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Renal > Renal Pharmacology Part 2 > Flashcards

Renal Pharmacology Part 2 Flashcards

1
Q

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

A

Memory T cells

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2
Q

What are the three signal approaches to immunosuppression?

A
  • Calcineurin
    • Cyclosporine, Tacrolimus
  • mTOR
    • Sirolimus
  • Cell Cycle
    • Azathioprine
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3
Q

What type of drug is cyclosporine?

How is it metabolized?

What is it’s half life?

A

Calcineurin inhibitor (binds to cyclophlin)

Metabolized by CYP3A4 in liver

Long half life (27 hours)

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4
Q

How does Cyclosporine lead to nephrotoxicity?

What are its other side effects?

A

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

  • Other SE
    • HTN
    • Hepatic dysfunction
    • Hypertrichosis (excessive hair growth)
    • GI
    • Gum hypertrophy
    • Hyperlipidemia
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5
Q

What are drug interaction that occur with cyclosporine?

A

Nephrotoxic drugs - NSAIDs, aminoglycosides

Drugs that induce CYP3A4 - phenytoin, carbamazepine

Drugs that inhibit CYP450 - erythromycin, ketoconazole

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6
Q

What is tacrolimus?

How is the same as cyclosporine?

How is it different?

A
  • 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
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7
Q

Tacrolimus SE

A

Pleural and pericardial effusions

Cardiomyopathy in children

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8
Q

What events should be monitored for when administering calcineurin inhibitors?

A
  • Hepatotoxicity
  • Cardiovascular (hypertension and hypercholesterolemia)
    • Tacrolimus has less cardiovasc. SE
  • Glucose intolerance
  • Neurotoxicity - seen more often with tacrolimus
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9
Q

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

Nephrotoxic agents:

Potassium sparing diuretics:

Antacids:

HMG-CoA reductase inhibitors (Statins):

A
  • 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
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10
Q

The calcineurin inhibitor most commonly used today is

A

Tacrolimus

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11
Q

What is the MOA of Sirolimus?

A
  • 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
Q

How is Sirolimus administered?

How is it metbolized?

What is its half life?

A

Oral

Metabolized by intestinal and liver CYP450

Very long half-life (60 hours)

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13
Q

What are some SE for Sirolimus?

A
  • Edema, ascites, HTN
  • GI
  • Hyperlipidemia
  • Hypokalemia
  • Hypophosphatemia
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14
Q

What drugs interact with Sirolimus?

A

Drugs that induce CYP3A4 - rifampicin

Drugs that inhibit CYP450 - itraconazole, ketoconazole

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15
Q

What are the benefits of Sirolimus over calcineurin inhibitors?

A
  • Potent prophylaxis against acute cellular rejection
  • Less vasoconstriction
  • No associated with acute or chronic renal insufficiency (sustained GFR)
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16
Q

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

A

Bone marrow suppression

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17
Q

Name two antiproliferative agents?

A

Mycophenolate Mofetil

Azathioprine

18
Q

What is the MOA of mycophenolate mofetil?

A
  • 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
19
Q

Where are the origins of mycopheonolate mofetil?

A

Mycophenolic acid (MPA) isolated from penicillim spp.

Mycopheonolate mofetil (MMF) is a prodrug of MPA

20
Q

Mycophenolate Mofetil administration?

Metabolized by?

Half life?

A

Oral or IV

Liver

Long (18 hours)

21
Q

What are some unwanted SE for Mycophenolate Mofetil?

A
  • HTN, edema, tachy
  • dyspnea
  • Leucopenia, thrombocytopenia, anemia
  • Opportunistic infections
  • Lymphoproliferative disease
22
Q

How does Mycophenolate Mofetil interact with the following?

Antacids:

Rifampin, phenytoin, phenobarbital:

Corticosteroids:

Tacrolimus, sirolimus:

A

Antacids: Decrease MPA levels

Rifampin, phenytoin, phenobarbital: decrease MPA levels

Corticosteroids, cyclosporine: decrease MPA levels

Tacrolimus, sirolimus: no change to MPA levels

23
Q

What is the MOA of azathioprine?

A
  • 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
Q

Azathioprine administration?

Half life?

A

Oral

Short half life (3-5 hours)

25
Q

SE of azathioprine?

A
  • Bone marrow suppression, leucopenia, thrombocytopenia
  • Hypersensitivity reactions, malaise, diziness
  • Opportunistic infections
  • Alopecia
26
Q

What drug interaction affects azathioprine?

A

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

27
Q

What are the clinical implications of the SE of…

Azathioprine:

MMF:

A

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
Q

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

A

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

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

Alemtuzumab (anti CD52) - humanized

29
Q

Basiliximab administration?

Half life?

SE?

A

IV

Very long half life (1 week)

Hypersensitivity reactions (rare)

30
Q

What is the MOA and use for Belatacept?

A
  • 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
Q

Belatacept half life?

SE?

A

Very long (8-10 days)

  • SE:
    • hypersensitivity reactions rarely occur
    • Lymphoproliferative disorder
32
Q

What is the MOA of corticosteroids (prednisolone)?

A
  • Inhibits pro-inflammatory transcription factors such as NF-kB
  • Activates anti-inflammatory genes
  • Reduces T-lymphocyte proliferation and increases apoptosis
33
Q

What are the SE of prednisolone?

A
  • Cushing syndrome effects
    • acne
    • hirsutism
    • HTN
    • osteoporosis
    • cataracts
    • glucose intolerance
34
Q

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

How and when are they administered?

A

Monoclonal or polyclonal antibodies

Administered intravenously immediately following surgery

35
Q

What agents are used to maintain immunosuppression in kidney transplants?

A

Prednisolone

Calcineurin inhibitors (cornerstone of immunosuppressive therapy)

Anti-proliferative agents: MMF, azathioprine, sirolimus

36
Q

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

A
  • Muromonab
  • Anti-thymocyte globulin
  • Basiliximab
  • Daclizumab
  • Alemtuzumab
  • FTY270
37
Q

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

Which were most common in 2003?

A

T-cell depleting type is most common today

IL-2 RA types was most common in 2003

38
Q

What is used more today, MMF or azathioprine?

A

Mycophenolate mofetil

39
Q

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

Which can treated with both ACEi and ARB?

A
  • IgA nephropathy and Focal segmental glomerulosclerosis - Only ACEi
  • Nephrotic syndrome and membranous nephropathy - ACEi or ARB
40
Q

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

Which can be treated with both corticosteroids and immunosuppressants?

A

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

IgA nephropathy, membranous nephropathy and FSGS - corticosteroids or immunosuppressants

Renal (17 decks)

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