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Cyclosporine: mechanism of action
- cyclosporine-cyclophilin inhibits calcineurin-mediated activation of NF-AT that leads to cytokine production
- Early activation of T cells is blocked
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Cyclosporine: Adverse Effects
- Nephrotoxicity
- Hypertension
- Neurotoxicity
- Hyperkalemia
- Hyperlipidemia
- Hirsutism
- Hyperuricemia
- Gigival hyperplasia
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Cyclosporine: Absolute contraindications
- Breastfeeding
- caution in patients with conditions that CsA's side effects can worsen
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Cyclosporine: Drug Interactions
- Substrate for CYP3A4
- Inhibitor of CYP3A4
- Substrate of pgp
- Inhibitor of pgp
- Avoid in combination with: Nephrotoxic drugs, drugs that cause hyperkalemia, ACE inhibitors and ARBs
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Tacrolimus: mechanism of action
- Tacrolimus-FKBP inhibits calcineurin-mediated activation of NF-AT that leads to cytokine production
- Early activation of T cells is blocked
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Tacrolimus: Adverse Effects
- Nephrotoxicity
- Hypertension
- Neurotoxicity
- Hyperkalemia
- Hyperglycemia / diabetes
- Elevated liver enzymes
- GI upset
- Hematological abnormalities
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Tacrolimus: Absolute contraindications
- Breast feeding
- caution in patients with conditions that Tacrolimus' side effects can worsen
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Tacrolimus: drug interactions
- Substrate for CYP3A4
- competes for binding of plasma proteins
- interacts with nephrotoxic drugs
- interacts with drugs that cause hyperkalemia, etc
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Sirolimus: mechanism of action
- sirolimus-FKBP inhibits mTOR, which blocks cell cycle progression to G1.
- so it inhibits T cell proliferation in response to cytokines
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sirolimus: adverse effects
- Hypertension
- Hyperlipidemia
- Elevated risk of lymphocele
- delayed graft function
- impaired wound healing
- clotting disorders
- anemia
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sirolimus: drug interactions
- substrate of CYP3A4
- substrate of pgp
- interacts with CsA causing increased sirolimus levels, and increased nephrotoxicity of CsA
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Mycophenolate: mechanism of action
- MPA is a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH).
- this enzyme is used in de novo purine synthesis converting IMP to GMP
- B and T cells depend on de novo synthesis
- so ultimate function of MPA is to inhibit protein synthesis (cytokines, antibodies, adhesion molecules) and inhibition of cell proliferation in B and T cells
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Mycophenolate: adverse effects
- GI upset
- Renal tubular necrosis
- myelosuppression
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Mycophenolate: absolute contraindications
None
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Mycophenolate: drug interactions
- MPA is conjugated w/ glucuronide, so CsA decreases MPA levels
- MPA is highly bound to plasma proteins
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Methotrexate: general information
- rarely used as immunosuppressant
- more common uses in cancer chemotherapy and inflammatory/autoimmune disease
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Azathioprine: mechanism of action
- Azathioprine is metabolized to 6-mercaptopurine (6-MP), which is converted to 6-thioguanine nucleotides (6-TGNs)
- 6-TGN is incorporated into WBC and causes mismatch repair, which then induces cell cycle arrest and apoptosis. This is a short term effect on activated T cells
- 6-MP to MeTIMP. MeTIMP inhibits de novo purine synthesis. this inhibits proliferation and is a long term effect.
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Azathioprine: adverse effects
- GI disturbances
- myelosuppression
- hepatotoxicity
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Azathioprine: absolute contraindications
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Azathioprine: drug interactions
- Allopurinol
- allopurinol inhibits xanthine oxidase, which breaks down 6-MP, so this increases 6-MP toxicity.
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Antithymocyte Globulin: mechanism of action
- antithymocyte antibodies bind to circulating T cells and opsonize them.
- thus, it depletes T cells!!
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Antithymocyte Globulin: adverse effects
- injection site reaction
- serum sickness
- antibodies made against the drug
- thrombocytopenia, neurtopenia (due to cross-reactivity)
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Antithymocyte: contraindications
hypersensitivity to rabbit / horse proteins
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Antithymocyte: drug interaction
did not discuss
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Muromonoab: mechanism of action
- Note: ONLY used for trating rejected transplated organs
- Muromonab antibody targets CD3, which causes the TCR to be internalized. This causes the T cell to either die or not work well (impaired cytokine secretion).
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Muromonab: adverse effects
- Cytokine release syndrome (CD3 binding causes T cell activation and rapid TNFalpha release --> high fever, flu-like symptoms)
- Severe Pulmonary edema
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Muromonab: absolute contraindications
- hypervolemia or uncompensated heart failure (since it predisposes patient to pulmonary edema)
- mouse protein hypersensitivity
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Muromonab: drug interactions
did not discuss
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Daclizumab & Basiliximab: mechanism of action
- Daclizumab antibodies directed against IL-2 receptor.
- Blocks IL-2 activation of T cells
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Daclizumab & Basiliximab: adverse effects
- minimal
- both can produce effects caused by foreign protein injection
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Daclizumab & Basiliximab: absolute contraindications
hypersensitivity
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Daclizumab & Basiliximab: drug interactions
did not discuss
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Belatacept: mechanism of action
antibody against proteins that bind CD28
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Belatacept: adverse effects
did not discuss
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Belatacept: absolute contraindications
EBV-negative, causes lymphoproliferative disorder
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Belatacept: drug interactions
did not discuss
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Glucocorticoids: general information
- used for prevention and treatment of rejection
- used for many other conditions of excess immune or inflammatory actions
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