0:00 Methotrexate is a popular disease modifying anti-romatic drug, and it is the 0:12 first-line 0:12 treatment for rheumatoid arthritis and other autoimmune diseases. 0:17 It is an immunosuppressant, meaning it suppresses the immune system. 0:22 Methotrexate is a folic analog and works by inhibiting dihydropholate reductase 0:29 . 0:29 Dihydropholate reductase is an important enzyme in the synthesis of nucleotides 0:34 . 0:35 Folic acid from our diet is converted to dihydropholate, and through dihydroph 0:41 olate reductase 0:42 becomes tetrahydropholate. 0:47 Tetrahydropholate is converted to 510-methyl tetrahydropholate, which through 0:51 the enzyme 0:52 of thymondylate synthase becomes dihydropholate. 0:58 And this is a double reaction because with thymondylate synthase, it also 1:04 converts duMP 1:06 to dTMP in the process, and dTMP through a series of reactions eventually makes 1:14 thymine, 1:15 which is part of the nucleotide that is required for DNA synthesis. 1:21 Dihydropholate reductase is known to inhibit dihydropholate reductase, but also 1:28 thymondylate 1:29 synthase, leading to decreased synthesis of thymine, which is required for DNA 1:38 synthesis. 1:40 510-methyl tetrahydropholate becomes 5-methyl tetrahydropholate through the 1:46 enzyme methylene 1:48 tetrahydropholate reductase. 1:53 5-methyl tetrahydropholate can be recycled to tetrahydropholate through a co-re 1:57 action with 1:58 methionine synthase, which uses vitamin B12. 2:04 The second reaction involves conversion of homocysteine to methionine. 2:10 So why is this important? 2:12 Well, as you can see, methotrexate essentially reduces levels of methionine, 2:17 and this results 2:18 in the disruption in the methionine cycle. 2:20 It reduces methionine levels and increases homocysteine levels. 2:28 Methotrexate also inhibits this long enzyme name by the name of amino, imidaz 2:35 ole, carboxamide, 2:37 ribonucleotide, formyltransferase, also known as AICART. 2:46 This enzyme is important in the conversion of AICAR to IMP, a precursor to pur 2:55 ines, adenine 2:56 and guinine, which are required for RNA and DNA synthesis. 3:01 And so, inhibiting AICART, it reduces the purineucleotides and increases AICAR. 3:13 Aside from impairing nucleic acid synthesis to make DNA, the reaction here also 3:20 increases 3:20 AICAR, which is thought to have anti-inflammatory effects. 3:30 Impaired nucleic acid synthesis suppresses rapidly dividing cells such as 3:38 immune cells. 3:39 And so, this will essentially disrupt the S-phase of the cell cycle, 3:43 responsible for 3:44 making DNA. 3:47 Thus in rheumatological diseases such as rheumatoid arthritis, psoriatic 3:50 arthritis, 3:51 it is immunosuppressive and reduces inflammation and joint destruction. 3:57 Because methotrexate affects nucleic acid synthesis and inhibits the cell cycle 4:01 from 4:02 progressing to the S-phase, methotrexate is also used in other conditions with 4:07 rapidly 4:08 dividing cells such as ectopic pregnancy and malignancy, which both have cells 4:15 dividing 4:15 rapidly. 4:17 Methotrexate is given as one weekly dosing orally or subcutaneous. 4:22 It can also be given intrathecal in cancer conditions. 4:27 Because of its inhibitory effects on dihydrofolate reductase, it should not be 4:32 used with trimetoprim, 4:34 which is a common antibiotic used for urinary tract infections. 4:40 This is because trimetoprim is also an inhibitor of folic acid metabolism and 4:45 can cause bone 4:46 marrow suppression essentially. 4:52 Due to its inhibitory effects of nucleotide synthesis and thus the cell cycle, 4:58 methotrexate 4:59 can be toxic to normal cells. 5:03 And so it can cause side effects such as hepatotoxicity, GI, hemorrhagic enter 5:09 itis, gum bleeding, 5:11 gum ulcers and bone marrow suppression causing cytopenias. 5:18 Methotrexate is known to be a cause of macrocytic anemia. 5:23 Caution, methotrexate should be avoided in renal and liver disease. 5:28 Again, due to its inhibitory effects of nucleotide synthesis, methotrexate can 5:35 be toxic to normal 5:36 cells. 5:37 Thus, folic acid is recommended. 5:40 Folic acid is preferentially taken up by normal cells and so it minimizes 5:45 toxicity of 5:45 methotrexate while preserving efficacy. 5:49 In cases of severe toxicity, emergency folic acid, also known as leukovorin, 5:57 can be given 5:58 to reduce methotrexate toxicity. 6:02 Folic acid is an active metabolite of folic acid and essentially bypasses the 6:10 inhibited 6:11 phosphoryloid reductase.
