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Pharm 2 - Exam 3 > Lecture 2 - Drugs for Transplantation > Flashcards

Lecture 2 - Drugs for Transplantation Flashcards

1
Q

How do glucocorticoids play a role in preventing organ transplant rejection?

A

inhibit gene expression of pro-inflammatory mediators

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2
Q

Which drugs inhibit clonal expansion of lymphocyte population?

A

cytotoxic antimetabolites

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3
Q

What are the indications for glucocorticoids like cortisol and prednisone?

A

organ transplant

autoimmune dz

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4
Q

What is the MOA of glucocorticoids?

A

both suppress T and B cell transcription as well as suppress inflammatory immune response via inhibiting arachodonic pathway

binds to GR (glucocorticoid) –> dimerizes

suppress T and B cell transcription of pro inflammatory mediator genes and cytokine genes (TNF alpha, IL, - 1, 2, 4, 6)

suppress inflammatory immune cell (monocytes, macrophages) production of prostaglandins and thromboxane A2 by:

  • up regulating lipocortin gene transcription. Lipocortin protein inhibits PLA2, thus preventing arachidonic acid mobilization
  • down regulating CoX2 transcription
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5
Q

What are the adverse effects of glucocorticoids?

A 
infections 
hyperglycemia
HTN
depression
osteoporosis
growth suppression in children 
impaired wound healing
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6
Q

Azathioprine

A

cytotoxic antimetabolite

used in organ transplant

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7
Q

What is the MOA or azithioprine?

A

prodrug

converted non-enzymatically to 6-MP (mercaptopurine), a purine analog that is subsequently converted to Thio-dGTP by de novo purine synthesis pathway.
Thio-dGTP incorporated into DNA of replicating immune cells, leading to suppression of T and B cell proliferation

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8
Q

What are the side effects of azathioprine?

A

melosuppression

drug interaction between azathioprine and allopurinol (used in Gout tx)
allopurinol inhibits XO metabolism of 6-MP, leading to life threatening myelosuppresion

pts on allopurinol for gout –decrease dosage of azathioprine

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9
Q

Which drugs should be used with caution when using azathioprine?

A

allopurinol
ACE-inhibitors –risk of potentiating myelosuppression (since ACE inhibitors ACE-I suppress erythropoeitin)

TPMT metabolized 6-MP; FDA recommends genotyping pts for inactive allele of TPMT; pts with inactive allele - decrease dosage of azathiprine

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10
Q

TPMT

A

thiopurine methytransferase

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11
Q

MM

A

Mycophenolate mofetil

“new” cytotoxic antimetabolite

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12
Q

What is the MOA of MM?

A

mycophenolate mofetil

prodrug hydrolyzed to mycophenolate, an inhibitor of IMP dehydrogenase (IMPDH) in B and T cells; decrease purine biosynthesis

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13
Q

What are the adverse reactions of MM?

A

mycophenolate mofetil

diarrhea
vomiting
leukopenia
congenital 
abnormalities
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14
Q

Why is MM considered less toxic overall compared to azathioprine, methotreaxate and glucocorticoids?

A

MM selectively targets lymphocyte population (B and T cells) d/t:

1) lymphocyte population dependent on de novo purine synthesis pathway (containing IMPDH) for synthesis of guanine nucleotide
other cell types can alternatively use purine salvage pathways for synthesis of guanine nucleotides

2) mycophenolate preferentially inhibits type 2 isoform of IMPDH, which is primarily expressed in lymphocytes

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15
Q

What drug drug interaction is seen with MM?

A

mycophenolate mofetil and tacrolimus

Tacrolimus impaires flucouronide conjugation of mycophenolic acid
therefor you want to decrease dosage of mycophenolate mofetil when combining with tacrolimus

no complications when combining mycophenolate mofetil with cyclosporine

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16
Q

Calcineurine Inhibitors

A

IL-2 production inhibitors

Cyclosporine
Tacrolimus

17
Q

Cyclosporine

A

Calcineurine inhibitor

18
Q

What is the MOA for cyclosporine?

A

binds to cyclophilin to inhibit calcineurine, leading to inactive NFAT and decreased IL-2 gene transcription in T-cells

19
Q

What are side effects of cyclosporine?

A

renal dysfunction
HTN in 50% of renal transplant pts and most cardiac transplant pts
diabetagenic

metabolized by CYP3A

20
Q

When cyclosporine is given with ____drug, it is diabetogenic?

A

glucorticosteroids

however it is given with steroids in order to lower the dose needed for cyclosporine

monitor glucose levels!

this is the same for Tacrolimus drugs

21
Q

Tacrolimus

A

calcineurine inhibitors

immunosuppressant for organ transplantation (not for autoimmune diseases)

22
Q

What are the indications for tacrolimus?

A

immunosuppressant for organ transplantation (not for autoimmune diseases)

23
Q

What are the indications for cyclosporine?

A

organ transplant

(off-label) autoimmune disease

24
Q

What is the MOA of tacrolimus?

A

calcineurin inhibitor

binds to FKBP -12 to inhibit calcineurin, leading to inactive NFAT and decreased IL-2 gene transcription in T-cells

25
Q

What are the side effects of tacrolimus?

A

renal dysfunction
HTN
diabetagenic

metabolized by CYP3A

26
Q

Sirolimus

A

rapamycin

used for immunosuppressant for organ transplantation

MOA:
mTOR inhibitor

binds to FKBP -12 to inhibit mTOR, leading to decreased translation of proteins needed for proliferation on T-cells

SE: 
hyperlipidemia
myelosupression 
HTN
lymphococele

metabolized by CYP3A

thought to be associated with less renal toxicity compared to calcineurin inhibitors

27
Q

What is the MOA of sirolimus?

A

rapamycin

mTOR inhibitor

binds to FKBP -12 to inhibit mTOR, leading to decreased translation of proteins needed for proliferation on T-cells

28
Q

What are the side effects of sirolimus?

A

hyperlipidemia
myelosupression
HTN
lymphococele

metabolized by CYP3A

29
Q

What are the indications for sirolimus?

A

used for immunosuppressant for organ transplantation

also can be used for targeted HER2 negative breast cancer tumors

Pharm 2 - Exam 3 (6 decks)

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