1. Clinical Overview
Methotrexate is a folate antagonist antimetabolite and immunosuppressive agent. In the 7.5mg strength, it is primarily used as a once-weekly oral dose for the management of autoimmune diseases like rheumatoid arthritis and psoriasis. It competitively inhibits dihydrofolate reductase (DHFR), disrupting DNA synthesis and cellular replication, leading to anti-inflammatory and immunomodulatory effects.
| Onset | Duration | Bioavailability |
|---|---|---|
| Clinical improvement in rheumatoid arthritis is typically seen within 3-6 weeks of initiation. Full therapeutic effect may take up to 12 weeks. | The pharmacodynamic effects (immunosuppression) last significantly longer than its plasma half-life, necessitating once-weekly dosing. | Approximately 60-70% for oral doses up to 15mg. Bioavailability decreases at higher doses due to saturation of absorption pathways. |
2. Mechanism of Action
Methotrexate competitively and irreversibly inhibits the enzyme dihydrofolate reductase (DHFR). DHFR is responsible for converting dihydrofolate to tetrahydrofolate, a crucial cofactor in the synthesis of thymidylate and purine nucleotides. This inhibition depletes intracellular reduced folate pools, leading to impaired synthesis of DNA, RNA, and proteins. In autoimmune conditions, it promotes adenosine release, which has potent anti-inflammatory effects, and induces apoptosis of activated T-lymphocytes.
3. Indications & Uses
- Active Rheumatoid Arthritis (moderate to severe) as a DMARD
- Severe, disabling Psoriasis (including psoriatic arthritis) not responsive to conventional therapy
4. Dosage & Administration
Adult Dosage: Rheumatoid Arthritis/Psoriasis: Initial dose: 7.5mg once weekly as a single oral dose. May be increased gradually, typically in 2.5mg increments every 2-4 weeks, up to a maximum of 20-25mg/week based on response and tolerability. Dose is often split (e.g., 2.5mg every 12 hours for 3 doses) to improve GI tolerance.
Administration: Take ONCE A WEEK on the same designated day. Can be taken with or without food, but food may reduce nausea. Avoid antacids containing aluminum within 2 hours of dose as they may reduce absorption. Concomitant folic acid (1-5mg daily or 5-10mg once weekly, excluding the day of methotrexate) is strongly recommended to reduce mucosal and GI toxicity. Do not crush or chew the tablet.
5. Side Effects
Common side effects may include:
- Nausea, vomiting, abdominal discomfort
- Stomatitis (mouth ulcers)
- Fatigue, malaise
- Headache, dizziness
- Elevated liver transaminases (asymptomatic)
- Alopecia (mild, reversible)
- Folic acid deficiency manifestations
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) e.g., Diclofenac, Naproxen | Competition for renal tubular secretion; can increase methotrexate levels and risk of hematologic/renal toxicity. | Major |
| Trimethoprim-Sulfamethoxazole (Cotrimoxazole) | Additive antifolate effect; dramatically increases risk of myelosuppression and megaloblastic anemia. | Major |
| Probenecid | Inhibits renal excretion of methotrexate, increasing plasma levels and toxicity. | Major |
| Phenytoin | Methotrexate may decrease phenytoin protein binding and clearance, increasing phenytoin toxicity. | Moderate |
| Oral Hypoglycemics (e.g., Sulfonylureas) | Methotrexate may potentiate hypoglycemic effect. | Moderate |
| Theophylline | Methotrexate may decrease theophylline clearance. | Moderate |
| Retinoids (e.g., Acitretin) | Increased risk of hepatotoxicity. | Major |
| Live Vaccines (e.g., MMR, Varicella, Yellow Fever) | Risk of disseminated vaccine-induced infection. | Major |
7. Patient Counselling
- DO take this medicine ONLY ONCE A WEEK on your prescribed day (e.g., 'Sunday Pill').
- DO take your prescribed folic acid supplement on the other days of the week as directed.
- DO report for ALL scheduled blood tests (CBC, LFT, creatinine).
- DO use effective contraception during and after treatment (discuss duration with doctor).
- DONT take the medicine daily. This can cause fatal poisoning.
- DONT consume ANY alcohol, including beer and wine.
- DONT take over-the-counter NSAIDs (like ibuprofen, diclofenac) without consulting your doctor.
- DONT receive live vaccines (e.g., MMR, chickenpox, yellow fever) without doctor's approval.
- DONT try to conceive or father a child while on this medicine.
8. Toxicology & Storage
Overdose: Symptoms typically appear within 24-48 hours. Includes severe leukopenia, thrombocytopenia, anemia, mucositis (mouth to gut ulceration, bleeding, diarrhea), hepatotoxicity, renal failure, skin erythema and desquamation, and sepsis. Can be fatal.
Storage: Store at room temperature (15-30°C) in a dry place, protected from light and moisture. Keep in the original container. Keep out of reach of children and pets. Do not use after the expiry date printed on the pack. Dispose of unused tablets safely; do not flush.