What is Leucovorin is used to decrease the toxicity of: and explain in detail?
Methotrexate (Mtx) It is one of the oldest and highly efficacious antineoplastic drugs; inhibits dihydrofolate reductase (DHFRase)-blocking the conversion of dihydrofolic acid (DHFA) to tetrahydrofolic acid (THFA) which is an essential coenzyme required for one carbon transfer reactions in de novo purine synthesis and amino acid interconversions. The inhibition is pseudoirreversible because Mtx has 50,000 times higher affinity for the enzyme than the normal substrate. Methotrexate has cell cycle specific actionkills cells in S phase; primarily inhibits DNA synthesis, but also affects RNA and protein synthesis. It exes major toxicity on bone marrow-low doses given repeatedly cause megaloblastic anaemia, but high doses produce pancytopenia. Desquamation and bleeding may occur in g.i.t. Methotrexate is absorbed orally, 50% plasma protein bound, little metabolized and largely excreted unchanged in urine. Salicylates, sulfonamides, dicumerol displace it from protein binding sites. Aspirin and sulfonamides enhance toxicity of Mtx by decreasing its renal tubular secretion. The toxicity ofMtx cannot be overcome by folic acid, because it will not be conveed to the active coenzyme form. However, Folinic acid (N5 formyl THFA, cirovorum factor) rapidly reverses the effects. Thymidine also counteracts Mtx toxicity. Methotrexate is apparently curative in choriocarcinoma: 15-30 mg/ day for 5 days orally or 2G-40 mg/m2 BSA i.m. or i.v. twice weekly.It is highly effective in maintaining remission in children with acute leukaemias, but not good for inducing remission: 2.5-15 mg/day. It is also useful in other malignancies, rheumatoid ahritis, psoriasis and as immunosuppressant. The use of folinic acid rescue has permitted much higher doses of Mtx and has enlarged its scope to many difficult-to-treat neoplasms. A nearly 100 times higher dose (250-1000 mg/m2 BSA) of Mtx is infused i.v. over 6 hours, followed by 3-15 mg i.v. calcium leucovorin within 3 hours, repeated as required. This procedure can be repeated weekly. Essentials of medical pharmacology K D Tripathi Sixth edition Pg no 823