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Methotrexate, or N-(4-{[(2,4-diamino-6-pteridinyl)methyl]-methylamino}benzoyl)-l-glutamic acid, is an antimetabolite chemotherapeutic agent that is also used for psoriasis, rheumatoid arthritis, systemic sclerosis, placenta accreta, and ectopic pregnancy. Most toxicity is caused by chronic oral overmedication. Inadvertent high-dose intrathecal, intravenous, and intramuscular methotrexate administration and acute intentional overdose have been reported.

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  1. Mechanism of toxicity

    1. Methotrexate is a folic acid antagonist that inhibits dihydrofolic acid reductase in the synthesis of purine nucleotide and thymidylate. It interferes with DNA synthesis and repair and with cellular replication. Tissues with active proliferation are more sensitive to this effect. It may affect immune function, but this mechanism remains unknown.

    2. Pharmacokinetics. Peak serum level occurs within 1–2 hours after ingestion. Bioavailability is 60% at a dose of 30 mg/m2 but significantly decreases at doses greater than 80 mg/m2. Peak serum concentration occurs 30–60 minutes after IM injection. The steady-state volume of distribution is 0.4–0.8 L/kg, with approximately 50% protein-bound. Drugs such as trimethoprim-sulfamethoxazole (TMP/SMX), probenecid, and salicylates can compete with methotrexate for protein binding sites, raising free levels. Methotrexate does not penetrate the blood–cerebrospinal fluid (CSF) barrier in therapeutic doses given orally or parenterally. The terminal half-life is approximately 3–10 hours with low doses (<15 mg/m2) and 8–15 hours after higher doses. Methotrexate accumulates in third-space fluid, so a prolonged half-life and clinical effects can be observed in patients with ascites, pleural effusion, and pericardial effusion. Ninety percent of the absorbed dose is excreted unchanged in the urine within 48 hours.

  2. Toxic dose

    1. Therapeutic doses vary widely, depending on the indication. Adults with rheumatoid arthritis often take 5–20 mg once a week. Ectopic pregnancy is treated with doses of 15–30 mg/d for 5 days. Neoplastic disease is treated with much higher doses (eg, 8–12 g/m2 IV for some sarcomas). Intrathecal doses of 0.2–0.5 mg/kg are given for some CNS neoplasms.

    2. Toxic doses are variable, depending on the route and chronicity. Bone marrow suppression can occur in 25% of patients receiving therapeutic doses used for treatment of cancers. Intrathecal injection of more than 500 mg is associated with severe morbidity or death. Toxicity often occurs after prolonged use (>2 years) or after a total oral dose of 1.5 g. Alcoholism, obesity, diabetes, advanced age, and decreased renal function are risk factors associated with chronic hepatic toxicity.

  3. Clinical presentation. Acute unintentional ingestion is generally benign. Chronic oral overmedication may occur in patients who misunderstand and take their weekly doses daily for several days. Severe toxicity usually results from an inadvertent high dose of intrathecal or IV methotrexate. Causes of death in severe toxicity are sepsis and multiple-organ failure.

    1. Gastrointestinal effects including nausea, vomiting, diarrhea, and ulcerative stomatitis are the most common reported adverse effects from oral methotrexate toxicity.

    2. Hematologic effects such as leukopenia, anemia, thrombocytopenia, and pancytopenia occur within a week after exposure and resolve in 2 weeks. Bone marrow suppression can lead to fatal systemic infections.

    3. Hepatic manifestations include acute elevated aminotransaminases and chronic fibrosis or cirrhosis ...

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