Chapter 46: Immunosuppressives

ORGANIZATION OF CLASS

Immunopharmacology is the study of the use of drugs to modulate, usually depress, the immune response. These drugs are used in the treatment of autoimmune diseases (myasthenia gravis and rheumatoid arthritis) and in organ transplantation.

CALCINEURIN INHIBITORS

Cyclosporine (also ciclosporin) binds to cyclophilin (an intracellular protein of the immunophilin family), while tacrolimus binds to the immunophilin FK-binding protein and this complex inhibits calcineurin. So, link cyclosporine and tacrolimus in your head.

PROLIFERATION SIGNAL INHIBITORS

Sirolimus and its derivative everolimus bind to an immunophilin called protein called FK506-binding protein 12. This complex blocks the molecular target of rapamycin (mTOR), which leads to the inhibition of interleukin-driven T-cell proliferation.

OTHER IMMUNOSUPRESSANTS

Mycophenolate mofetil is administered as a prodrug that is activated to mycophenolic acid—the active compound. It is a highly selective inhibitor of a crucial enzyme in the de novo synthesis of guanosine. Proliferating lymphocytes are dependent on the de novo pathway for purine biosynthesis. Most other cell lines can maintain function with the salvage pathway. Therefore, mycophenolic acid is a very specific lymphocyte inhibitor.

Azathioprine (prodrug for mercaptopurine) is thought to be immunosuppressive by interfering with DNA synthesis. Azathioprine and cyclophosphamide you should remember from the anticancer drugs (see Chapter 37).

BIOLOGICS FOR TRANSPLANTATION

Basiliximab and daclizumab block the interleukin-2 (IL-2)–mediated activation of T lymphocytes by binding to CD25, which is the α chain of the interleukin-2 receptor. These antibodies were designed to selectively inhibit T-cell activation. Both are used to prevent rejection after organ transplantation.

Belatacept blocks T-cell stimulation and has been used in transplant medicine.