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31 Cards in this Set
- Front
- Back
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Pharmacologic classes
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Alter gene expression
Cytotoxic agents - deplete lymphocytes Inhibitors of cytokines - blocks signaling/expansion Depletion of specific immune cells Inhibitors of co-stimulation (promotes anergy) Block cell adhesion (prevent migration) Inhibit innate immunity (complement) |
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Agents that inhibit gene expression
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Glucocorticoids
Broad anti-inflammatory effects |
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Antimetabolites
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Act as cytotoxic agents
Azathrioprine Mycophenolate mofetil Methotrexate Leuflunomide |
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Azathioprine mechanism and use
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1st drug used following trasplant
Cytotoxic drug Metabolized to 6-mercaptopurine (6MO) Feedback inhibits purine de novo synthesis Uses: organ transplant (esp renal), autoimmune |
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Azathioprine adverse effects
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Fever, bone marrow suppression, GI, secondary infection, malignancy
Is teratogenic Requires TPMT for metabolism If taking drugs for hyperuricemia or with renal dysfunction, reduce dose No renal toxicity |
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Mycophenolate mofetil mechanism and use
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Cytotoxic - antimetabolite
Newer, less side effects than azathioprine Prodrug for mycophenolic acid (MPA) Use - organ transplant (better than AZA), lupus, MG Mechanism - inhibits IMP dehydrogenase - de novo GMP synthesis, preferentially acts on lymphocytes (isoform in lymphocytes) - can induce apoptosis |
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Mycophenolate mofetil adverse effects
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Dose dependent
GI disturbances, HTN, pain, rash Pregnancy D risk Relative lack of nephrotoxicity |
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Methotrexate
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Cytotoxic antimetabolite
Analog of dihydrofolate - inhibits folate-dependent enzymes |
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Leuflunomide
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Cytotoxic antimetabolite
Prodrug whose metabolite inhibits pyrimidine nucleotide synthesis |
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Cyclophosphamide mechanism and use
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Cytotoxic alkylating agent, one of most efficacious immunosuppressives
Cell-cycle nonspecific prodrug Mechanism - transformed in liver (CYP450) to metabolites that creates cross links within DNA - prevent replication Cytotoxic to B and T cells, also some resting cells Use - autoimmune, transplant, cancer chemotherapy |
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Cyclophosphamide adverse effects
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Sterility in both sexes (all alkylating agents)
GI disturbances Alopecia Infection Bone marrow suppression Higher doses - secondary malignancies, hemorrhagic cystitis |
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Cytokine inhibiting agents
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Cyclosporin - macrolide antibiotic
Tacrolimus Sirolimus |
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Cyclosporin mechanism
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Activation of TCR leads to increased intracellulaer Ca
Activates calcineurin (CaN) - cytoplasmic phosphatase that activates T-cell specific transcription factor NFATc - production of IL-2 T cells require IL-2 for proliferation Cyclosporin binds to immunophilin - cyclophilin Cyclosporin-cyclophilin complex binds to and inhibits CaN - no IL-2 production - decreased T cell proliferation Note - once T cells have been stimulated to produce IL-2 by APCs, CsA cannot suppress |
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Cyclosporin actions and uses
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Suppresses cell-mediated immunity
Specificity for T cells, B cells not impacted Uses - organ transplant, graft v host disease, RA, psoriasis Commonly used for keratoconjunctivitis sicca Usually combined with low dose corticosteroids |
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Cyclosporin adverse effects
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MC - nephrotoxicity (reversible)
HTN - treat with Ca channel blockers Gingival hyperplasia Hyperlipidemia Neurotoxicity (mild tremor) Hepatotoxicity Infections (herpes, CMV) Hirsutism (treat with metronidazole) |
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Tacrolimus mechanism
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Macrolide, 10-100x more potent than CsA
Mechanism similar to CsA, but binds to different immunophilin - FKBP (binds calcineurin) Metabolized by CYP3A4 (like CsA) |
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Tacrolimus uses
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Liver and kidney transplant
Rescue therapy in patients who fail standard therapy Given with corticosteroid (lower dose than CsA) |
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Tacrolimus adverse effects
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Nephro- and neurotoxicity
Post transplant malignancy and opportunistic infection Diabetes mellitus!!!! Lower incidence of hyperlipidemia, HTN than CsA Any drug that affects CYP3A4 will affect activity |
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Sirolimus mechansim
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Rapamycin, similar to tacrolimus
Binds to FKBP, complex blocks cellular response to IL-2 (does not block calcineurin/IL-2 production) Inhibits mTOR - stops cell cycle progression (G1 to S) |
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Sirolimus actions/uses
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Inhibits signaling after IL-2 receptor
Stops T cell and B cell proliferation Used alone or with CsA (synergistic) Acute rejection of kidney transplant Graft v host disease Sirolimus-eluting stents - treatment of CAD |
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Sirolimus adverse effects
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Bone marrow suppression
Myelosuppression - thrombocytopenia, leucopenia Hyperlipidemia Hepatotoxicity Minimal renal toxicity |
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Antibody drugs
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Polyclonal and monoclonal (mAb)
Murine Ab drugs - short half life, produce human anti-mouse Ab response (HAMA), doses must go up Humanized - less likely to generate immune response, better for chronic therapy |
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TNF alpha inhibitors
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Etanercept
Infliximab Adalimumab |
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Anakinra mechanism
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IL-1 inhibitor, recombinant form of IL-1R antagonist
IL-1 - bridge between innate and adaptive immunity IL-1 stimulates IL-6 - adhesion molecules, cell proliferation |
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Anakinra uses
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Moderate to severe RA - modest effect on pain, reduces bone erosion
Fever disorders - Muckle-Wells, Hiberian fever (driven by IL-1) |
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Anakinra side effects
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Neutropenia, increased infections
Do not use with TNF alpha inhibitors - serious infections |
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OKT3 mechanism and use
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Muromonab CD3 - murine mAb to CD3 on T cells
Binds to CD3, prevents T cell activation; binding can lead to transient activation of T cells and cytokine storm, then depletion Use - Acute rejection of transplant, deplete T cells in marrow of donors before BMT, second line agent if CsA/glucocorticoids fail |
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OKT3 adverse effects
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Cytokine release syndrome - fever, myalgia, nausea, chills, pulmonary edema
GI HAMA response Malignancies and infections Profound immunosuppression |
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Basiliximab
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Mechanism - prevents activation of T cells - IL-2 antagonist
mAb against CD25 (IL-2R alpha chain) - activated cells only Use - prophylaxis in renal transplant, combined with corticosteroids and CsA for general immunosuppression following transplant, graft v host Side effect - GI |
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Rituximab
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Chimeric mAb against CD20 - B cells
Binds CD20, recruits immune effectors for B cell lysis Use - treatment of non-Hodgkin's B cell lymphoma Side effects - bone marrow suppression, fever, hypersensitivity |
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Abatacept
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Chimeric protein, complexes with B7 on APCs
Prevents delivery of costimulation (signal 2) to T cell T cell anergy, apoptosis - downregulates T cells Use - refractory RA Side effects - bronchitis exacerbation, infection Do not administer with TNF alpha inhibitor or anakinra |
