Methotrexate

Question 1

Mechanism of action ?

Answer 1

Methotrexate is a tetrahydrofolate reductase inhibitor, this enzyme converts dietary folic acid to tetrahydrofolate FH4 necessary for DNA and protein synthesis, it thus stops cellular replication. Active dividing cells are particularly sensitive to it.
It also has anti-inflammatory and immunosuppressive effects, underlying mechanism is yet unknown but it inhibits IL-6/8, TNFa.

Question 2

Indications ?

Answer 2

• Rheumatoid arthritis, as a disease-modifying treatment (Polyarthtrite rhumatoide).
• Cancer; leukemia, lymphoma and some types of solid cancer.
• Severe psoriasis, resistant to other therapies.

Question 3

Disease-modifying treatment/Antirhumatismaux modificateurs de la maladie?

Answer 3

Disease-modifying antirheumatic drugs (DMARDs/ARMM) is a category of otherwise unrelated drugs defined by their use in rheumatoid arthritis to slow down disease progression. (other than/not referring to : NSAIDs/SAIs)

Question 4

Important AE (dose-related)?

Answer 4

Dose-related : Mucosal damage (sore throat, gastrointestinal upset) and bone marrow suppression (neutropenia)

Question 5

Important AE (rare) ?

Answer 5

Rarely : Hypersensitivity reactions (cutaneous, hepatitis, pneumotitis)

Question 6

Important AE (prolonged use) ?

Answer 6

Prolonged use : Cirrhosis and Pulmonary fibrosis

Question 7

Important AE (overdose) ?

Answer 7

Overdose : Renal and hepatic impairment, headaches, seizures and coma may occur.

Question 8

Important cautions ?

Answer 8

Methotrexate is teratogenic, both genders taking the drug must use contraception during and 3months after treatment.
CI in severe renal impairment (renaly excreted) and abnormal liver function (causes hepatotoxicity)

Question 9

Important interactions ?

Answer 9

Toxicity risk increases if combined with :

• drugs that inhibits its renal excretion; NSAIDs, penicillines.
• drugs that are folate antagonists; Thrimethoprim and Phenytoin (risk of hematological abnormalities).
• Clozapine (increased risk of neutopenia)

Question 10

Trimethoprime ?

Answer 10

Anti-infectieux, famille : diaminopyrimidines, principalement utilisé en association avec le sulfaméthoxazole pour le traitement de la cystite et les infections urinaires. COTRIMOXAZOLE

Question 11

Clozapine ?

Answer 11

Antipsychotique, antagoniste de la serotonine.

Question 12

How is Methotrexate prescribed (RA)?

Answer 12

RA :Once weekly, orally 7,5-20 mg.
Folic acid 5 mg may be taken during the other 6days of the week to rescue normal cells and reduce AE. Good hydration and urine alkalinisation for promoting excretion.

Question 13

How is Methotrexate prescribed (Chemotherapy)?

Answer 13

Cancer : IV/IM/intrathecal to induce remission, then orally for maintenance treatment.
Folic acid 5 mg may be taken during the other 6days of the week to rescue normal cells and reduce AE. Good hydration and urine alkalinisation for promoting excretion.

Question 14

Intrathecal route ?

Answer 14

Injection into the spinal canal/ subarachnoid space so that it reaches the cerebrospinal fluid (LCR). Useful in spinal anaesthesia, chemotherapy or pain management.