1. Clinical Overview
Methotrexate is a potent antimetabolite and antifolate agent, primarily used as a disease-modifying antirheumatic drug (DMARD) and chemotherapeutic agent. It competitively inhibits dihydrofolate reductase (DHFR), disrupting DNA synthesis and cellular replication. In the Indian context, it is a cornerstone therapy for rheumatoid arthritis, psoriasis, and various malignancies, valued for its efficacy and cost-effectiveness.
| Onset | Duration | Bioavailability |
|---|---|---|
| Clinical improvement in inflammatory conditions (e.g., RA) is typically seen within 3-6 weeks of initiation. Cytotoxic effects in malignancies are rapid, within the cell cycle. | Variable; anti-inflammatory effects can last for the duration of weekly dosing. Intracellular polyglutamated forms can persist for weeks, contributing to prolonged action. | Approximately 60-70% for oral doses <30mg. Bioavailability of the parenteral solution (15mg/ml) is 100% when administered via IM, SC, or IV routes. |
2. Mechanism of Action
Methotrexate competitively and irreversibly inhibits the enzyme dihydrofolate reductase (DHFR). This enzyme is responsible for converting dihydrofolate to tetrahydrofolate (THF), a crucial cofactor in the synthesis of thymidylate, purine nucleotides, and certain amino acids. Inhibition depletes intracellular THF pools, leading to impaired DNA, RNA, and protein synthesis, thereby inhibiting cellular proliferation, particularly in rapidly dividing cells.
3. Indications & Uses
- Moderate to Severe Rheumatoid Arthritis (DMARD)
- Severe Plaque Psoriasis
- Acute Lymphoblastic Leukemia (ALL) - part of combination chemotherapy
- Gestational Trophoblastic Neoplasia (Choriocarcinoma, hydatidiform mole)
4. Dosage & Administration
Adult Dosage: **Rheumatology/Dermatology:** Initial: 7.5-10 mg once weekly, orally/SC/IM. May increase gradually by 2.5 mg every 2-4 weeks to a usual max of 20-25 mg/week based on response and tolerability. **Oncology:** Varies drastically by protocol. E.g., ALL: up to 12 gm/m² as IV infusion with leucovorin rescue. GTN: 15-30 mg IM/PO daily for 5 days, repeated.
Administration: **For 15mg/ml solution:** For subcutaneous (SC) or intramuscular (IM) use. Use a tuberculin syringe for accurate measurement. Rotate injection sites (thigh, abdomen). Do NOT administer intrathecally unless specifically formulated for that route. Oral doses should be taken on the same day each week. Missed dose: If remembered within 2 days, take it. If closer to next dose, skip it. DO NOT double dose.
5. Side Effects
Common side effects may include:
- Nausea, vomiting, abdominal discomfort
- Mucositis/stomatitis (mouth ulcers)
- Fatigue, malaise
- Elevated liver transaminases (asymptomatic)
- Mild leukopenia
- Headache, dizziness
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| NSAIDs (e.g., Diclofenac, Naproxen) | Competitively inhibit renal tubular secretion of methotrexate, increasing serum levels and risk of severe myelosuppression and GI toxicity. | Major |
| Trimethoprim-Sulfamethoxazole (Co-trimoxazole) | Synergistic antifolate effect; dramatically increases risk of myelosuppression and megaloblastic anemia. | Major |
| Probenecid | Inhibits renal excretion of methotrexate, leading to increased and prolonged plasma levels. | Major |
| Phenytoin | Methotrexate may decrease phenytoin protein binding and clearance, increasing phenytoin toxicity risk. | Moderate |
| Retinoids (e.g., Acitretin) | Increased risk of hepatotoxicity. | Moderate |
| Theophylline | Methotrexate may decrease theophylline clearance. | Moderate |
| Live Vaccines (MMR, Varicella, Yellow Fever) | Risk of disseminated vaccine-induced infection due to immunosuppression. | Major |
7. Patient Counselling
- **DO** take your dose on the same day each week. **DO** take prescribed folic acid supplements (usually 5mg once weekly, 24 hours after methotrexate). **DO** get regular blood tests (CBC, LFT, creatinine) as advised. **DO** inform all your doctors and dentists you are on methotrexate. **DON'T** take a double dose if you miss one. **DON'T** take NSAIDs (like ibuprofen, diclofenac) without consulting your doctor. **DON'T** self-prescribe any new medicine, including antibiotics.
8. Toxicology & Storage
Overdose: Manifestations typically occur 3-7 days after overdose. Symptoms include severe leukopenia, thrombocytopenia, anemia, mucositis (mouth to anus), vomiting, diarrhea, GI ulceration/bleeding, hepatotoxicity, renal failure, and sepsis.
Storage: Store at 20°C to 25°C. Protect from light. Do not freeze. Keep the vial/ampoule in the outer carton. Keep out of reach of children. Discard any unused solution appropriately. Do not use if the solution is discolored or contains particulate matter.