Anticancer Pharmacology Immune System Pharmacology

Methotrexate Pharmacology!

Jul 30th, 2021
methotrexate pharmacology

Methotrexate Pharmacology

Here, we review the must-know facts about methotrexate pharmacology; an important drug that carries with it significant risks that healthcare professionals must be cognisant of. In this review, we learn more about the drug’s indications, mechanism of action, side effects, and clinical pharmacology.

Methotrexate, formerly known as amethopterin, is a drug used to treat a wide variety of conditions. First introduced as an anticancer agent in the 1940s, MTX quickly went on to become a staple drug in the treatment of autoimmune disorders such as psoriasis and rheumatoid arthritis. However, methotrexate use is not without risk. It comes with a whole panoply of adverse effects – many of which we list below.

Methotrexate is used to treat conditions such as:

  • Cancer – including leukemias, lymphomas and some solid tumors
  • Autoimmune disease – a disease-modifying agent used to treat conditions such as psoriasis and rheumatoid arthritis
  • Pregnancy – where it is used as an abortifacient

Whether the drug works as an immunosuppressant DMARD or as an antineoplastic agent depends on its mechanism of action, as it does not work the same for both indications.

Mechanism of action

Methotrexate works through a variety of means, depending on which indication it is being used to treat.

For cancer chemotherapy, methotrexate – or MTX – is used as a folate antagonist.

More specifically, MTX works to inhibit dihydrofolate reductase, an enzyme required for the production of folic acid-intermediaries that are needed for DNA replication and protein synthesis. MTX is most effective in actively dividing cells, hence its advantage as an anticancer drug.

For treating autoimmune disease, though, MTX acts through a different means. MTX has both anti-inflammatory and immunosuppressive properties – not least mediated through its inhibition of interleukin-6, interleukin-8 and TNF-α.

Side effects

Methotrexate is associated with a series of common and serious side effects.

Common side effects associated with MTX include:

  • Gastrointestinal effects – nausea, vomiting, upset stomach
  • Mucosal damage – mouth sores
  • Menstrual changes
  • Blurred vision
  • Headache
  • Fatigue

Methotrexate is also associated with more serious side effects such as hepatic cirrhosis, pulmonary fibrosis and neutropenia.

As methotrexate must be taken once weekly, there are often cases of accidental overdose where the patient has instead taken the medicine daily – a toxic dose that can lead to seizures, coma, renal failure and death.

Folinic acid can be used to reverse the effects of methotrexate overdose.

Clinical Pharmacology

When we talk about the clinical pharmacology of methotrexate, we need to think about the following factors:

  • Methotrexate must be taken once weekly. Folic acid is typically co-prescribed, though must be taken on a different day than MTX. This is because, if taken on the same day, folic acid can interfere with the mechanism of action of methotrexate.
  • Methotrexate is teratogenic and so should be avoided in pregnancy.
  • Methotrexate, because it is eliminated renally, is contraindicated in patients with severe renal impairment. Lower doses are required in patients with mild kidney damage.
  • Methotrexate should be avoided in patients with hepatic dysfunction.
  • Methotrexate toxicity is more likely if taken with other medicines – such as penicillins or NSAIDs or probenecid – that reduce its renal excretion.
  • Blood disorders are more likely if MTX is taken alongside other folate antagonists, such as trimethoprim or phenytoin.
  • The risk of neutropenia is increased if MTX is taken with clozapine.
  • In cancer chemotherapy, MTX may be administered IV or IM to induce remission until a maintenance dose is warranted.
  • Folinic acid is used to reverse the effects of methotrexate in overdose.
  • Brand names of methotrexate include Trexall and Xatmep and Otrexup and Rheumatrex.
  • Routes of administration: by mouth, intravenous, intramuscular, subcutaneous, intrathecal.
  • MTX has approximately 60% bioavailability at lower doses, though this percentage is lower when MTX is given at higher doses.
  • At lower doses, MTX has an elimination half-life of approximately 3-10 hours. At higher doses, this increases to approximately 8-15 hours.

Methotrexate continues to remain a highly effective drug in the treatment of cancer and autoimmune disorders. However, it is also associated with significant risks – many of which we have outlined here. Healthcare professionals should continue to remain vigilant in prescribing and dispensing this medicine to patients.

That concludes our rapid revision of methotrexate pharmacology! Check back to our PharmaFactz blog soon for more exclusive content to help you master the science of drugs and medicines!

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