Calcineurin Inhibitors

® Cyclosporine and tacrolimus belong to a class of immunosuppressants called the calcineurin inhibitors. These agents are considered by many to be the cornerstone of immunosuppression protocols. The calcineurin inhibitors work by complexing with cytoplasmic proteins (cyclosporine with cyclophylin and tacrolimus with FK binding

protein-12). ' ' ' These complexes then inhibit calcineurin phosphatase, which results in reduced IL-2 gene transcription. The final outcome is a decrease in IL-2 syn-

thesis and a subsequent reduction in T-cell activation. ' ' '

Cyclosporine

Cyclosporine USP was first approved by the FDA in 1983, but was associated with a variable oral absorption. The development of a newer formulation, cyclosporine microemulsion USP introduced in 1994, allowed for a more consistent drug exposure

due to a more reliable pharmacokinetic profile. Cyclosporine microemulsion is the formulation of choice for most transplant centers that use cyclosporine for maintenance immunosuppression due to the above mentioned benefit. The two formulations are not interchangeable.

FIGURE 55-1. Identification of the sites of action of the various immunosuppressive medications. Antigen-major histocompatibility complex (MHC) II molecule complexes are responsible for initiating the activation of CD4 T cells. These MHC-peptide complexes are recognized by the T-cell recognition complex (TCR). A costimulatory signal initiates signal transduction with activation of second messengers, one of which is calcineurin. Calcineurin removes phosphates from the nuclear factors (NFAT-P), allowing them to enter the nucleus. These nuclear factors specifically bind to interleuk-in-2 (IL-2) promoter gene facilitating IL-2 gene transcription. Interaction of IL-2 with the IL-2 receptor (IL-2R) on the cell membrane surface induces cell proliferation and production of cytokines specific to the T cell. (APCs, antigen producing cells; MPA, myophenolic acid; OKT-3, muronomab-CD3.) (From Schonder KS, Johnson HJ. Solid organ transplantation. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1463.)

FIGURE 55-1. Identification of the sites of action of the various immunosuppressive medications. Antigen-major histocompatibility complex (MHC) II molecule complexes are responsible for initiating the activation of CD4 T cells. These MHC-peptide complexes are recognized by the T-cell recognition complex (TCR). A costimulatory signal initiates signal transduction with activation of second messengers, one of which is calcineurin. Calcineurin removes phosphates from the nuclear factors (NFAT-P), allowing them to enter the nucleus. These nuclear factors specifically bind to interleuk-in-2 (IL-2) promoter gene facilitating IL-2 gene transcription. Interaction of IL-2 with the IL-2 receptor (IL-2R) on the cell membrane surface induces cell proliferation and production of cytokines specific to the T cell. (APCs, antigen producing cells; MPA, myophenolic acid; OKT-3, muronomab-CD3.) (From Schonder KS, Johnson HJ. Solid organ transplantation. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill, 2008:1463.)

Induction therapy?

Note: ATG/RATG?

IL-2RA]

IV mAtMyprwiniftnlono

Maintenance therapy based on center-specHic protocols. Usuaily consists ol: CI (OSA or TAC) ± MP A orSRL ± Steroids

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