Methotrexate

Question 1

What class of drugs does Methotrexate belong to?

Answer 1

Antimetabolites and drugs which affect the immune response - MIMS, BNF

Question 2

What are other drugs in the same class as methotrexate?

Answer 2

In RA:
Azathioprine
Leflunomide
Ciclosporin
Cyclophsphamide

Question 3

What is methotrexate indicated for?

Answer 3

Treatment of cancers,
some cases of psoriasis

Active rheumatoid arthritits in adults where DMARD indicated,
Severe polyarticular active juvenile idiopathic arthritis where NSAIDs inadequate,

Question 4

What is the mechanism of action of methotrexate

Answer 4

MTX is a dihydrofolate reductase inhibitor, preventing folic acid reduction to tetrahydrofolic acid. Thus interfering with DNA synthesis, repair and cellular replication.

Actively proliferating tissues (such as those in an inflammatory response and cancer) are more sensitive to MTX.

Question 5

What is the dose of MTX given to patients with Rheumatoid Arthritis?

Answer 5

start on 7.5-15mg/week. (max25mg/week)

If >20mg is required, need to switch to subcutaneous route to increase bioavailability

Question 6

What should be prescribed with MTX in rheumatoid arthritis patients?

Answer 6

Folic acid 5-20mg/week.

MTX on monday, Folic acid on friday

Question 7

What are the important pharmacokinetic/pharmacodynamic parameters for MTX?

Answer 7

~60% oral bioavailabiltiy in adults
~50% protein bound in serum
Extensively metabolised in liver to form polyglutamates.
Mostly excreted in kidney (<10% excreted in faeces)

Elimination half life 3-10hours.

Question 8

What are the precautions with MTX use?

Answer 8

Take extreme caution in blood disorders, peptic ulceration, ulcerative colitits, diarrhoea and ulcerative stomatitis, immunisation with live virus.

Avoid in pregnancy (class D - teratogen) fertility reduced in therapy but this may be reversible. 
Avoid in breastfeeding, severe hepatic and severe renal impairment

Question 9

What are the major interactions with methotrexate?

Answer 9

avoid concomittant use with anaesthetics (MTX increased by NO)

MTX excretion reduced by ulcer healing drugs and NSAIDs –> increased toxicity. Monitor dose very carefully

Increased risk of toxicity when given with leflunomide

MTX increases plasma concentration of theophylline

Question 10

What are the alarm bells with MTX use?

Answer 10

May cause abrupt bone marrow suppression. In case of clinically significant WBC or platelet drop, WITHDRAW IMMEDIATELY + give supportive therapy

Do not initiate treatment if any abnormality of LFT, or liver biopsy development. Can continue if abnormalities return to normal within 2 weeks.

Monitor for symptoms at each visit for pulmonary toxicity. Discontinue if pneumonitis suspected.

Advised not to conceive within 2 years of stopping the drug.

Question 11

What are the common adverse effects of MTX?

Answer 11

anorexia, abdominal discomfort, dyspepsia, GI ulceration + bleeding, diarrhoea, toxic megacolon, hepatotoxicity
Rash, pruritus, alopecia, mouth ulcers, stomatitis, marrow suppression, liver toxicity, pneumonitis.

Question 12

What kinds of monitoring should be taken with MTX?

Answer 12

Chest xray before starting therapy.

Full blood count, U&E, LFT baseline every 2 weeks until stable for 6 weeks. Then monitor monthly until stable for a year. Then monitor every 2-3 months

Question 13

What is the role of MTX in drug therapy in Rheumatoid arthritis?

Answer 13

First line gold standard DMARD. generally well tolerated

Question 14

What drugs should be avoided when on MTX?

Answer 14

trimethoprim, cotrimoxazole as they can cause marrow aplasia