Pharmacology Notes

Methotrexate is a folic acid analogue, which binds to dihydrofolate reductase and antagonises folic acid. As folic acid is essential for DNA synthesis, methotrexate impairs cell division. It is cytotoxic at high doses.

Methotrexate has a very long half-life and, for noncancer indications, is given on one day per week.

The most common adverse effects are nausea and mouth ulcers, which occur in about 5% of individuals, but can decrease with continued use. These adverse effects can be limited by a dose reduction, co-administration of folic acid, and parenteral delivery of the methotrexate. Folic acid supplementation is always recommended with methotrexate therapy—at a dose of around 10 mg weekly in a single or split doses, generally not on the day that the methotrexate is administered.

Abnormal liver function tests are common, particularly in those with diabetes, obesity, abnormal renal function, or excessive alcohol intake. Hepatotoxicity correlates with total cumulative dose, and manifests as fibrosis of increasing severity, culminating in cirrhosis. The mechanism is unknown. It is rare in appropriately selected patients in the absence of abnormalities in albumin or transaminases. However, regular monitoring of liver function tests is essential (see Monitoring). Liver biopsy is necessary for early detection and characterisation of this complication, but whether this is justified and how often it should be performed is controversial. Methotrexate should be used cautiously in patients with pre-existing liver disease, or alcohol abuse. A liver biopsy prior to commencement of methotrexate may be useful in these patients; specialist advice should be sought.

Methotrexate can also cause leucopenia, thrombocytopenia and anaemia. The frequency of these haematological events is low, but is higher in the elderly, those with reduced renal function, and in patients with acute illness (eg viral infection, dehydration). Treatment should be ceased temporarily in patients who are acutely unwell.

Dose reduction is required when using methotrexate in patients with mild renal impairment, and methotrexate is contraindicated in moderate to severe renal impairment.

Methotrexate has also been associated with rash, menorrhagia, pneumonitis, fatigue, alopecia and depression.

Methotrexate is teratogenic. It should be avoided in pregnancy, and ceased 3 months before conception if possible. For more detail, see the discussion in Use of antirheumatic drugs in pregnancy.

The combination of methotrexate with other drugs that inhibit folic acid synthesis, such as trimethoprim+sulfamethoxazole (cotrimoxazole), trimethoprim alone, or triamterene should be avoided, because of increased risk of haematological toxicity (eg pancytopenia, megaloblastic anaemia).

Methotrexate concentrations are increased if given concurrently with probenecid, penicillins, aspirin or other NSAIDs. These drugs also block the secretion of methotrexate by the renal tubules.

A full blood examination, including haemoglobin, white cell and platelet counts, creatinine, and liver function tests should be performed monthly for the first 6 months, then every 1 to 2 months thereafter. In patients with a low risk of toxicity, consideration may be given to increasing the intervals between blood tests. Patients with abnormal liver function tests should have more frequent monitoring, and may require liver biopsy if there is a persisting rise in transaminases that does not normalise after cessation of methotrexate.

Due to the toxicity of methotrexate, a reminder system should be put in place to ensure that the laboratory monitoring and subsequent clinical review actually occurs.

Methotrexate is valuable in treatment of severe unresponsive psoriasis and a number of other dermatological conditions requiring immunosuppression. Toxicity due to bone marrow depression and mucositis is less likely in dermatological applications than when higher doses are used, but regular monitoring with blood counts is necessary.

The mechanism of action of methotrexate in Crohn’s disease is unknown, but may involve inhibiting inflammatory cell activation and cytokine release. Response to therapy is seen over several months.

For Crohn’s disease, methotrexate is generally commenced as a single weekly dose of 25 mg given intramuscularly or subcutaneously. If there is a clinical response, parenteral therapy can be changed to oral therapy after 16 weeks. Doses less than 15 mg per week are ineffective in active Crohn’s disease.

The mechanism of action of methotrexate, at the comparatively low dose used in rheumatoid arthritis, may involve increasing intracellular adenosine and thus inhibiting inflammatory cell activation. In the treatment of rheumatoid arthritis, methotrexate is generally commenced as a single oral weekly dose of 5 to 10 mg.

Response to therapy is seen after 1 to 2 months. Dose escalation protocols vary depending on the severity of the disease, but should allow 4 to 6 weeks at each dose level to assess response. The dose increment can vary from 2.5 to 10 mg. The maximum recommended dose is usually 15 to 25 mg weekly in rheumatoid arthritis, but higher doses can be needed in inflammatory myopathies or psoriasis.

Methotrexate is generally well tolerated, but dose-limiting toxicity occurs in 10% to 15% of patients with rheumatoid arthritis. Some patients experience a flare of their arthritis for a day or two following each dose.

Subcutaneous and intramuscular methotrexate is sometimes used if adverse effects limit the maximum dose, or when the maximum dose is ineffective when given orally.

Patients taking a combination of leflunomide and methotrexate should have full blood examination and liver function tests performed at least monthly. In patients with a low risk of toxicity, consideration may be given to increasing the intervals between blood tests.

For patients taking a combination of methotrexate, sulfasalazine and hydroxychloroquine (‘triple therapy’), monitoring would include a full blood examination and liver function tests every 2 weeks for 8 weeks and then 4- to 6-weekly thereafter, and yearly eye checks if continuing on hydroxychloroquine.