Methotrexate gastrointestinal effects

Low-dose methotrexate is used for treatment of rheumatoid arthritis despite side effects such as disorders of the gastrointestinal tract and the liver. Leflunomide is also approved for this indication, however, hepatoxicity limits its use as first option. 

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. 

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). 

Etodolac This drug has effects similar to those of the other NSAIDs. Gastrointestinal problems may be less common. However, other adverse effects such as fluid retention and abnormal kidney and liver function have been reported. Etodolac may increase the serum levels and thus raise the risk of adverse reactions caused by digoxin, lithium, methotrexate, and enhance the nephrotoxicity of cyclosporine. 

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... 

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). 

Gastrointestinal adverse effects (stomatitis, anorexia, abdominal pain, dyspepsia, nausea, vomiting, diarrhea, and weight loss) are very common, particularly after oral administration of methotrexate (up to 50%), and often require dosage adjustment (3). Folic acid supplementation reduces the incidence of several gastrointestinal adverse effects. 

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. 

Adverse effects of methotrexate include ulceration of the mouth and lower gastrointestinal tract and bone marrow suppression. With high doses of methotrexate synthetic folinates are used to prevent irreversible bone marrow damage. 

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. 

Answer C. Ocular toxicity is characteristic of chloroquine and hydroxychloroquine. Corneal deposits are reversible, but retinal pigmentation can ultimately lead to blindness. Patients will complain about gastrointestinal distress, visual dysfunction, ringing in the ears (note that tinnitus also occurs in salicylism), and itchy skin. Hydroxychloroquine also promotes oxidative stress that can lead to hemolysis in G6PD deficiency. DMARDs include gold salts (e.g., auranofin), methotrexate, and etanercept, but thioridazine is a phenothiazine used as an antipsychotic it lacks an antiinflammatory effect, but does cause retinal pigmentation. 

Toxicity Common adverse effects include bone marrow suppression and toxie effects on the skin and gastrointestinal mucosa (mucositis). The toxic effects of methotrexate on normal cells may be reduced by administration of fohnie aeid (leucovorin) this strategy is called leucovorin rescue. Long-term use of methotrexate has led to hepatotoxieity and to pulmonary infiltrates and fibrosis. Salicylates, NSAlDs, sulfonamides, and sulfonylureas enhance the toxicity of methotrexate. 

---