Immunosuppressive Drugs

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cyclophosphamide

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only alkylating agent used for immunosuppression. Alklates DNA particularly in proliferating cells therby interfering with DNA synthesis and function. Destroys proliferating T and B cells and resting cells. TOXICITY: hemorrghagic cystitis, pancytopenia (of bone marrow), infertility (gametogenesis affected), alopecia (hair loss), DRUG INTERACTION REMEMBER -- cimetidine and allopurinol delay metabolism (due to metabolism by P450 system)

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methotrexate

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antimetabolite. Inhibits folate dependent enzymes involved in purine synthesis. Toxic to all rapidly dividing cells including GI epithelium and bone marrow. TOXICITY: Liver (hepatic fibrosis), Kidney (nephrotoxicity), Lung (interstitial pneumonitis), Hair (alopecia), abortion/Teratogenesis

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azathioprine

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antimetabolite, purine derivative. Pro-drug (Active component is 6-mercaptopurine). Inhibits purine synthesis. Prevents proliferation of helper CD4+ cels and CD8 cells. SIDE EFFECTSs (generally toxic to rapidly dividing cells) -- pancytopenia, alopecia, hepatotoxicity, increased squamous cell CA and lymphoma in organ transplantation due to prolonged use. DRUG INTERACTIONS: Xanthine oxidase inhibitors (allopurinol) interfers with metabolism of azathioprine causing increased risk of toxicity and severe immunosuppression. Trimethroprim-sulfamethoxazole (bactrim) -- severe neutropenia DEADLY interaction (mech unknown).

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mycophenolate

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antimetabolite, purine analog and prodrug. Active metabolite is mycophenolic acid (MPA). Potent inhibitor of inosine monophosphate dehydrogenase, enzyme critical for purine synthesis. Prevents proliferation of CD4 and CD8 T cells. MAJOR SIDE EFFECTS: toxicity virtually idential to azathioprine (pancytopenia, alopecia, hepatotoxicity, squamous cell CA and lymphoma in organ transplantation due to prolonged use) but less severe, but can also have more GI bleeds. No concern for drug interactions.

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sirolimus

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antimetabolite. Macrocyclic lactone produced by streptomyces hygroscopicus. Inhibits T lymphocyte activationa nd proliferation. Forms complex with FKBP12 to bind and inhibit mammalian kinase (mTOR) resulting in CELL CYCLE ARREST. VERY SPECIFIC -- opened door to targeted therapy in immunosuppression. Indications: organ transplantation (reduced dose of steroids needed). SIDE EFFECTS: same as MPA plus increase in serum triglyceride and cholesterol levels. DRUG INTERACTOIN: CYP3A4 pathway (e.g. grapefruit juice...endless list)

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cyclosporine

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calcineurin inhibitor. Inhibits IL-2 mediated T cell response to antigenic stimuli. Binds cyclophillin to form complex resulting in inhibition of calcineurin phosphatase activity (so that dephosphrorlation and translocaiton of cytosolic regulatory proteins does not occur). Revolutionized transplantation field. Reduced risk of opportunistic infections and cancer; steroid sparing; no marrow suppression (unclear why). TOXICITY: nephrotocoity, hepatotoxicty (transaminases), hyperglycemia (diabetes), secondary tumors and infections, hirsutism/gum hypertrophy, expensive. CYP3A DRUG INTERACTIONS: ACCELERATE CLEARANCE -- phenytoin (anti-epileptic), rifampin (used in TB), trimethoprin-sulphamethoxazole. DECREASE CLERAANCE -- calcium channel blockers, amphotericin B (antimicrobial), erythromycin (macrolide antibiotic), ketoconazole (antifungal). Monitor drug levels closely.

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tacrolimus

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calcineurin inhibitor. Inhibits IL-2 mediated T cell response to antigenic stimuli. Binds FKBP to form complex resulting in inhibition of calcineurin phosphatase activity (so that dephosphrorlation and translocaiton of cytosolic regulatory proteins does not occur). TOXICITY: nephrotoxocity, hepatotoxict, hyperglycemia/diabetes, neurotoxicity, secondary rumosr and infections. expensive. CYP3A DRUG INTERACTIONS: ACCELERATE CLEARANCE -- phenytoin (anti-epileptic), rifampin (used in TB), trimethoprin-sulphamethoxazole. DECREASE CLERAANCE -- calcium channel blockers, amphotericin B (antimicrobial), erythromycin (macrolide antibiotic), ketoconazole (antifungal). Monitor drug levels closely.

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polyclonal antibodies

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indications: solid organ transplantation as an anti-ACUTE REJECTION therapy, in combination with cyclosporine, prednisone, and or azathioprine; used prior to BMT to prevent GVH disase; induction/prophylaxis of immunosuppression. MAJOR SIDE EFFECTS: clinical toxicity have allergy-like symptoms-- chills, fever, erythemema, pruritus, thrombycytopenia (mech unknown). Profound immunosuppression. Animal source = serum sickness. Repeated use develops anti antibodies.

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anti-CD3 aka OKT3 aka muromonoab-CD3

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Ab binds Cd3 of T cells, blocks recognition, signaling. Cell receptor is internalizd. Lymphocytes are oposonized by RE system. Depletion of peripheral lymphocytes an reduction of IL2 formation. MAJOR SIDE EFFECTS: Cytokine release syndrome (within 30min.) -- associated with TNFalpha releease, fever, pulmonary edema, aspectic meningitis, diarrhea...life threatening!!. Prevent side effects by prophylactic treatment of steroids, acetaminophen (purely to treat fever) and histamine antagonist.

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anti-IL2 receptor Ab (anti-CD25)

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daclizumab and basiliximab monoclonal Ab's block IL-2 mediated T cell activation.

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anti-TNF alpha Ab (adalimumab, infliximab, enterecept)

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monoclonal Ab. Used with methotrexate in treatment of RA and Crohn's. Blocks TNF alpha binding ot receptor.