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Renal Exam > Renal Pharmacology 2 (post-transplant) > Flashcards

Renal Pharmacology 2 (post-transplant) Flashcards

1
Q

What are the 2 calcinurin inhibitors?

A

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

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2
Q

What is calcinurin inhibitors MOA?

A
  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
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3
Q

What are some things to know about Cyclosporine administration?

A

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

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4
Q

What are side effects of cyclosporin?

A
  • 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
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5
Q

What are some drugs that interact with cyclosporine?

A

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

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6
Q

What are some things to know about tacrolimus administration?

A 
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
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7
Q

What are the side effects of tacrolimus?

A

Pleural and pericardial effusions

Cardiomyopathy in children

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8
Q

Which calcineurin inhibitor is used more often?

A

Tacrolimus

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9
Q

What is the mTOR inhibitor we need to know?

A

Sirolimus

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10
Q

What is the MOA of Sirolimus?

A
  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
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11
Q

What are some things you should know about siroliums administration?

A

oral

  • gut absorption modulated by p-glycoprotein
  • metabolized by intestinal and liver CYP450
  • very long half life
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12
Q

What are some side effects of sirolimus?

A
  • Lymphocele (renal transplant complication can cause ureteric compression)
  • Edema, ascites, tachycardia, hypertension
  • GI – abdominal pain, nausea, diarrhea
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13
Q

What are some overall benefits of sirolimus?

A

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

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14
Q

What does Mycophenolate mofetil do?

A

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

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15
Q

What are some things to know about mycophenolate mofetil administration?

A

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

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16
Q

What are some side effects of mycophenolate mofetil?

A
  • hypertension, edema, tachycardia
  • dyspnea, cough
  • dizziness, insomnia, tremor, seizures
  • leucopenia, thrombocytopenia, anemia
  • opportunistic infections: viral cytomegalovirus, bacterial urinary tract
  • lymphoproliferative disease, skin cancer
17
Q

What does azathioprine do?

A

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
Q

What are some alternatives to azathioprine?

A

Methotrexate

Cyclophosphamide

19
Q

What are some things about azathioprine administration?

A

oral

• Short half-life (3-5 hrs)

20
Q

What are some side effects of azathioprine?

A
  • bone marrow suppression leucopenia, thrombocytopenia
  • hypersensitivity reactions, malaise, dizziness, GI tract, fever, rash, hypotension
  • opportunistic infections
  • alopecia
  • small risks for lymphomas
21
Q

What are the drug interactions with azathioprine?

A

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

22
Q

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

A

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

23
Q

What should you know about Basiliximab (Simulect) administration?

A

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

24
Q

What are the side effects of Basiliximab (Simulect)?

A

hypersensitivity reactions rarely occur

25
Q

What is Belatacept?

A

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

26
Q

What is Belatacept used for?

A

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

27
Q

What should you know about Belatacept administration?

A

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

28
Q

What are the side effects of Belatacept ?

A
  • hypersensitivity reactions rarely occur

- lymphoproliferative disorder in those with no prior exposure to Ebstein-Barr virus

29
Q

What is Prednisolone?

A

Corticosteroid

30
Q

How do corticosteroids work?

A
  • 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
Q

What are side effects of steroids?

A 
 Acne
 Cushingoid facial appearance
 Hirsutism
 Mood disorders
 Hypertension 
 Glucose intolerance
 Cataracts
 Osteoporosis
 Growth retardation in children
32
Q

Advances in transplant immunosuppression have contributed to what?

A

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

33
Q

More choices for immunosuppression post transplant has lead to what?

A

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

34
Q

What are induction agents for immunosuppression?

A

 Monoclonal or polyclonal antibodies

 Administered intravenously immediately following surgery

35
Q

What are the maintenance agents of immunosuppression?

A

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

36
Q

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

A 
Muromonab 
Anti-thymocyte globulin 
Basiliximab (Simulect)
Daclizumab (Zenapax)
Alemtuzumab (Campath-1H)
FTY 720
37
Q

What is Muromonab ?

A

humanized anti-CD3

38
Q

What is Anti-thymocyte globulin (ATGAM)?

A

deplete circulating lymphocytes

39
Q

What is FTY 720?

A

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

Renal Exam (22 decks)

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