Methotrexate

What is Methotrexate?

Methotrexate is in a class of medications known as antimetabolites. Methotrexate is an antirheumatic and antineoplastic agent and an antimetabolite. 

Uses of Methotrexate [3., 4.] 

Methotrexate is FDA-approved as a folic acid antagonist, commonly used in treating rheumatoid arthritis and juvenile idiopathic arthritis. 

It is a primary chemotherapeutic agent used for various cancers and is also effective in managing autoimmune conditions such as psoriasis, systemic lupus erythematosus, inflammatory bowel disease, and vasculitis. 

Due to its anti-inflammatory properties, methotrexate is beneficial in connective tissue diseases and organ transplantation to prevent rejection. 

It is often used in combination with anti-TNF agents for conditions like ulcerative colitis and lymphoma. 

However, it is contraindicated in patients with blood dyscrasias and pregnant women.

Mechanism of Action of Methotrexate [2., 4.] 

Methotrexate’s mechanisms of action are different in chemotherapy and autoimmune diseases. 

As a cancer treatment, methotrexate works by stopping the growth of cancer cells, which are cells that grow and divide very quickly.

In the setting of autoimmune conditions, methotrexate reduces inflammation and slows down the disease, helping to relieve symptoms and prevent joint damage.

Methotrexate as a Cancer Treatment

In cancer treatment, it acts as an antifolate antimetabolite, inhibiting dihydrofolate reductase, an enzyme essential for DNA and RNA synthesis, leading to a cytotoxic effect on cancer cells. 

Methotrexate's action of inhibiting the enzyme dihydrofolate reductase (DHFR) halts the conversion of dihydrofolate to tetrahydrofolate, an essential step in the synthesis of purines and pyrimidines, which are building blocks of DNA and RNA. 

By inhibiting DHFR, methotrexate disrupts the production of these nucleotides, ultimately interfering with cell division and growth. 

This mechanism is particularly effective against rapidly dividing cells such as cancer cells.

Methotrexate in Autoimmune Diseases

In autoimmune diseases, methotrexate inhibits AICAR transformylase, resulting in the accumulation of adenosine, which has anti-inflammatory effects by repressing T-cell activation and down-regulating B-cell activity.

Methotrexate’s anti-inflammatory properties contribute to its efficacy in treating conditions like rheumatoid arthritis and psoriasis. 

The drug's ability to modulate the immune system and reduce inflammation makes it a valuable option for managing various autoimmune and inflammatory conditions.

Methotrexate Drug Interactions [4.] 

Drugs that Affect Protein Binding

Drugs displacing methotrexate from plasma proteins can increase its blood levels.

Drugs that Affect Renal Clearance

Drugs affecting renal clearance can elevate methotrexate concentration.

Common Interactions

NSAIDs, PPIs, salicylates, TMP, penicillin, warfarin, valproate, proton pump inhibitors, and cyclosporin increase the risk of methotrexate toxicity.

Drugs that Inhibit Absorption

Aminoglycosides, neomycin, and probenecid reduce methotrexate absorption.

Live Vaccines

Some live vaccines, including the MMR vaccine, the varicella virus and the zoster vaccine are contraindicated. [DYNAMED>>>>>>>>>>>

Significant Risks of Specific Drugs with Methotrexate

Notably, NSAIDs and PPIs due to their frequent use.

Methotrexate Uses

Rheumatoid Arthritis

Methotrexate is widely recognized as a cornerstone treatment for rheumatoid arthritis. Its effectiveness in managing this chronic inflammatory condition stems from its ability to suppress the overactive immune response that leads to joint inflammation and damage. 

In rheumatoid arthritis, methotrexate is typically administered weekly in low doses, which allows for long-term use with a favorable risk-benefit profile. [2.] 

The drug's anti-inflammatory properties help reduce joint pain, swelling, and stiffness, ultimately improving patients' quality of life and slowing disease progression.

Psoriasis [6.] 

Methotrexate is used for moderately severe to severe psoriasis due to its cytostatic and anti-inflammatory properties. 

Despite its widespread use, large robust studies on its efficacy and safety are limited. One study showed that nearly 40% of patients achieved a 75% improvement in the Psoriasis Area and Severity Index (PASI) score at 16 weeks with methotrexate. [8.] 

Common side effects include nausea, vomiting, diarrhea, and fatigue, with hepatotoxicity being a well-known risk.

By reducing skin cell turnover and modulating the immune response, methotrexate helps alleviate the symptoms of psoriasis, including the formation of thick, scaly patches on the skin. Its use in psoriasis treatment may lead to significant improvements in skin appearance and patient comfort.

Cancer Treatment [5.] 

Methotrexate is a chemotherapy drugs used to treat cancer, particularly hematologic malignancies such as lymphoma and leukemia, as well as being used to treat breast, lung, bladder, cervical, gastric, and ovarian carcinomas. [1.] 

Its effectiveness comes from its easy entry into cells and subsequent intracellular modification, and how strongly it inhibits the enzyme dihydrofolate reductase (DHFR), which is vital for cell replication.

Methotrexate works by entering cells through a specific transport system that usually carries 5-methyltetrahydrofolate. 

Once inside, methotrexate attaches to glutamate molecules, enhancing its ability to inhibit DHFR. This enzyme, DHFR, helps produce folate, which cells need to make DNA and divide. By inhibiting DHFR, methotrexate prevents cancer cells from making DNA, thus stopping their growth.

Despite its effectiveness, some tumors can become resistant to methotrexate. This resistance can happen in several ways:

Increased DHFR Levels

Tumors might produce more DHFR to overcome the drug’s effects.

Mutant DHFR

Some tumors have a mutated form of DHFR that doesn’t bind well with methotrexate.

Decreased Drug Uptake

Tumors might reduce the uptake or modification of methotrexate, making it less effective.

Researchers have studied DHFR extensively, including its structure and how it interacts with methotrexate. They’ve used techniques like NMR and X-ray crystallography to understand these interactions better. 

Additionally, they’ve explored new forms of methotrexate, called prodrugs, which are designed to target tumors more selectively, potentially increasing the drug’s effectiveness.

Overall, the extensive research on methotrexate has not only improved its use in treating cancer but also guided the development of other similar drugs and strategies in chemotherapy.

Ectopic Pregnancy [7.] 

Methotrexate (MTX) is the primary pharmacological treatment for ectopic pregnancy (EP), administered typically in a single or multi-dose regimen. It works by inhibiting DNA synthesis, leading to the death of rapidly dividing cells, including trophoblast cells. 

The effectiveness of MTX in treating ectopic pregnancies ranges from 70% to 90%, depending on the treatment regimen. 

Suitable for patients without symptoms indicating hemodynamic instability or fallopian tube rupture, MTX is not recommended for those with significant liver or renal diseases, bone marrow dyscrasias, immunodeficiency, peptic ulcer disease, breastfeeding, or concurrent intrauterine pregnancy. 

Optimal conditions for use include serum β-hCG levels below 1500 IU/L (or even up to 4000 IU/L) and a gestational follicle size not exceeding 35 mm. Regular monitoring of β-hCG levels is essential to assess treatment effectiveness and detect complications like fallopian tube rupture, which occurs in 7-14% of cases. 

MTX treatment is contraindicated for patients who cannot be adequately monitored or are unable to attend follow-up appointments. 

Researchers are exploring other substances, such as aromatase inhibitors (e.g., letrozole), gefitinib (an EGFR inhibitor), potassium chloride (KCl), and absolute ethanol, to provide less toxic and more effective treatments for ectopic pregnancy. 

While MTX is effective for many cases, the search for alternative treatments continues to minimize adverse effects and provide more options for patients with contraindications to MTX.

Other Uses for Methotrexate

Methotrexate has also been used in other conditions including systemic lupus erythematosus (SLE) and other autoimmune conditions, irritable bowel disease, vasculitis, and in some asthma cases. [4., 9.] 

Methotrexate Administration

Oral Administration

Oral administration is a common and convenient method for delivering methotrexate, particularly in the treatment of chronic conditions such as rheumatoid arthritis and psoriasis. 

Methotrexate tablets or solution are typically taken once a week, with the dose carefully calibrated based on the patient's condition, body weight, and response to treatment. The oral route allows for easy self-administration at home, improving patient compliance. 

However, oral methotrexate may have variable absorption rates, which can affect its efficacy and potential for side effects.  This must also be taken into account when switching a patient to or from an oral form to an injected form, due to the possibility of differences in bioavailability. [3.] 

Methotrexate Injection

Methotrexate injection is another widely used method of administration, especially in cancer treatment and severe cases of autoimmune disorders. Injections can be given subcutaneously, intramuscularly, or intravenously, depending on the specific treatment protocol. 

The injection route often provides more predictable drug levels in the body compared to oral administration, which can be beneficial in certain clinical scenarios.

High Dose Methotrexate [4.] 

High dose methotrexate refers to treatment regimens higher than 500 mg/ml. High dose methotrexate requires regular monitoring and assessment to avoid methotrexate toxicity. 

Common side effects include nausea, mucosal ulceration, alopecia, fatigue, fever, increased infection risk, leukopenia, gastrointestinal bleeding, pancreatitis, cirrhosis, aplastic anemia, lymphoproliferative disorders, infections, interstitial pneumonitis, renal impairment, and teratogenesis.

Managing methotrexate toxicity requires immediate administration of leucovorin, the active form of folic acid, which rescues normal cells from methotrexate's toxic effects, particularly preventing myelosuppression, gastrointestinal toxicity, and neurotoxicity. 

In cases of renal failure, adequate hydration and urinary alkalinization with sodium bicarbonate are essential. 

The three primary antidotes for methotrexate toxicity are leucovorin, thymidine, and glucarpidase. Leucovorin reduces methotrexate's toxic effects by providing active folates. 

Thymidine, although still under investigation, helps rescue cells from methotrexate's cytotoxic effects. 

Glucarpidase converts methotrexate into non-toxic metabolites (DAMPA and glutamate), rapidly reducing methotrexate levels by 97% within 15 minutes and is used alongside leucovorin, with hydration and urine alkalinization continued. 

Leucovorin therapy should continue for 48 hours after glucarpidase administration. 

Additional treatments include hemodialysis and hemoperfusion to lower methotrexate levels. 

Monitoring Methotrexate Use

Patients on methotrexate require careful and regular monitoring due to potential side effects and drug interactions. 

Laboratory Tests [3., 4.] 

Initial and Regular Testing: 

Weekly monitoring of complete blood count (CBC), serum creatinine, and liver transaminases (AST, ALT) for the first four weeks, then at least every two months.

Liver Function: 

Regular liver function tests and, if necessary, liver biopsy to monitor for hepatotoxicity.

Renal Function: 

Monitor creatinine clearance (must be at least 50 ml/min before prescribing) to avoid nephrotoxicity.

Methotrexate Levels: 

Check plasma methotrexate levels in patients with significant fluid accumulations (e.g., pleural effusion, ascites).

Bone Marrow Toxicity: 

Regular CBC to watch for signs of myelosuppression, particularly in elderly patients.

Pregnancy Test: 

Conduct a pregnancy test in women of childbearing potential before starting treatment.

Physical Examinations [3., 4.] 

Pulmonary Function: 

Monitor for signs of lung toxicity such as dry cough, fever, or dyspnea. Baseline chest radiographs are recommended.

Infection: 

Check for signs of infection during and after treatment.

Myelosuppression: 

Watch for sudden drops in blood counts.

Hepatotoxicity: 

Closely monitor liver function, especially in patients with risk factors such as obesity, diabetes, or chronic liver conditions.

Additional Monitoring [3., 4.] 

Tuberculosis: 

Screen for tuberculosis in endemic areas before starting methotrexate.

Hydration: 

Ensure patients maintain adequate hydration to reduce the risk of nephrotoxicity.

Periodic Reassessments: 

Reevaluate liver and renal function, especially before reinitiating therapy after a break.

Specific Conditions [3., 4.] 

Psoriasis and Rheumatoid Arthritis: 

Monitor improvement in symptoms such as lesion reduction and decreased joint pain to assess efficacy.

Cancer Treatment: 

Regularly check blood counts and monitor for clinical signs of remission or progression.

Lab Testing for Methotrexate

Test Information, Sample Collection and Preparation

Monitoring serum methotrexate levels is a critical component of managing patients receiving high-dose methotrexate (HDmethotrexate) therapy. 

The measurement of methotrexate concentrations in the blood provides valuable information about drug clearance and potential toxicity risks. 

Sample collection requires a venipuncture. It is important to consult with the ordering provider regarding timing of sample collection. 

Frequency of Testing

The frequency of methotrexate testing varies depending on the treatment regimen and individual patient factors. 

For patients receiving high dose methotrexate, frequent monitoring is crucial, especially in the immediate post-infusion period and the following days. 

In cases of suspected delayed elimination or toxicity, more frequent testing may be necessary. 

For patients on long-term, low-dose methotrexate therapy, such as those with rheumatoid arthritis or psoriasis, regular monitoring is still important but may be less frequent. 

The specific testing schedule should be determined by the treating physician based on the patient's clinical status, treatment response, and risk factors for toxicity.

Methotrexate Side Effects [3., 4.] 

Methotrexate, while an effective treatment for various conditions, can cause a range of side effects that require careful monitoring and management. 

Gastrointestinal

• Nausea

• Vomiting

• Mucosal ulcers

• Loss of appetite

• Gastrointestinal bleeding

• Pancreatitis

Dermatologic

• Alopecia

• Rash

• Photosensitivity

• Erythema multiforme

• Skin cancer

• Stevens-Johnson syndrome

• Toxic epidermal necrolysis

Hematologic

• Thrombocytopenia

• Leukopenia

• Aplastic anemia

• Pancytopenia

• Agranulocytosis

• Bone marrow suppression

Hepatic

• Hepatotoxicity

• Cirrhosis

• Hepatic fibrosis

• Acute hepatitis

• Elevated liver function tests

Renal

• Renal failure

• Nephrotoxicity

Neurologic

• Headache

• Encephalopathy

• Leukoencephalopathy

• Neurotoxicity

• Seizures

Respiratory

• Interstitial pneumonitis

• Pulmonary fibrosis

• Pulmonary toxicity

• Bronchitis

• Nasopharyngitis

Infectious

• Increased risk of infections

• Opportunistic infections

• Reactivation of tuberculosis

Immunologic

• Anaphylaxis

• Malignant lymphoma

Systemic

• Fatigue

• Fever

• Teratogenesis

Cardiovascular

• Thromboembolic disorder

Frequently Asked Questions About Methotrexate

Methotrexate is a widely used medication with various applications in medical treatment. This FAQ section aims to address common questions about methotrexate, its uses, side effects, and important considerations for patients. 

If you have specific concerns about your treatment, always consult your healthcare provider for personalized advice.

What is Methotrexate Used For?

Methotrexate is used to treat a variety of conditions including certain types of cancer, rheumatoid arthritis, psoriasis, and as part of medical termination of an ectopic pregnancy. 

It's also employed in the treatment of other cancers including acute lymphoblastic leukemia, choriocarcinoma, trophoblastic tumors, and carcinomas of the breast, tongue, pharynx, and testis. 

Additionally, it's used for non-malignant conditions such as asthma, sarcoidosis, and in transplantation therapy.

What are the Most Common Side Effects of Methotrexate?

Common side effects of methotrexate include bone marrow suppression, hepatic or renal dysfunction, gastrointestinal distress, mucocutaneous damage, and neurotoxicity. 

Some patients may experience nausea, vomiting, fatigue, and mild hair loss. 

It's important to note that side effects can vary in severity and frequency depending on the dosage and individual patient factors. Patients on methotrexate should be monitored regularly. 

How Long Does Methotrexate Stay in Your System?

The duration methotrexate stays in your system can vary depending on the dosage and individual factors. 

Regular monitoring of serum methotrexate levels is crucial, especially for patients receiving high-dose therapy. 

Your healthcare provider will determine the appropriate monitoring schedule based on your specific treatment regimen.

What Should I Expect After Taking Methotrexate for Ectopic Pregnancy?

Methotrexate is used in the medical management of ectopic pregnancies. After treatment, you may experience abdominal pain, vaginal bleeding, and fatigue. 

It's important to follow up with your healthcare provider for monitoring and to discuss any concerns or unexpected symptoms.

What Painkillers Can I Take with Methotrexate?

The choice of pain killers to use with methotrexate should be discussed with your healthcare provider. 

Some pain medications may interact with methotrexate or increase the risk of side effects. 

Always consult your doctor or pharmacist before taking any over-the-counter pain medications while on methotrexate.

How Can I Boost My Immune System While Taking Methotrexate?

Methotrexate can affect the immune system, so it's important to maintain overall health. Eating a balanced diet, getting adequate sleep, and managing stress can support immune function. 

However, avoid taking immune-boosting supplements without consulting your doctor, as they may interfere with your treatment.

What is the Methotrexate Drug Class?

Methotrexate belongs to the class of drugs known as antifolates or folic acid antagonists. It works by inhibiting the enzyme dihydrofolate reductase, which is crucial for DNA synthesis and cell division.