Chapter 22 Immunosuppressive Drugs and Drugs Used in the Treatment of Rheumatic Disorders and Gout
1. These drugs are used to suppress immune responses under a wide number of conditions where an overactive immune system contributes to pathogenesis (Table 22-2).
(2) Converted to 6-mercaptopurine (6-MP) by glutathione-S-transferases and then to 6-thiouric acid by xanthine oxidase
Table 22-1 Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation
| Drug | Site of action |
|---|---|
| Glucocorticoids | Glucocorticoid response elements in DNA (regulate gene transcription) |
| Muromonab-CD3 | T-cell receptor complex (blocks antigen recognition) |
| Cyclosporine | Calcineurin (inhibits phosphatase activity) |
| Tacrolimus | Calcineurin (inhibits phosphatase activity) |
| Azathioprine | Deoxyribonucleic acid (false nucleotide incorporation) |
| Mycophenolate Mofetil | Inosine monophosphate dehydrogenase (inhibits activity) |
| Daclizumab Basiliximab | Interleukin-2 receptor (block IL-2−mediated T-cell activation) |
| Sirolimus | Protein kinase involved in cell-cycle progression (mTOR) (inhibits activity) |
Table 22-2 Clinical Uses of Immunosuppressive Agents
| Autoimmune diseases | Immunosuppressive agents |
|---|---|
| Idiopathic thrombocytopenic purpura | Prednisone, vincristine, occasionally mercaptopurine or azathioprine, high-dose gamma globulin, plasma immunoabsorption |
| Autoimmune hemolytic anemia | Prednisone cyclophosphamide, chlorambucil, mercaptopurine, azathioprine, high-dose gamma globulin |
| Acute glomerulonephritis | Prednisone mercaptopurine, cyclophosphamide |
| Acquired factor XII antibodies | Cyclophosphamide plus factor XII |
| Miscellaneous “autoreactive” disorders: Systemic lupus erythematosus, Wegener’s granulomatosis, rheumatoid arthritis, chronic active hepatitis, inflammatory bowel disease | Prednisone, cyclophosphamide, azathioprine, cyclosporine, infliximab, etanercept, adalimumab, interferons |
| Rh0[D] immune globulin | |
| Cyclosporine, azathioprine, prednisone, ALG, muromonab-CD3 monoclonal antibody, tacrolimus, basiliximab, daclizumab | |
| Liver | Cyclosporine, prednisone, azathioprine, tacrolimus |
| Bone marrow (HLA-matched) | Cyclosporine, cyclophosphamide, prednisone, methotrexate, ALG, total body irradiation, donor marrow purging with monoclonal anti-T cell antibodies, immunotoxins |
ALG, antilymphocytic globulin.
(1) Its principal mechanism of action at the low doses used in the rheumatic diseases probably relates to inhibition of amino imidazolecarboxamide ribonucleotide (AICAR) transformylase and thymidylate synthetase
(2) At higher doses, it inhibits dihydrofolate reductase, thus blocks folate-requiring reactions in the biosynthesis of nucleotides needed for cell proliferation
(2) Metabolized extensively in liver by cytochrome CYP3A4 to at least 25 metabolites, some of which are biologically active
(3) Drugs that decrease clearance via inhibition of hepatic microsomal enzymes can cause cyclosporine toxicity (e.g., nephrotoxicity, seizures).
• Examples: androgens, clarithromycin, diltiazem, erythromycin, estrogens, nefazodone, nicardipine, verapamil, and azole antifungal drugs
(4) Drugs that increase clearance of cyclosporine by stimulating its metabolism may lead to graft rejection.
• Examples: nafcillin, omeprazole; rifampin; and certain anticonvulsants such as carbamazepine, phenytoin, phenobarbital, primidone, and St. John’s Wort
(1) One of several polypeptide antibiotics produced by certain fungi that have immunosuppressive activity
(2) Cyclosporine complexes with cyclophilin, which inhibits calcineurin (a phosphatase) and blocks production of cytokines (e.g., interleukin-2 [IL-2], interleukin-3 [IL-3], TNFα) by antigen-stimulated T-helper cells that otherwise stimulate T-cell growth and differentiation.
(3) Cyclosporine does not affect suppressor T-cells or T-cell independent, antibody-mediated immunity.
(4) Immunosuppressive actions involve inhibition of the production and/or release of various lymphokines including IL-1 and IL-2.
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