Immunosuppressive agents: sites of action

2 Proliferation

Agent Prednisone Cyclosporine Azathioprine Methotrexate Dactinomycin Cyclophosphamide Antilymphocytic globulin and monoclonal antiT-cell antibodies Rh3(D) immune globulin Tacrolimus

Site 2, 5 2, 3 2 2 2, 3 2 1, 2, 3
4 Cytokine secretion

3 Differentiation synthesis T cells or antibody Complement Interaction Antigen

1 Antigen recognition (B and T cells)

H IG H-YI E LD SYSTE MS

5 Tissue injury
(Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology, 7th ed. Stamford, CT: Appleton & Lange, 1997:924.)

Cyclosporine

Mechanism Clinical use Toxicity

Binds to cyclophilins. Complex blocks the differentiation and activation of T cells by inhibiting calcineurin, thus preventing the production of IL-2 and its receptor. Suppresses organ rejection after transplantation; selected autoimmune disorders. Predisposes patients to viral infections and lymphoma; nephrotoxic (preventable with mannitol diuresis).

Tacrolimus (FK506)

Mechanism Clinical use Toxicity

Similar to cyclosporine; binds to FK-binding protein, inhibiting secretion of IL-2 and other cytokines. Potent immunosuppressive used in organ transplant recipients. Signicantnephrotoxicity, peripheral neuropathy, hypertension, pleural effusion, hyperglycemia.

M USC U LOSKE LETAL

Azathioprine

Mechanism Clinical use Toxicity

Antimetabolite derivative of 6-mercaptopurine that interferes with the metabolism and synthesis of nucleic acids. Toxic to proliferating lymphocytes. Kidney transplantation, autoimmune disorders (including glomerulonephritis and hemolytic anemia). Bone marrow suppression. Active metabolite mercaptopurine is metabolized by xanthine oxidase; thus, toxic effects may be by allopurinol.

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M U S C U LO S K E LE TAL AN D CO N N E C T I V E T I S S U EP HAR MACO LO G Y ( continue d) Recombinant cytokines and clinical uses

M USC U LOSKE LETAL

H IG H-YI E LD SYSTE MS

Agent Aldesleukin (interleukin-2) Erythropoietin (epoetin) Filgrastim (granulocyte colony-stimulating factor) Sargramostim (granulocytemacrophage colonystimulating factor) -interferon -interferon -interferon Oprelvekin (interleukin-11) Thrombopoietin

Clinical uses Renal cell carcinoma, metastatic melanoma Anemias (especially in renal failure) Recovery of bone marrow Recovery of bone marrow

Hepatitis B and C, Kaposis sarcoma, leukemias, malignant melanoma Multiple sclerosis Chronic granulomatous disease Thrombocytopenia Thrombocytopenia

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