CNIs

Calcineurin inhibitors (CNIs) are a class of immunosuppressive drugs that inhibit the phosphatase activity of calcineurin, a calcium/calmodulin-dependent enzyme essential for T cell activation. The principal systemic CNIs are cyclosporine and tacrolimus (FK506); pimecrolimus and topical tacrolimus are used in dermatology as topical formulations. CNIs work by binding to intracellular immunophilins (cyclophilin for cyclosporine and FKBP-12 for tacrolimus), and the drug-immunophilin complex inhibits calcineurin. This prevents dephosphorylation and nuclear translocation of NFAT transcription factors, leading to reduced interleukin-2 production and diminished T cell proliferation.

Clinically, CNIs are primarily used to prevent organ transplant rejection and to treat a range of autoimmune conditions. Systemic CNIs are common in kidney, liver, and heart transplantation, where they are part of combination immunosuppression regimens. Tacrolimus is also used for certain autoimmune diseases and, in topical form, for inflammatory skin conditions such as atopic dermatitis. Topical tacrolimus and pimecrolimus provide localized immunosuppression with a different systemic exposure profile than oral forms.

Safety and monitoring are important with CNIs. Drug levels are monitored to maintain efficacy while limiting toxicity, and dosing is adjusted accordingly. CNIs have several potential adverse effects, most notably nephrotoxicity and neurotoxicity, as well as hypertension, hyperlipidemia, hyperkalemia, increased susceptibility to infection, and heightened risk of certain malignancies. They are metabolized by the liver via cytochrome P450 3A4 and interact with many drugs and foods, necessitating careful management of concomitant therapies and dietary sources.