calcineuroninhibitors

Calcineurin inhibitors are a class of immunosuppressive drugs that target the phosphatase calcineurin to prevent T-cell activation. The principal systemic agents are cyclosporine (cyclosporin A) and tacrolimus (FK506). In addition, topical calcineurin inhibitors such as pimecrolimus and tacrolimus ointments are used for inflammatory skin conditions, and newer systemic agents like voclosporin have expanded clinical applications.

Mechanism of action: Both cyclosporine and tacrolimus bind intracellular immunophilins—cyclophilin and FKBP-12, respectively. The resulting complexes inhibit calcineurin, a calcium-dependent phosphatase that activates the transcription factor NF-AT. Inhibition prevents dephosphorylation and nuclear translocation of NF-AT, reducing interleukin-2 transcription and T-cell proliferation.

Clinical use: Systemic CNIs are primarily employed to prevent organ transplant rejection and to treat certain autoimmune diseases. They are often used in combination with corticosteroids and other immunosuppressants. Topical CNIs are used for atopic dermatitis and other inflammatory skin disorders, and cyclosporine eye drops are used for chronic dry eye and other ocular inflammatory conditions.

Pharmacology and safety: CNIs are typically dosed to achieve target trough levels and require regular monitoring due to a narrow therapeutic window. They are primarily metabolized by CYP3A4 and interact with numerous drugs and foods, notably azole antifungals, macrolides, and grapefruit-containing products. Nephrotoxicity is a major dose-limiting toxicity, with other risks including hypertension, neurotoxicity, hyperlipidemia, diabetes, increased infection risk, and certain malignancies. Careful patient selection, monitoring, and dose adjustment are essential.

History and significance: Cyclosporine was discovered in the 1970s and revolutionized organ transplantation. Tacrolimus followed in the 1980s, further expanding options for immunosuppression and autoimmune disease management.