Transplant Drugs

Question 1

What are the three strategies for maintenance therapy in organ transplants?

Answer 1

• Inhibit gene expression of proinflammatory mediators (glucocorticoids)
• Inhibit clonal expansion of lymphocytes (cytotoxic metabolites)
• Inhibit intracellular signaling in lymphocytes to prevent activation and expansion (Calcineurin/IL2 inhibitors and MTOR inhibitors)

Question 2

What are the indications for glucocorticoids?

Answer 2

Graft vs host re bone marrow transplants

Autoimmune disease Tx (RA, SLE, MS)

Limit allergic reactions to Ab-immune Tx

Block 1st dose cytokine storm reaction of transplant drugs

Question 3

What is the MOA of glucocorticoids?

Answer 3

• Bind GRE (glucocorticoid response element) to suppress T and B cell transcription of proinflammatory mediator genes and cytokine genes (TNF alpha, ILs)
• Suppress inflammatory immune cell (macrophages etc) production of prostaglandins by
  
  • upregulating lipocortin to inhibit arachidonic acid
  • down-regulating COX-2

Question 4

What are the side effects of glucocorticoids (prednisone, cortisol)?

Answer 4

• Growth suppression re kids
• Osteopenia
• Infection
• Cataracts
• Decreased wound healing
• HTN
• Depression
• Hyperglycemia (and diabetogenic with calcineurin inhibitors)

Question 5

What are the indications for Azathioprine?

Answer 5

Organ transplants (hi dose)

Autoimmune disease like RA (low dose)

Question 6

What is the MOA of azathioprine?

Answer 6

• Prodrug converted to 6-mercaptopurine (6-MP)
• The de novo purine synthesis pathway converts it to Thio-dGTP
• Thio-dGTP (instead of regular dGTP) is then incorporated into the DNA causing DNA lesions -> apoptosis
• Decreased T cells and B cells

Question 7

What are the side effects of azathioprine?

Answer 7

It affects all rapidly dividing cells so it can cause:

GI toxicity, alopecia, hepatotoxicity, pancreatitis

Myelosuppression (WBC, RBC, platelets)

Question 8

What three factors make the myelosuppression from azathioprine (AZA) worse?

Answer 8

• Allopurinol inhibits xanthine oxidase, an enzyme that metabolizes AZA so reduce dose re gout patients
• ACE inhibitors because they suppress EPO
• Some patients do not make TPMT, an enzyme that metabolizes AZA, so FDA recommends genotyping and decreasing the dose in these patients.

Question 9

What are the indications for use of mycophenolate mofetil?

Answer 9

Organ transplants

Autoimmune diseases

Question 10

Why does mycophenolate mofetil have fewer side effects than AZA?

Answer 10

It selectively targets lymphcytes and has less effect on rapidly dividing cells.

Question 11

What is the MOA of mycophenolate mofetil?

Answer 11

Prodrug hydrolyzed to mycophenolic acid -> inhibits IMP dehydrogenase in the de novo purine synthesis pathway

This blocks conversion of IMP to GTP and dGTP ( building blocks for DNA)

Specific to T cells and B cells because they prefer the de novo pathway, while other cells can use the salvage pathway

Question 12

What are the side effects of mycophenolate mofetil?

Answer 12

Diarrhea

Vomiting

Leukopenia

Congenital abnormalities and miscarriage!

Question 13

Can you combine mycophenolate mofetil with tacrolimus (a calcineurin inhibitor)?

Answer 13

Yes, but you must decresae the dosage of MM because Tacrolimus inhibits its metabolism

Question 14

What are the two calcineurin inhibitors?

Answer 14

Cyclosporine and TaCrolimus

are the Calcineurin inhibitors

Question 15

What are the indications for calcineurin inhibitors?

Answer 15

Immunosuppression re organ transplant

Cyclosporine used off label at lower dose for MANY autoimmune diseases (RA, IBD, psoriasis, etc)

Question 16

What is the MOA of calcineurin inhibitors?

Answer 16

They decrease gene transcription of IL-2 which is critical for T-cell clonal expansion, differentiation and maturation

(and also activation of B-cells)

• Cyclosporine binds to cyclophilin
• Tacrolimus binds to FKBP-12

Question 17

What is the ADME for the calcineurin inhibitors?

Answer 17

IV or oral

Oral dose has variable bioavailability so must monitor blood

Dosed by signs of rejection not by toxicity

Metabolized by CYP3A so adjust dose re other CYP3A drugs

Excreted in feces

Question 18

What are the side effects of calcineurin inhibitors?

Answer 18

Renal dysfunction (dose-limiting and cause for D/C)

HTN re kidney and cardiac transplant patients

Diabetogenic (especially combined with glucocorticoids)

Infections and malignancies (esp nonmelanoma skin CA)

Question 19

What should you consider when deciding to prescribe Cyclosporine or Tacrolimus?

Answer 19

Cyclosporine is worse re kidneys, HTN, diabetogenesis

Tacrolimus has neurotoxic effects: HA, tremor, seizures, motor disturbances

Question 20

You have a heart transplant patient who is taking a calcineurin inhibitor and gets HTN. What can you use to treat the HTN?

Answer 20

CCBs, BBs, diuretics

Careful re ACE inhibitors if also on AZA

Question 21

What are the indications for Sirolimus (aka Rapamycin)?

Answer 21

Immunosuppression re organ transplant

Question 22

What is the MOA of sirolimus?

Answer 22

It is an mTOR inhibitor

It binds to FKBP-12 and inhibits mTOR (a key enzyme for T-cell activation and proliferation through translation of mRNA)

Question 23

What is the ADME for Sirolimus?

Answer 23

Oral administation

Metabolized by CYP3A so dose adjust

Bioavailability varies widely so follow blood levels

Excretion: fecal

Question 24

What are the side effects of Sirolimus?

Answer 24

Hyperlipidemia (dose dependent)

Myelosuppression (less with calcineurin inhibitors)

Hypertension (dose dependent)

Lymphocoele (lymphatic fluid around kidney transplant)

Renal toxicity if pre-existing nephropathy

Question 25

Which two transplant drugs should NOT be combined?

Answer 25

Sirolimus and Cyclosporine

Combination increases the renal toxicity of cyclosporine

and the hyperlipidemia and myelosuppression of sirolimus

These two do not play well together!