1. Clinical Overview
Methotrexate is a folate antagonist antimetabolite and immunosuppressive agent. It is a disease-modifying anti-rheumatic drug (DMARD) used primarily in oncology and autoimmune diseases. In the 15mg strength, it is most commonly used for weekly dosing in conditions like rheumatoid arthritis, psoriasis, and certain inflammatory disorders. It works by inhibiting dihydrofolate reductase, thereby interfering with DNA synthesis, repair, and cellular replication.
| Onset | Duration | Bioavailability |
|---|---|---|
| Clinical improvement in autoimmune conditions (e.g., RA) is typically seen within 3-6 weeks of initiation. For psoriasis, improvement may be seen in 2-4 weeks. Cytotoxic effects in oncology occur within hours to days. | The immunosuppressive and anti-inflammatory effects last approximately 1 week, which is why it is dosed weekly for autoimmune conditions. The cytotoxic effects are related to the cell cycle and duration of exposure. | Approximately 60-70% for oral administration. Absorption is dose-dependent and saturable; higher doses (>15mg) may have reduced and more variable bioavailability. |
2. Mechanism of Action
Methotrexate competitively and irreversibly inhibits dihydrofolate reductase (DHFR), the enzyme responsible for converting dihydrofolate to tetrahydrofolate (THF). THF is essential for the synthesis of thymidylate, purine nucleotides, and certain amino acids. This inhibition depletes intracellular reduced folate cofactors, leading to impaired DNA and RNA synthesis, and inhibition of cellular proliferation. In autoimmune diseases, additional anti-inflammatory mechanisms include: inhibition of aminoimidazole carboxamide ribonucleotide (AICAR) transformylase, leading to accumulation of adenosine with potent anti-inflammatory effects; inhibition of T-cell activation; suppression of interleukin-1 (IL-1) and other pro-inflammatory cytokines; and promotion of apoptosis of activated T-cells.
3. Indications & Uses
- Rheumatoid Arthritis (moderate to severe, active)
- Psoriasis (severe, recalcitrant, disabling)
- Polyarticular Juvenile Idiopathic Arthritis (active)
4. Dosage & Administration
Adult Dosage: Rheumatoid Arthritis/Psoriasis: Initial dose: 7.5 mg once weekly. May be increased gradually to a usual effective dose of 15-20 mg once weekly. Maximum recommended weekly dose for non-oncologic use is 25-30 mg. Dose is administered as a single weekly dose or divided into 3 doses over 24 hours (e.g., 5mg every 12 hours for 3 doses).
Administration: Take ONCE A WEEK on the same designated day. Can be taken with or without food, but taking with food may reduce GI upset. Avoid splitting/crushing tablets if enteric-coated. MUST be supplemented with folic acid 5 mg, taken at least 24 hours after the methotrexate dose, to reduce mucosal and hematologic toxicity. Maintain adequate hydration.
5. Side Effects
Common side effects may include:
- Nausea, vomiting, abdominal discomfort
- Stomatitis (mouth ulcers)
- Fatigue, malaise
- Mild, transient elevation of liver transaminases
- Headache, dizziness
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| NSAIDs (e.g., Ibuprofen, Naproxen, Diclofenac) | Competitively inhibit renal tubular secretion of methotrexate, potentially increasing serum levels and risk of severe toxicity (myelosuppression, mucositis). | 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 serum concentrations. | Major |
| Phenytoin | Methotrexate may decrease phenytoin protein binding and clearance, increasing phenytoin toxicity risk. | Moderate |
| Oral Hypoglycemics (e.g., Sulfonylureas) | Methotrexate may potentiate hypoglycemic effect; monitor blood glucose. | Moderate |
| Theophylline | Methotrexate may decrease theophylline clearance. | Moderate |
| Retinoids (e.g., Acitretin) | Increased risk of hepatotoxicity. | Moderate |
| Live Vaccines (MMR, Varicella, Yellow Fever) | Risk of disseminated vaccine-induced infection due to immunosuppression. | Major |
7. Patient Counselling
- DO take this medicine ONLY ONCE A WEEK on your designated day (e.g., 'Methotrexate Monday').
- DO take your prescribed folic acid supplement (usually 5mg once weekly, the day after methotrexate) to reduce side effects.
- DO maintain good oral hygiene to minimize mouth sores.
- DO drink plenty of fluids on the day you take methotrexate.
- DO use effective contraception (both men and women) during and after treatment.
- DO keep all scheduled blood test appointments (CBC, LFTs, renal function).
- DON'T take any other medicines, including over-the-counter painkillers (like Ibuprofen, Diclofenac), without consulting your doctor.
- DON'T consume ANY ALCOHOL (beer, wine, spirits).
- DON'T take the dose daily by mistake. This can be fatal.
- DON'T get pregnant or breastfeed while on this medication.
8. Toxicology & Storage
Overdose: Symptoms typically appear 3-7 days after overdose. Includes severe leukopenia, thrombocytopenia, anemia, hemorrhagic complications, severe mucositis (stomatitis, pharyngitis, esophagitis, enteritis), nausea, vomiting, diarrhea, hepatotoxicity (elevated transaminases, jaundice), renal failure, and skin rash. Can be fatal.
Storage: Store in a cool, dry place, protected from light and moisture. Keep the container tightly closed. Store at room temperature (15-30°C). Keep out of reach of children and pets. Do not use after the expiry date printed on the pack. Do not flush unused medication. Dispose of as per local pharmaceutical waste guidelines.