1 - METHOTREXATE Flashcards
Methotrexate is a chemotherapeutic agent
True (cytotoxic and teratogenic)
Methotrexate is an immunosuppressive agent
True
MTX is often used with TNF-alpha antagonists
True (FDA approved in patients with arthritis)
Methotrexate is a potential competitive antagonist and inhibitor of dihydrofolate reductase
True
Methotrexate is structurally similar to folic acid
True
Folic acid is the natural substrate for the enzyme dihydropteroate synthetase and dihydrofolate reductase
True
Methotrexate can be administered orally
True
Methotrexate can be administered intravenously
True
Methotrexate can be administered intramuscularly
True
Methotrexate can be administered subcutaneously
True
Methotrexate is rapidly absorbed through the GI tract
True
Peak plasma levels of orally administered Methotrexate are reached more slowly than intravenous or subcutaneous/intramuscular route
True
The oral route of Methotrexate provides more reliable blood levels than parenteral administration even though the absorption of oral methotrexate may be incomplete and variable with doses > 15mg
True
Concurrent food intake, particularly milk-based meals may reduce bioavailability in children
True (though bioavailability in adults is not affected by concurrent food ingestion)
The bioavailability of methotrexate in adults is not affected by concurrent food ingestion
True
The absorption of methotrexate may be reduced by non-absorbable antibiotics such as neomycin
True
Methotrexate does not penetrate the blood brain barrier well
True (the reason why intrathecal methotrexate is needed in some chemotherapy regimens)
The level of plasma Methotrexate once absorbed, has a triphasic reduction
True
The first phase of the triphasic reduction of plasma methotrexate occurs rapidly over 0.75 hours and reflects distribution of the drug throughout the body
True
The second phase of the triphasic reduction of plasma methotrexate occurs over 2-4 hours and reflects renal excretion
True
The third phase of the triphasic reduction of plasma methotrexate occurs between 10 and 27 hours and reflects the terminal half life and slow release of methotrexate primarily bound to dihydrofolate reductase from the tissues
True
Methotrexate is a weak organic acid and is excreted through the kidneys
True
Methotrexate is a weak organic acid predominately excreted through the kidneys; MTX glomerular filtration and active tubular secretion are susceptible to drug interactions with other weak acids I.e. Salicylates, probenecid, and sulfonamides
True
Approx 50% of methotrexate is bound to plasma proteins and 50% is the unbound free fraction/active portion of the drug
True
The beneficial effects and potential for toxicity is increased when the unbound free fraction of methotrexate is increased by certain drugs I.e. Salicylates, sulfonamides, probenecid
True
Methotrexate is metabolised intracellularly in all cells that it is actively transported into, including the liver
True
Methotrexate is metabolised intracellularly to polyglutamated forms/metabolites which are potent inhibitors of dihydrofolate reductase and play a key role in methotrexate toxicity
True
The polyglutamated metabolites of intracellular methotrexate metabolism contributes toward methotrexate toxicity
True (the metabolites are also dihydrofolate reductase inhibitors)
Methotrexate has a greater affinity to dihydrofolate reductase than the enzyme’s natural substrate folic acid
True
Folic acid (natural substrate of dihydrofolate reductase) is converted to tetrahydrofolate by dihydrofolate reductase
True
Tetrahydrofolate is converted to DNA by thymidylate synthetase
True
Methotrexate competitively and irreversibly binds to dihydrofolate reductase with a greater affinity than folic acid
True (prevents conversion of dihydrofolate to tetrahydrofolate)
Methotrexate prevents the conversion of dihydrofolate to tetrahydrofolate by competitively and irreversibly binding to dihydrofolate reductase
True
Methotrexate also competitively and partially reversibly inhibits thymidylate synthetase within 24 hours of methotrexate administration to prevent thymidine and purine nucleotide synthesis to take place from tetrahydrofolate
True (affects DNA synthesis)
The overall effect of methotrexate is inhibition of DNA synthesis/cell division which takes place during the S phase of the cell cycle
True
The competitive and irreversible inhibition of dihydrofolate reductase by methotrexate can be bypassed by Leucovorin (folinic acid)
True (thus folinic rescue may reverse the acute haematologic toxicity secondary to methotrexate)
Leucovorin (folinic acid) may reverse the acute haematologic toxicity secondary to methotrexate
True
Methotrexate acts via an immunosuppressive mechanism by affecting the proliferation of lymphocytes
True
Methotrexate affects the proliferation of lymphocytes
True
Methotrexate blocks migration of activated T cells
True
The anti-inflammatory effects of methotrexate are predominately mediated by adenosine
True
There is decrease methotrexate efficacy with concomitant folic acid
True (folic acid is no longer routinely recommended unless adverse effects arise I.e. GI upset or haematologic toxicity
The use of folic acid as a method of inhibiting Methotrexate induced GI adverse effects and pancytopenia is controversial
True
Salicylates increase methotrexate levels and toxicity due to decreased renal excretion and displacement from plasma proteins
True
NSAIDS increase methotrexate levels and toxicity due to decreased renal excretion and displacement from plasma proteins
True
Sulfonamides increase methotrexate levels and toxicity due to decreased renal excretion, displacement from plasma proteins and inhibition of dihydropteroate synthetase (converts folic acid to dihydrofolate)
True
Probenecid increase methotrexate levels and toxicity due to increased intracellular accumulation and decreased renal excretion
True
Dipyridamole increase methotrexate levels and toxicity due to increased intracellular accumulation
True
Chloramphenicol increase methotrexate levels and toxicity due to displacement from plasma proteins
True
Phenothiazines increase methotrexate levels and toxicity due to displacement from plasma proteins
True
Phenytoin increase methotrexate levels and toxicity due to displacement from plasma proteins
True
Tetracyclines increase methotrexate levels and toxicity due to displacement from plasma proteins
True
Trimethoprim inhibits dihydrofolate reductase (coverts dihydrofolate to tetrahydrofolate) in the folate pathway resulting in increased haematologic toxicity
True (methotrexate and trimethoprim are competitive inhibitors of dihydrofolate reductase)
Folic acid is also converted to dihydrofolate by dihydropteroate synthetase
True (and folic acid can be converted to tetrahydrofolate by dihydrofolate reductase)
Dapsone and sulfonamides inhibit dihydropteroate synthetase (coverts folic acid to dihydrofolate) and thus can amplify the inhibition of dihydrofolate reductase by methotrexate due to less dihydrofolate being available to the enzyme, resulting in increased haematologic toxicity
True
Therapeutic doses of folic acid competes with methotrexate for dihydrofolate reductase to decrease the adverse effects of methotrexate by increasing tetrahydrofolate production
True
Systemic retinoids may synergistically increase hepatotoxicity if given concomitantly with methotrexate due to the liver being the common target organ for toxicity in both drugs
True
Alcohol may synergistically increase hepatotoxicity if given concomitantly with methotrexate due to the liver being the common target organ for toxicity in both drugs
True
Trimethoprim and sulphamethoxazole in combination markedly increase the risk of haematologic toxicity when used with methotrexate due to a more complete inhibition of 2 step folate pathway
True (trimethoprim inhibits dihydrofolate reductase, and sulphamethoxazole being a sulfonamide inhibits dihydropteroate synthetase)
Methotrexate is absolutely contraindicated in pregnancy
True (category X)
Methotrexate may cause hepatotoxicity in the form of liver fibrosis
True (procollagen type III peptide non-invasive test) L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Methotrexate may cause infections
True L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Methotrexate may cause idiosyncratic acute pneumonitis and pulmonary fibrosis with small doses of methotrexate
True (CXR only if patient develops symptoms suggesting penumonitis) L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Methotrexate may cause pancytopenia
True (risk significantly reduced by folic acid supplementation, consider supplementation regardless of whether patient is experiencing GI side effects) L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Poor renal function may precipitate haematologic toxicity associated with methotrexate
True (due to increased free methotrexate in plasma) - avoid combining trimethoprim/sulphamethoxazole and NSAIDS with methotrexate and consider folic acid supplementation regardless of whether the patient is experiencing GI side effects
Folic acid supplementation is usually given to improve the GI side effects associated with methotrexate
True
Regardless of whether GI side effects are present, consider folic acid supplementation to reduce the risk of pancytopenia associated with methotrexate
True
Should significant myelosuppression develop from methotrexate, Leucovorin (folinic acid) can be given promptly to treat this
True
Patients who inadvertently take methotrexate daily are at a greater risk for pancytopenia
True
A high MCV without anaemia is common in dermatologic dosage levels of methotrexate
True (not a cause for concern)
Lymphoma has been reported in patients with psoriasis on methotrexate
True (although EBV has been found within these lymphomas and demonstrated regression of the lymphoma with cessation of methotrexate, there is no statistical evidence that methotrexate increases the risk of developing a subsequent malignancy in psoriasis patients) L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
The subject of folic acid compromising efficacy of methotrexate remains contradictory due to mixed reports
True
Nausea and anorexia are common adverse reactions to methotrexate
True L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Diarrhoea, vomiting and ulcerative stomatitis are less frequent adverse effects of methotrexate
True L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Methotrexate should be ceased if diarrhoea and ulcerative stomatitis is observed
True L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Men on methotrexate should be counselled with regard to possible reversible oligospermia
True
Men on methotrexate should avoid impregnating a woman
True (although a recent study did not reveal any congenital malformations or spontaneous abortions associated with these men)
In dermatological doses, methotrexate is not likely to cause renal toxicity
True (encountered in the higher doses used in chemotherapy secondary to precipitation of methotrexate in renal tubules) L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Methotrexate is phototoxic
True (may cause phototoxicity and sunburn recall) L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Methotrexate may cause sunburn recall
True L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Deaths due to methotrexate induced cirrhosis have occurred in patients with psoriasis
True L - Liver toxicity I - Infections M - Marrow suppression/Malignancy I - Idiopathic pulmonary fibrosis T - Teratogenecity G - GI effects P - Phototoxicity S - Sunburn recall
Patients with diabetes or obesity are presumed to be at greater risk for liver toxicity
True (increased incidence of non-alcoholic steatohepatitis in this group) - avoid prescribing methotrexate
Patients with history of exposure to hepatotoxins I.e. Alcohol or IV drugs are presumed to be at greater risk for liver toxicity
True (avoid prescribing methotrexate)
Avoid prescribing methotrexate in patients with personal or family history of liver disease
True (higher risk of hepatoxicity)
Patients with abnormal baseline LFTs or hepatitis serology are presumed to be at greater risk for liver toxicity
True (avoid prescribing methotrexate)
The need for repeated liver biopsies is based on the total dose of methotrexate - generally after every 1.5g total dose
True
Patients with grade I (normal vs mild fatty infiltration) or II (moderate to severe fatty infiltration) liver histology findings may continue methotrexate
True
Patients with grade IIIa (mild fibrosis) liver histology findings may continue methotrexate but should have a repeat liver biopsy in 6 months
True
Patients with grade IIIb (moderate to severe liver fibrosis) or IV (cirrhosis) liver histology findings need to stop methotrexate
True (also needs careful follow up of liver biopsies)
If the WBC count is <3500/mm3, discontinue or reduce the dose of methotrexate
True (methotrexate may be restarted at a lower dose if the lab abnormality has resolved after 2-3 weeks)
If the platelet count is <100,000 /mm3, discontinue or reduce the dose of methotrexate
True (methotrexate may be restarted at a lower dose if the lab abnormality has resolved after 2-3 weeks)
If the liver transaminases increase over twice the upper normal value, discontinue or reduce the dose of methotrexate
True (methotrexate may be restarted at a lower dose if the lab abnormality has resolved after 2-3 weeks)
Methotrexate is usually given as a single weekly dose
True
Methotrexate may be given in 3 divided doses over a 24 hour period each week I.e. Day 1 8am and 8pm followed by Day 2 8am
True (equally effective with similar toxicity to the once weekly dose)
Intramuscular methotrexate may be considered in patients non-compliant to the oral dose or patients who develop nausea from the oral dose
True
A methotrexate test dose of 5-10mg is generally given followed by a FBC and LFTs 6-7 days later
True
Patients receiving IM or IV methotrexate are able to tolerate higher doses due to more rapid renal clearance
True
