Corticosteroid

Uses: Leukemias/lymphomas (lympholytic effects) ;Short term (1-3 weeks) post transplant to decrease rejection; given high dose to rescue in acute rejection; combo with other immunosuppressives in transplant pts; minimize allergic responses; autoimmune disease

Immunosuppressive Effects: General immunosuppressive, affects entire immune system: cause lysis of lymphocytes, decrease activation of NF-kB, increase apoptosis of activated T-cells, inhibit T cell proliferation and decrease IL-1,2,6 gene expression; Inhibit response of cytotoxic T cells and NK cells to IL-2 and other cytokines

Side effects: hyperglycemia; osteoporosis; suppression of hypothalamic-pituitary-adrenal axis; cushings syndrome; immune suppression

T-Cell suppressant: Calcineurin inhibitor

Uses: Transplant rejection prophylaxis, BM transplants, autoimmune disorders (psoriasis, RA)

Mechanism: Binds cyclophilin, blocks T cell activation by preventing IL-2 transcription (Inhibiting calcineurin)

Side effects (Worse): No BM suppression, Nephrotoxicity, HTN, hyperlipidemia, hyperglycemia, CNS (tremor), gingival hyperplasia

COMPARE/CONTRAST WITH TACROLIMUS/SIROLIMUS

Dx Interactions (CYP 3A4 spec.):

- Induce CYP3A, decrease cyclosporin concentration = Phenobarbital, phenytoin, rifampin

- Inhibit CYP3A, increasing cyclosporin concentration = Erythromycin, ketoconazole, verapamil

NO GRAPEFRUIT JUICE

T-cell suppressant: Calcineurin inhibitor

Uses: prevent rejection in transplant particulalry liver, kidney, heart; "rescue: of rejection

Mechanism: binds FK506 binding protein (FKBP); Blocks T cell activation by preventing IL-2 transcription; decreases IL-2 and IL-4; inhibits calcineuron

Side effects (Better): no BM suppression; nephrotoxicity, HTN, Hyperglyemia (especially with corticosteroids, may need insulin), CNS (tremor, headache, insomnia); Opportunistic infections and neoplams especially skin cancer

COMPARE/CONTRAST WITH CYCLOSPORINE

Dx Interactions (CYP 3A4 spec.):

- Induce CYP3A, decrease cyclosporin concentration = Phenobarbital, phenytoin, rifampin

- Inhibit CYP3A, increasing cyclosporin concentration = Erythromycin, ketoconazole, verapamil

NO GRAPEFRUIT JUICE

Other Drugs: Pimecrolimus (Elidel®) - topical cream for atopic dermatitis; causes skin irritation

Belatacept (Nulojix) - specifically for prevention of kidney transplant rejection with history of epstein barr

Cell proliferation Inhibitors

Uses: Kidney transplant rejection prophylaxis

Mechanism: mTOR inhibitor; binds FKBP; blocks T cell activation and B cell differentiation by preventing IL-2 signal transduction

Side effects: NON-NEPHROTOXIC; causes BM suppression, increases cholesterol/TAG; profound myelosuppression; anemia, leucopenia

COMPARE/CONTRAST WITH CYCLOSPORINE

Cell proliferation inhibitor

Uses: prevent rejection (combo with cyclosporine/tacrolimus and glucocorticoids)

Mechanism: (Inhibits T and B cells): Prodrug converted to mycophenolic acid; Inhibits monophosphate dehydrogenase (IMP dehydrogenase) which is needed for de novo purine synthesis in T and B lymphocytes; selectively suppresses lymphocyte proliferation and antibody formation by B cells

Side effects: Rash; Infections

NOT FOR PREGNANT, MUST BE ON CONTRACEPTION

Cell proliferation inhibitor

Uses: Transplant rejections prophylaxis, Severe RA, Crohn, glomerulonephritis, other autoimmune conditions

Mechanism: Antimetabolite precursor of 6-mercaptopurine (allopurinol = less azathiprine should be given); Inhibits lymphocyte proliferation by blocking nucleotide synthesis

Side effects: Bone marrow suppression, Teratogenic (fetal tox); Infection risk, especially herpes; leukopenia, anemia, thrombocytopenia

Interaction w/ allopurinol: Reduce dose if used by allopurinol (6-MP degraded by xanthine oxidase, which is inhibited by allopurinol, increasing toxicity of 6-MP)

Other Drugs: Leflunomide (Arava®) - RA drug, causes liver damage, teratogenic

Cell proliferation inhibitor: Alkylating agent

Unique uses: Can destroy T-cells, and block response to new antigens; can inhibit established immune response -> Organ tansplant rescue/BM transplants; Antineoplastic; severe MS, RA and SLE

Mechanism: binds DNA at guanine; directly effects B and T cells

Side effects (& how to decrease): CYP450 activated (Inhibitors make cycophosphamide less effective i.e. ketoconazole, rifampin); Hemorrhagic cystitis (hydrate + MESNA); BM suppression, bladder fibrosis, TERATOGENIC

Cell proliferation Inhibitor

Uses: Immunosuppression (organ transplant recipients, RA, psoriasis

Mechanism (immunosuppressive effects): folic acid analog that inhibitis dihydrofolate reducase; Decreases lymphocyte and macrophage functions

Side effects: BM suppression, teratogenic!; alopecia, hepatotoxicity with chronic use

Cell proliferation inhibitor

Use: Many uses; Multiple myeloma, prvent graft vs. host reactions, acute myelogenous leukemia; solid tumors; HIV wasting, decreases ulcer, causes weight gain

Mechanism: Suppresses TNF-a: shifts T cell response toward TH2 subset, with increased IL-4 and IL-5; Decreases activity of neutrophils while enhancing cell mediated immunity by T-cells

Precautions: TERATOGENIC!!! DVT risk in hematologic cancers

Antibody Immunosuppressant

Use: Acute transplant rejection, steroid resistant rejection, kidney rejection; Deplete T cells from donor bone marrow

Mechanism: Monoclonal antigody to CD3 glycoprotein on T lymphocytes (binding site); T cells are then removed from circulation - no CD3 or antigen recognition sites

Side effects: Cytokine release syndrome -> Ranges from flu-like symptoms to anaphylactoid shock; fever, chills, nausea common

Antibody Immunosuppressant

Use: Prophylaxis for renal rejection (given in 2 injections immediately after transplant), used at induction at transplant

Mechanism: Humanized/chimeric monoconal antibodies that bind to and block IL-2 receptor on activated T cells,inhibits further IL-2 activation

Adverse: VERY FEW

Antibody Immunosuppressant

Use: Prophylaxis for renal rejection, used at induction of transplant

Mechanism: Humanized/chimeric monoconal antibodies that bind to and block IL-2 receptor on activated T cells, inhibits further IL-2 activation

Adverse: VERY FEW

Antibody Immunosuppressant

Use: Rescue a rejection episode

Mech: Binds T cells, pulling them out of circulation

Side effects: Not human so cytokine release syndrome or allergic reactions; People will get really sick

Other Drugs: Efalizumab (Raptiva) - psoriasis, anti-CD11

Immunomodulator/Immunostimulant

Uses: Chronic Hep B and C (alfa-2a only HCV) with ribavirin, Hairy cell carcinoma/AIDS kaposi's sarcoma

Mechanism: increases response to viruses

Side effects: depression, suicide; flu like symptomes, BM suppression, alopecia

Other Drugs: Interferon B-1b (Betaseron®) - increases response to viruses; MS

Interferon Gamma (Actimmune®) - activates macrophages, higher toxicity

Immunostimulant

Uses: Metastatic renal cell carcinoma (5-10% effective), malignant melanoma

Mechanism: Turns everything on. Stimulates production and activity of T cells; increases number of B cells, stimulates macrophages, increases killer cell and NK cell activity, induces interferon gamma productino

Side effects: severe hypotension, pulmonary, hematologic, fever, chills, pain

Immunomodulator/Immunostimulant

Uses: Neutropenia caused by stem cell transplant, chemotherapy, HIV treatment or interferon

Mechanism: human recombinant C-CSF that stimulates  granulocyte formation

Side effects: Bone pain, injection site reaction

Immunomodulator/Immunostimulant

Uses: Anemia from chemo, EPO deficient pts with CKD

Mechanism: action on EPO receptor on RBC progenitors to stimulate erythroid proliferation

Side effects: HTN, increase risk of thrombosis