhibitor (binds to FKBP)
  • Similarities
    • Metabolized by liver
    • Given orally or IV
  • Differences
    • Highly variable half life (must monitor)
    • Does not stimulate TGF-ß
    • More water soluble

7

Tacrolimus SE

Pleural and pericardial effusions

Cardiomyopathy in children

8

What events should be monitored for when administering calcineurin inhibitors?

  • Hepatotoxicity
  • Cardiovascular (hypertension and hypercholesterolemia)
    • Tacrolimus has less cardiovasc. SE
  • Glucose intolerance
  • Neurotoxicity - seen more often with tacrolimus

9

Why are the following be monitored for drug interaction with calcineurin inhibitor drugs?

Nephrotoxic agents:

Potassium sparing diuretics:

Antacids:

HMG-CoA reductase inhibitors (Statins):

  • Nephrotoxic agents:
    • NSAIDS may have increased toxicity with hepatic impairment
  • Potassium sparing diuretics:
    • hyperkalemia has been reported
  • Antacids: May inhibit absorption of CNIs (take 2 hours after CNI dose)
  • HMG-CoA reductase inhibitors (Statins):
    • Increased risk of rhabdomyolysis and bone marrow suppression

10

The calcineurin inhibitor most commonly used today is 

Tacrolimus

11

What is the MOA of Sirolimus?

  • Binds to FKBP12
  • Complex binds and modulates the acitivity of mTOR
  • Blocks signal 3 leading to inhibition of cytokine/IL-s induced cycle progression from G1 to S phase

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12

How is Sirolimus administered?

How is it metbolized?

What is its half life?

Oral

Metabolized by intestinal and liver CYP450

Very long half-life (60 hours)

13

What are some SE for Sirolimus?

  • Edema, ascites, HTN
  • GI
  • Hyperlipidemia
  • Hypokalemia
  • Hypophosphatemia

14

What drugs interact with Sirolimus?

Drugs that induce CYP3A4 - rifampicin

Drugs that inhibit CYP450 - itraconazole, ketoconazole

15

What are the benefits of Sirolimus over calcineurin inhibitors?

  • Potent prophylaxis against acute cellular rejection
  • Less vasoconstriction
  • No associated with acute or chronic renal insufficiency (sustained GFR)

16

What side effect of sirolimus is not a side effect of cyclosporine or tacrolimus?

Bone marrow suppression

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17

Name two antiproliferative agents?

Mycophenolate Mofetil

Azathioprine

18

What is the MOA of mycophenolate mofetil?

  • Competitive, reversible inhibition of IMPDH, a critical rate limiting enzyme in de novo purine synthesis
  • Lymphocytes dependent on de novo pathway vs. salvage pathway
  • Inhibits proliferation of B and T cells

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19

Where are the origins of mycopheonolate mofetil?

Mycophenolic acid (MPA) isolated from penicillim spp.

Mycopheonolate mofetil (MMF) is a prodrug of MPA

20

Mycophenolate Mofetil administration?

Metabolized by?

Half life?

Oral or IV

Liver

Long (18 hours)

21

What are some unwanted SE for Mycophenolate Mofetil?

  • HTN, edema, tachy
  • dyspnea
  • Leucopenia, thrombocytopenia, anemia
  • Opportunistic infections
  • Lymphoproliferative disease

22

How does Mycophenolate Mofetil interact with the following?

Antacids:

Rifampin, phenytoin, phenobarbital:

Corticosteroids:

Tacrolimus, sirolimus:

Antacids: Decrease MPA levels

Rifampin, phenytoin, phenobarbital: decrease MPA levels

Corticosteroids, cyclosporine: decrease MPA levels

Tacrolimus, sirolimus: no change to MPA levels

23

What is the MOA of azathioprine?

  • Purine analog that is metabolized in the liver to 6-mercaptopurine and then to thiosinosin monophosphate (TIMP)
  • TIMP decreases synthesis of DNA precursors and incorporates into DNA
  • Blocks CD28 co-stimulation of T cells

24

Azathioprine administration?

Half life?

Oral

Short half life (3-5 hours)

25

SE of azathioprine?

  • Bone marrow suppression, leucopenia, thrombocytopenia
  • Hypersensitivity reactions, malaise, diziness
  • Opportunistic infections
  • Alopecia

26

What drug interaction affects azathioprine?

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

27

What are the clinical implications of the SE of...

Azathioprine:

MMF:

Azathioprine: Complete blood counts should be performed regularly to montior for hematologic side effects

MMF: Same as above but note that GI side effects are more common when dose is high and respond to dose reduction or more frequent administration in smaller doses

28

What are three IL2 receptor antibodies and what are they made up of?

Basiliximab (anti CD-25) - 75% human; 25% mouse

Daclizumab (anti CD-25) - 95% human; 5% mouse

Alemtuzumab (anti CD52) - humanized 

29

Basiliximab administration?

Half life?

SE?

IV

Very long half life (1 week)

Hypersensitivity reactions (rare)

30

What is the MOA and use for Belatacept?

  • Fusion protein that binds CD80 and CD86 molecules - blocks co-stimulatory action with Cd28 on T-cell activation
  • Used for renal transplantation in patients seropositive for Ebstein-Barr virus

31

Belatacept half life?

SE?

Very long (8-10 days)

  • SE:
    • hypersensitivity reactions rarely occur
    • Lymphoproliferative disorder

32

What is the MOA of corticosteroids (prednisolone)?

  • Inhibits pro-inflammatory transcription factors such as NF-kB
  • Activates anti-inflammatory genes
  • Reduces T-lymphocyte proliferation and increases apoptosis

33

What are the SE of prednisolone?

  • Cushing syndrome effects
    • acne
    • hirsutism
    • HTN
    • osteoporosis
    • cataracts
    • glucose intolerance

34

What types of agents are used to induce immunosuppression for kidney transplants?

How and when are they administered?

Monoclonal or polyclonal antibodies

Administered intravenously immediately following surgery

35

What agents are used to maintain immunosuppression in kidney transplants?

Prednisolone

Calcineurin inhibitors (cornerstone of immunosuppressive therapy)

Anti-proliferative agents: MMF, azathioprine, sirolimus

36

What are some induction agents used to combat kidney transplant rejection?

  • Muromonab
  • Anti-thymocyte globulin
  • Basiliximab
  • Daclizumab
  • Alemtuzumab
  • FTY270

37

What type of induction agents are the most commonly used today?

Which were most common in 2003?

T-cell depleting type is most common today

IL-2 RA types was most common in 2003

38

What is used more today, MMF or azathioprine?

Mycophenolate mofetil

39

What diseases that we have learned about are treated with only ACEi?

Which can treated with both ACEi and ARB?

  • IgA nephropathy and Focal segmental glomerulosclerosis - Only ACEi
  • Nephrotic syndrome and membranous nephropathy - ACEi or ARB

 

40

Which diseases that we have learned about are treated with only corticosteroids?

Which can be treated with both corticosteroids and immunosuppressants?

Anti-GBM/Goodpastures syndrome and Lupus Nephritis (Class V) - only corticosteroids

IgA nephropathy, membranous nephropathy and FSGS - corticosteroids or immunosuppressants