Dr Sharon Rees @reesprescribe
Day 1: In the 1950s, designing a folate analogue was an anti-cancer strategy. Used at high levels, the good tolerability of #methotrexate and the option of folinic acid rescue if bone marrow toxicity occured was considered advantageous. #methotrexate was FDA licensed in 1953.
Dr Sharon Rees @reesprescribe
(cont) However, a role for #methotrexate in rheumatoid arthritis was slow to emerge, as sulfasalasine and gold were preferred agents. Considerable evidence supports #methotrexate ef~ cacy as a disease modifying anti-rheumatic drug, a lot of which emerged in comparison trials with newer biologic agents.
Dr Sharon Rees @reesprescribe
Day 2: There is now considerable evidence to support #methotrexate is now well-established as the 1st line immune-suppressive drug for rheumatoid arthritis (RA), being effective and relatively cheap. Also used for flare & remission of Crohn's disease and severe psoriasis. The weekly dose is mostly oral 7.5-25mg (typically 7.5–15mg for RA).
Dr Sharon Rees @reesprescribe
Day 3: Mechanism of action – Nucleotide synthesis is necessary for RNA and DNA production. #methotrexate inhibits multiple enzymes required for the process, hence exerts anti-inflammatory, anti-proliferative and cytotoxic effects.
Dr Sharon Rees @reesprescribe
(cont) One of the main actions of #methotrexate is competitive inhibition of dihydrofolate reductase, which converts folic acid to its active form for use in DNA synthesis. This, and inhibition of several other key enzymes, prevents cell division and confers anti-inflammatory effects.
Dr Sharon Rees @reesprescribe
Day 4: Kinetics – Ceiling effect on oral doses over 25mg, as the gut transport system is saturable. The half-life (t ½) depends on dose; this is approximately 3–10 hours (adult). Renal excretion occurs with 80% of drug unchanged. This is a saturable process, hence renal impairment/drug interactions that inhibit excretion are problematic re toxicity.
Dr Sharon Rees @reesprescribe
Day 5: Adverse drug reactions (ADRs)- there is some variation depending on route of administration. Common for oral; anaemia, poor appetite, GI disorders, nausea, headache. Uncommon serious; bone marrow disorders, haemorrhage, hepatic disorders, nephropathy, mood disturbance.
Dr Sharon Rees @reesprescribe
Day 5 (cont): Depletion of folic acid re #methotrexate can contribute to ADRs; it is usual to co-prescribe oral folic acid taken on a non-methotrexate day, as this can offset toxicity, while not changing efficacy. If bone marrow suppression/toxicity, folinic acid rescue i.m/i.v can bypass the enzyme ‘block’.
Dr Sharon Rees @reesprescribe
Day 6: As #methotrexate is mostly excreted whole, competition for renal tubular secretion binding sites is relevant, typically lowering #methotrexate clearance. This occurs with penicillins, NSAIDs and PPIs. Ciprofloxacin can also alter elimination. Many drugs increase the risk of nephrotoxicity such as tacrolimus.
Dr Sharon Rees @reesprescribe
Day 6 (cont): All live vaccines carry ‘red’ warning as increased risk of infection re #methotrexate related immunosuppression.
Dr Sharon Rees @reesprescribe
Day 7: #methotrexate takes weeks to months to work as it is not treating the symptoms of inflammatory conditions, but modifying the underlying immune/inflammatory response. Methotrexate may support action of biologics taken concomitantly, possibly because of opposing antibody formation to the biologic agent.