December 1, 2023: What is the toxicity of methotrexate overdose?

nichoae2 — Fri, 01 Dec 2023 22:00:20 +0000

December 1, 2023: What is the toxicity of methotrexate overdose? nichoae2 Fri, 12/01/2023 - 16:00 RSS:

TOXICOLOGY QUESTION OF THE WEEK

December 1, 2023

What is the toxicity of methotrexate overdose?

Methotrexate (MTX) is currently prescribed for conditions such as rheumatoid arthritis and psoriasis. MTX is a folate antimetabolite that inhibits DNA synthesis, repair, and cellular replication. When taken in overdose the primary effects are seen in rapidly dividing cells such as the bone marrow and gastrointestinal tract. Acute symptoms of toxicity include nausea, vomiting, diarrhea, acute renal failure, acute lung injury, and pancytopenia.

Potential treatments for MTX toxicity include leucovorin, glucarpidase, and urinary alkalinization. Leucovorin, folinic acid, is the primary treatment for repeated ingestion of MTX which results in high MTX concentrations. It works by displacing MTX from its binding sites and restores the folate that is necessary for DNA synthesis. Glucarpidase, primarily used following intrathecal injection of MTX, hydrolyzes MTX to inactive metabolites, glutamate and DAMPA. Urine alkalinization (urine pH of 7) through the administration of sodium bicarbonate prevents the precipitation of MTX in the kidneys.

While patients are in the hospital it is recommended that serial CBC with differentials and renal function tests are obtained. If the patient is requiring leucovorin, it is recommended that serial MTX levels are obtained to guide the length of treatment.

REFERENCES

Methotrexate and related agents. Greenwood Village, CO: Truven Health Analytics. http://micromedex.com/. Updated September 14, 2023. Accessed November 10, 2023.

Leucovorin Calcium. Lexi-Drugs. Hudson, OH: Lexicomp, 2023. http://online.lexi.com/. Updated October 6, 2023. Accessed November 10, 2023.

Glucarpidase. Lexi-Drugs. Hudson, OH: Lexicomp, 2023. http://online.lexi.com/. Updated July 18, 2023, Accessed November 10, 2023.

Bateman DN, Page CB. Antidotes to coumarins, isoniazid, methotrexate and thyroxine, toxins that work via metabolic processes. Br J Clin Pharmacol. 2016;81(3):437-445. doi:10.1111/bcp.12736

Hamed KM, Dighriri IM, Baomar AF, et al. Overview of Methotrexate Toxicity: A Comprehensive Literature Review. Cureus. 2022;14(9):e29518. Published 2022 Sep 23. doi:10.7759/cureus.29518

Question submitted by Quynh-Thu Musick, PharmD, CSPI

Comment: Single ingestion of MTX does not usually cause significant toxicity due to saturable GI absorption and rapid renal elimination. The duration of exposure to MTX is a more important factor in causing toxicity than the peak drug concentration. Therapeutic error from repeated oral daily dosing allows much greater absorption than a single ingestion and therefore, the toxicity is much greater. The patient (healthy with normal renal function) should do well following a single oral ingestion (unless there has been a massive ingestion). Leucovorin is usually indicated following elevated MTX concentrations from repeated oral daily dosing. Glucarpidase is used more commonly following intrathecal administration.

Take home point: Therapeutic error from repeated daily dosing is the setting for toxicity and need for rapid treatment. There are so many variations with this overdose. Good thing you can always call the Poison Center to discuss the case.

I am interested in any questions you would like answered in the Question of the Week. Please email me with any suggestions at donna.seger@vumc.org.

DONNA SEGER, MD
Professor Emeritus
Department of Medicine
VUMC

TENNESSEE POISON CENTER

24/7 FREE MEDICAL HOTLINE

POISON HELP | 800.222.1222

TNPOISONCENTER.ORG

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December 1, 2023: What is the toxicity of methotrexate overdose?

TOXICOLOGY QUESTION OF THE WEEK

What is the toxicity of methotrexate overdose?