Folate gastrointestinal effects

The adverse effects of methotrexate include gastrointestinal complaints, bone marrow suppression, alopecia and nephrotoxicity. The toxic effects of methotrexate may be terminated by administering the fully reduced folate coenzyme leucovorin (folinic acid). Leucovorin rescue permits the administration of high doses of methotrexate, for example in situations where partially resistance has occurred or to obtain cytotoxic concentrations of methotrexate in the CNS. 

Severe cyanocobalamin (vitamin B12) deficiency results in pernicious anemia that is characterized by megaloblastic anemia and neuropathies. The symptoms of this deficiency can be masked by high intake of folate. Vitamin B12 is recycled by an effective enterohep-atic circulation and thus has a very long half-hfe. Absorption of vitamin B12 from the gastrointestinal tract requires the presence of gastric intrinsic factor. This factor binds to the vitamin, forming a complex that... 

Sulfasalazine has a high incidence of adverse effects, most of which are attributable to systemic effects of the sulfapyridine molecule. Slow acetylators of sulfapyridine have more frequent and more severe adverse effects than fast acetylators. Up to 40% of patients cannot tolerate therapeutic doses of sulfasalazine. The most common problems are dose-related and include nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppression, and malaise. Hypersensitivity to sulfapyridine (or, rarely, 5-ASA) can result in fever, exfoliative dermatitis, pancreatitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis. Sulfasalazine has also been associated with oligospermia, which reverses upon discontinuation of the drug. Sulfasalazine impairs folate absorption and processing hence, dietary supplementation with 1 mg/d folic acid is recommended. 

The effects of methotrexate may be reversed by the administration of leucovorin, the reduced folate. This leucovorin rescue prevents or reduces the toxicity of methotrexate, which is expressed as mouth lesions (stomatitis), injury to the gastrointestinal epithelium (diarrhea), leukopenia, and thrombocytopenia (see Chapter 62). 

The well-known dose-related side effects include gingival hyperplasia (due to altered collagen metabolism), cerebellar-vestibular effects (nystagmus, vertigo, ataxia), behavioural changes (confusion, drowsiness, hallucinations), increased seizure frequency, gastrointestinal disturbances (nausea, anorexia), osteomalacia (due to reduced calcium absorption and increased vitamin D metabolism) and megaloblastic anaemia (due to reduced folate absorption). 

METHOTREXATE ANTIMALARIALS -PYRIMETHAMINE t antifolate effect of methotrexate Pyrimethamine should not be used alone and is combined with sulfadoxine. Pyrimethamine and methotrexate synergistically induce folate deficiency Although the toxic effects of methotrexate are more frequent with high doses of methotrexate, it is necessary to do an FBC, liver and renal function tests before starting treatment even with low doses, repeating these tests weekly until therapy is stabilized and thereafter every 2-3 months. Patients should be advised to report symptoms such as sore throat and fever immediately, and also any gastrointestinal discomfort. A profound drop in white cell count or platelet count warrants immediate stoppage of methotrexate therapy and initiation of supportive therapy... 

Reduced folates are co-factors for the 5-fluorodeoxy-uridine monophosphate-thymidilate synthetase reaction. Leucovorin (calcium fohnate) therefore potentiates the toxicity of 5-fluorouracil, and fatal adverse effects have been reported in patients over 65 years of age receiving high-dose treatment with leucovorin simultaneously with fluorouracil. This has led some groups to recommend that initial dose levels of fluorouracil should be lowered by 20% and that therapy be stopped temporarily at the first sign of distal gastrointestinal adverse effects (SEDA-15, 414). 

Raised methotrexate serum concentrations (over 100 nmol/1 at 36-42 hours after ingestion) are expected to increase the likelihood of several adverse effects, that is, gastrointestinal and hematological effects, but similar adverse effects can be found even with low methotrexate serum concentrations. Reduced red cell folate concentrations during methotrexate treatment also related to adverse effects and rises in liver enzjmes, and red cell folate concentrations above 800 nmol/1 protected against common adverse effects and treatment withdrawal (6). Several investigators now advocate the concomitant use of folic acid (5-7 mg/week and up to 27.5 mg/week) to reduce some of methotrexate-associated adverse effects without reducing its efficacy (7). 

In a meta-analysis of 307 patients with rheumatoid arthritis from seven randomized clinical trials, of whom 147 took folate supplementation, hematological adverse effects were not significantly reduced in the folate group (8). However, there was a 79% reduction in mucosal and gastrointestinal adverse effects in patients taking folic acid and a non-significant trend toward a reduction (42%) in patients taking folinic acid. Disease activity was not modified by low doses of folate. Finally, the authors noted that folinic acid is more expensive. 

Methotrexate inhibits DNA synthesis by decreasing avail-ability of pyrimidine nucleotides. Methotrexate competitively inhibits the enzyme dihydrofolate reductase, thus decreasing the concentrations of the tetrahydrofolate essential to the methylation of the pyrimidine nucleotides and consequently the rate of pyrimidine nucleotide synthesis. Leucovorin, a folate analog, is used to rescue host cells from methotrexate inhibition as a synthetic substrate for dihydrofolate reductase, leucovorin administration allows resumption of tetrahydrofolate-dependent synthesis of pyrimidines and reinitiation of DNA synthesis. Methotrexate is a nonspecific cytotoxin, and prolongation of blood levels appropriate to killing tumor cells may lead to severe, unwanted cytotoxic effects such as myelosuppression, gastrointestinal mucositis, and hepatic cirrhosis. 

Tumor cells acquire resistance to methotrexate as the result of several factors, which include the deletion of a high-afQnity, carrier-mediated transport system for reduced folates, an increase in the concentration of dihydrofolate reductase, and the formation of a biochemically altered reductase with reduced affinity for methotrexate. To overcome this resistance, higher doses of methotrexate need to be administered. The effects of methotrexate may be reversed by the administration of leucovorin, the reduced folate. This leucovorin rescue prevents or reduces the toxicity of methotrexate, which is expressed as mouth lesions (stomatitis), injury to the gastrointestinal epithelium (diarrhea), leukopenia, and thrombocytopenia. 

The possible effects of OCAs on folate metabolism, as indicated by these studies of serum folate concentrations, may therefore be mild but could assume considerable importance in subjects with gastrointestinal disease and decreased absorption of folate, women with marginal dietary folate intake, and those who subsequently become pregnant and then have an increased requirement for folic acid. Studies that followed were warranted by these considerations. 

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