Methotrexate

Usage

Methotrexate is prescribed for various medical conditions, including:

• Certain cancers such as acute lymphoblastic leukemia (ALL), non-Hodgkin’s lymphoma, gestational trophoblastic neoplasia, and osteosarcoma.
• Autoimmune diseases such as rheumatoid arthritis, psoriasis, psoriatic arthritis, and Crohn’s disease.
• Ectopic pregnancy.

Pharmacological Classification: Antimetabolite, antineoplastic, immunosuppressant, antifolate.

Mechanism of Action: Methotrexate primarily inhibits dihydrofolate reductase (DHFR), an enzyme crucial for folate metabolism. This inhibition blocks DNA, RNA, and protein synthesis, impacting rapidly dividing cells like cancer cells and immune cells. It also has anti-inflammatory properties.

Alternate Names

• Amethopterin
• 4-amino-10-methylfolic acid

Brand Names: Examples include Trexall, Otrexup, Jylamvo, Maxtrex, Methofill, Metoject, Nordimet, Zlatal.

How It Works

Pharmacodynamics: Methotrexate’s primary effect is the inhibition of cell proliferation. In cancer, this leads to tumor regression; in autoimmune diseases, it dampens the overactive immune response. At higher doses used in cancer treatment, it has cytotoxic effects. At lower doses employed for inflammatory conditions, its immunosuppressant and anti-inflammatory effects predominate.

Pharmacokinetics:

• Absorption: Oral absorption is variable and dose-dependent, decreasing at higher doses. Subcutaneous and intramuscular routes provide more consistent absorption. Intrathecal administration bypasses the blood-brain barrier for CNS conditions.
• Metabolism: Partially metabolized in the liver, primarily by aldehyde oxidase, to inactive metabolites and polyglutamates, some of which also possess antifolate activity.
• Elimination: Primarily renal excretion. Dosage adjustment is necessary for renal impairment.

Mode of Action: Methotrexate competitively inhibits dihydrofolate reductase (DHFR), ultimately halting thymidylate and purine nucleotide synthesis. Polyglutamation of methotrexate within cells results in prolonged intracellular retention and enhanced inhibition of other folate-dependent enzymes.

Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Methotrexate’s main mechanism involves DHFR inhibition. It also inhibits other folate-dependent enzymes, including thymidylate synthase, aminoimidazole carboxamide ribonucleotide transformylase, and AICAR transformylase.

Elimination Pathways: Primarily renal excretion, with a small portion excreted in bile. Polyglutamated forms may undergo enterohepatic recirculation, contributing to prolonged effects.

Dosage

Dosage varies significantly depending on the condition, route of administration, and patient-specific factors. It is crucial to individualize the dosage based on careful assessment and close monitoring.

Standard Dosage

Adults:

• Rheumatoid Arthritis: Starting dose is usually 7.5 mg orally once weekly, which can be gradually increased up to a maximum of 20-25 mg weekly, based on response and tolerance.
• Psoriasis: Starting dose ranges from 10-25 mg orally once weekly, which may be adjusted to a maximum of 30 mg weekly.
• Crohn’s disease: Maintenance dose is typically 10-25 mg orally once weekly.

Children:

• Polyarticular Juvenile Idiopathic Arthritis (pJIA): Starting dose is often 10 mg/m² orally once weekly, titrated based on response and tolerance up to a maximum of 30 mg/m² weekly.
• Other conditions: Dosage calculations based on body surface area (BSA) are common in pediatrics and must be determined by a doctor.

Special Cases:

• Elderly Patients: Start at lower doses and monitor closely for adverse reactions.
• Patients with Renal Impairment: Dosage reduction is necessary based on creatinine clearance.
• Patients with Hepatic Dysfunction: Close monitoring and dosage adjustment are essential.
• Patients with Comorbid Conditions: Individualized dosing and careful consideration of potential drug interactions are required.

Clinical Use Cases

Methotrexate’s use in scenarios like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations primarily relates to its role in managing underlying conditions like rheumatoid arthritis or inflammatory bowel disease during these critical periods. Dosage modifications during these times often depend on the patient’s stability and the impact of the acute situation on their overall health. Its use in high-dose chemotherapy regimens requires careful consideration and specific protocols, often including leucovorin rescue. For instance, acute lymphoblastic leukemia treatment might involve high-dose methotrexate followed by leucovorin. Dosing in such cases needs to be tailored to the individual and disease protocol.

Dosage Adjustments

Dosage modifications are based on patient response, renal and hepatic function, concomitant medications, and potential drug interactions. Therapeutic drug monitoring and assessment of relevant laboratory parameters are essential.

Side Effects

Common Side Effects: Nausea, vomiting, stomatitis, diarrhea, fatigue, alopecia, headache, myelosuppression (leukopenia, thrombocytopenia, anemia).

Rare but Serious Side Effects: Hepatotoxicity, pulmonary fibrosis, nephrotoxicity, opportunistic infections, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Long-Term Effects: Liver cirrhosis, bone marrow suppression, infertility.

Adverse Drug Reactions (ADR): Severe myelosuppression, anaphylaxis, pneumonitis, renal failure.

Contraindications

• Pregnancy (especially first trimester)
• Breastfeeding
• Active severe liver disease
• Pre-existing blood dyscrasias
• Alcoholism
• Hypersensitivity to methotrexate.

Drug Interactions

• Nonsteroidal anti-inflammatory drugs (NSAIDs): Increased risk of methotrexate toxicity.
• Proton pump inhibitors (PPIs): Increased methotrexate levels.
• Antibiotics (e.g., trimethoprim-sulfamethoxazole, penicillin): Reduced methotrexate clearance.
• Other immunosuppressants: Increased risk of infection.

Pregnancy and Breastfeeding

Methotrexate is contraindicated during pregnancy due to its teratogenic effects. It is also contraindicated during breastfeeding due to potential harm to the infant.

Drug Profile Summary

• Mechanism of Action: Inhibits dihydrofolate reductase (DHFR), blocking DNA, RNA, and protein synthesis.
• Side Effects: Nausea, vomiting, stomatitis, myelosuppression, hepatotoxicity, pulmonary fibrosis.
• Contraindications: Pregnancy, breastfeeding, liver disease, blood dyscrasias.
• Drug Interactions: NSAIDs, PPIs, antibiotics, immunosuppressants.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: Variable based on indication and patient factors; refer to detailed dosage guidelines.
• Monitoring Parameters: Complete blood count (CBC), liver function tests (LFTs), renal function tests (RFTs).

Popular Combinations

Methotrexate is often used in combination with other medications, such as:

• Rheumatoid Arthritis: Other disease-modifying antirheumatic drugs (DMARDs) like sulfasalazine, hydroxychloroquine, and biologics (TNF inhibitors).
• Cancer: Combined with other chemotherapeutic agents as part of specific protocols.

Precautions

• General Precautions: Monitor blood counts, liver and kidney function regularly.
• Specific Populations: Closely monitor pregnant or potentially pregnant women exposed to methotrexate. Women of childbearing age should use effective contraception during and for a period after treatment.
• Lifestyle Considerations: Avoid alcohol consumption during therapy.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Methotrexate?

A: The dosage is highly dependent on the indication and patient-specific factors. For rheumatoid arthritis, the starting dose is typically 7.5 mg orally once weekly. For psoriasis, the starting dose is 10-25 mg orally once weekly. Pediatric doses are calculated based on body surface area (BSA).

Q2: How should Methotrexate be administered?

A: It can be administered orally, subcutaneously, intramuscularly, or intrathecally. The route depends on the condition and the desired effect.

Q3: What are the major side effects to watch out for?

A: Common side effects include nausea, vomiting, and stomatitis. Serious side effects include myelosuppression, hepatotoxicity, and pulmonary fibrosis.

Q4: Are there any contraindications to Methotrexate use?

A: Yes, contraindications include pregnancy, breastfeeding, active liver disease, blood dyscrasias, and hypersensitivity to methotrexate.

Q5: What are the key drug interactions with Methotrexate?

A: Significant interactions can occur with NSAIDs, PPIs, antibiotics (especially trimethoprim-sulfamethoxazole), and other immunosuppressants.

Q6: What monitoring parameters are essential during Methotrexate therapy?

A: Close monitoring of complete blood count (CBC), liver function tests (LFTs), and renal function tests (RFTs) is crucial.

Q7: What is the role of folic acid or folinic acid supplementation during Methotrexate treatment?

A: Folic acid or folinic acid supplementation is often recommended to reduce the risk of certain side effects, particularly myelosuppression and gastrointestinal issues, without compromising the efficacy of methotrexate.

Q8: Can Methotrexate be used in elderly patients?

A: Yes, but lower starting doses and careful monitoring are generally advisable in elderly patients due to potential age-related decreases in organ function.

Q9: How should Methotrexate be dosed in patients with renal impairment?

A: Dosage reduction is necessary based on the patient’s creatinine clearance to prevent drug accumulation and toxicity.

Q10: What is the mechanism of action of Methotrexate in cancer treatment?

A: At high doses, methotrexate exerts its anti-cancer effects primarily through inhibition of DHFR, which leads to the disruption of DNA, RNA, and protein synthesis in rapidly dividing cancer cells. Leucovorin rescue is often used to minimize toxicity to normal cells.