Calcineurin Inhibitors Study Documents

Calcineurin inhibitors CYCLOSPORINE  Cyclic peptide composed of 11 aminoacids.  Extracted from a soil fungus Tolyplocladium inflatum. Mechanism  of action Target intracellular signalling pathway and blocks induction of cytokine genes.  It bind to the cytosolic protein cyclophilin (immunophilin) of immunocompetent lymphocytes, especially T-lymphocytes.  This complex of cyclosporine and cyclophilin inhibit calcineurin, which is responsible for activating the transcription of IL 2.  Selectively inhibit T lymphocyte proliferation, IL-2 & other cytokine production & response of inducer T cells to IL-1, without any effect on suppressor T cells.  Selectively suppresses CMI, leaves the recipient with enough immune activity.  Free of toxic effects on BM & RE system. Uses: Most effective drug for prevention and treatment of Kidney, liver, cardiac, BM & other allogenic transplants graft rejection reaction.  More effective when administered with glucocorticoids.  Most active when administered before antigen exposure.  Alternative to methotrexate for treatment of severe active RA.  Autoimmune diseases.  2nd line drug for uveitis, bronchial asthma etc. Toxicity :  Renal dysfunction  Gum hyperplasia  Tremor  Hirsuitism  Hypertension, Hyperlipidemia , Hyperuricemia  Calcineurin inhibitors + Glucocorticoids = Diabetogenic Drug interactions  Nephrotoxic drugs - AGs, vancomycin, amphotericin B and NSAIDs ↑es its toxicity.  By depressing renal function can reduce excretion of many drugs.  Enzyme inducers lower its blood levels- transplant rejection.  Erythromycin, ketaconozole and related drugs (CYP3A4 inhibitors) increase their levels – toxicity.  K+ sparing diuretics – hyperkalemia. Tacrolimus (FK506)  Also known as Fujimycin.  Newer immunosuppressant.  Macrolide that is isolated from soil bacteria Streptomyces tsukubaensis. Mechanism of action  Same MOA, 100 times more potent than cyclosporine.  Binds to different cytoplasmic immunophilin protein (FKBP).  Orally as well as i.v infusion.  Uses and Toxicity profile - similar to cyclosporine Sirolimus (rapamycin)  Macrolide antibiotic.  Obtained from bacteria Streptomyces hygroscopicus.  Mechanism of action-  Binds to FKBP -12.  FKBP- sirolimus complex binds to mammalian target of rapamycin (mTOR).  Blocks progression of activated T cells from G1 to S phase of cell cycle.  It does not lower IL-2 but inhibit cellular response of IL-2.  Extensively metabolized by CYP3A4.  Elimination via biliary route.  Use- Prophylaxis of organ transplant rejection along with other drugs.  Toxicity  – Peripheral edema, hypercholesterolemia, anemia, thrombocytopenia etc.