0:00 Hello, in this video we're going to talk about the pharmacology of calcineurin 0:10 inhibitors. 0:12 Calcineurin inhibitors such as tachrolimus and cyclosporin are immunosuppress 0:17 ants. 0:17 They are used mainly to prevent organ transplant rejection in combination with 0:23 microphenolate 0:24 and steroids. It can also be used for severe atopic dermatitis. They're not 0:31 really used 0:31 as much for rheumatological conditions anymore, possibly can be used for lupus 0:38 nephritis. 0:40 Calcineurin inhibitors essentially inhibit the synthesis of interleukin 2. 0:45 Normally, 0:46 antigen presenting cells such as macrophages picks up an antigen, a new one, 0:50 either foreign 0:51 or a self antigen, processes it and then presents it on an MHC class II 0:58 molecule towards T cells. 1:03 These T cells will become activated and they require interleukin 2, a key ot 1:09 ocrine T cell 1:09 activator. Activation of T cells will stimulate the adaptive immune response 1:16 consisting of 1:17 cytotoxic T cells, T-hopper cells and then they will also activate plasma cells 1:22 , the antibody 1:23 producing cells. Calcineurin inhibitors inhibit calcineurin, a key protein 1:30 required to allow 1:32 transcription of interleukin 2, the key otocrine T cell activator. 1:41 The mechanism of action is a bit more complicated. Let's take a closer look at 1:45 how naive T cells 1:46 become activated. So an antigen is presented to T cell receptors which will 1:57 initiate a 1:57 cascade of intracellular events. This begins with activation of phospholipase C 2:03 . Phospholipase 2:05 C hydrolyzes phosphotidylinositol45 is phosphate, also known as PIP2. To 2:12 generate the secondary 2:13 messengers in acetol 145 triphosphate, IP3 and diacylglyceral DAG. IP3 2:20 increases intracellular 2:23 calcium levels. Calcium binds to calmodulin, later binding to calcineurin, a 2:33 calcium calmodulin 2:36 dependent phosphatase. Calcineurin, when it's bound to all the stuff, dephosph 2:43 orylizes 2:44 nucleic factor of activated T cells, NFAT, which when dephosphorylated targets 2:56 the interleukin 2:57 2 gene to make interleukin 2 cytokines. Interleukin 2 is released by the T 3:04 cells, which in turn 3:06 acts as an autocrine molecule, binding onto interleukin 2 receptors on the 3:12 surface of 3:13 the T cells. Interleukin 2 will activate this T cell, and eventually will 3:22 initiate the activation 3:24 of the adaptive immune system. Cyclosporin is a calcineurin inhibitor, which 3:31 works by 3:31 binding to the intracellular receptor cyclophilin 1, producing a complex known 3:39 as cyclosporin 3:40 cyclophilin. This complex subsequently inhibits calcineurin, which in turn 3:47 stops the dephosphorylization 3:50 as well as the activation of the nuclear factor of activated T cells. Tacrol 3:56 amus is the other 3:57 calcineurin inhibitor, which binds to a intracellular protein called NKBP12. It 4:06 then continues 4:07 to form a complex consisting of the tacrolamus, FKBP12, calcium calmodulin, and 4:15 then later 4:16 calcineurin, which will inhibit the phosphatase activity of calcineurin. And 4:24 when the phosphatase 4:25 activity is inhibited, the NFAT doesn't get dephosphorylated. Calcium 4:33 inhibitors have 4:34 a number of side effects, hyperurisemia, increasing the risk of gout, nephrot 4:41 oxicity, hypertension 4:43 and hyperlipidemia, as well as hyperglycemia. The side effects are more common 4:48 in certain 4:49 types of calcineurin inhibitors. For example, hyperglycemia is more common with 4:54 tacrolamus. 4:55 Hypertension, hyperlipidemia, and hyper uresemia is more common for patients 5:01 using cyclosporin. 5:03 I hope you enjoyed this video on calcineurin inhibitors and their mechanism of 5:06 action. 5:07 Thank you for watching. 5:13 You
