Which of these drugs is a calcineurin inhibitor?
Ans, a. Cyclosporine (Ref: Goodman Gilman life p1008; Katzung I2/e p986; KDT 7/ep880, 6/e p837-839)Cyclosporine is a caicineurin inhibitor, which targets intracellular signaling pathways induced as a consequence of T celt--receptor activation."Perhaps the most effective immunosuppressive drugs in routine use are the caicineurin inhibitors. cyclosporine and tacrolimus, which target intracellular signaling pathways induced as a consequence of T cell-receptor activation. Although they are structurally unrelated and bind to distinct (albeit related) molecular targets. they inhibit normal T-cell signal transduction essentially by the same mechanism. Cyclosporine and tacrolimus do not act per se as immunosuppressive agents. Instead, these drugs bind to an immunophilin (cyclophilin for cyclosporine or FKBP-12 for tacrolimus). resulting in subsequent interaction with caicineurin to block its phosphatase activity. "-- Goodman Gilman 12e p1008CyclosporineCyclosporine is produced by fungus Beauveria niveaQ.Cyclosporine suppresses some humoral immunity but is more effective against T cell dependent immune mechanisms such as those underlying transplant rejection and some forms of autoimmunityQ.Mechanism of Action:It preferentially inhibits antigen-triggered signal transduction in T lymphocytes, blunting expression of many lymphokines, including 1L-2 & expression of anti-apoptoiic proteins.Cyclosporine forms a complex with cyclophilin, a cytoplasmic-receptor protein present in target cells. This complex binds to calcineurin, inhibiting Ca2+ stimulated dephosphorylation of the cytosolic component of NFATQ.Calcineurin phosphatase activity is inhibited after physical interaction with the cyclosporine/ cyclophilin complexQ.Cyclosporine increases expression of TGF-b, a potent inhibitor of IL- 2-stimulated T-cell proliferation and generation of cytotoxic T lymphocytes (CTLs)Q.Therapeutic Uses:Clinical indications for cyclosporine are kidney, liver, heart & other organ transplantation: rheumatoid arthritis; and psoriasisQ.Approved by the FDA to prevent & treat graft-versus-host disease in bone-marrow transplantationQSide-effects:Renal dysfunction, hypertension; tremor, hirsutism, hyperlipidemia & gum hyperplasiaQHypertension occurs in ~50% of renal transplant and almost all cardiac transplant patientsQ.Hyperuricemia may lead to worsening of gout, increased P-glycoprotein activity, and hypercholesterolemiaQ.Nephrotoxicity occurs in the majority of patients and is the major reason for cessation or modification of therapyQ.It is nephrotoxic, neurotoxic, causes hypertension (due to renal vasoconstriction & increased sodium reabsorption ), and increases the risk of squamous cell carcinoma & infectionsQ.
Cyclosporine
Methotrexate
Azathioprine
Mycophenolate mofetil
Anti-Neoplastic Agents