antimetabolites Flashcards
Anti-metabolites are generally more effective when cell is active in the ______-phase of the cell cycle.
Many are structural analogs of naturally occurring substances found within the cell.
Anti-metabolites act by either (2)
Anti-metabolites are generally more effective when cell is active in the S-phase of the cell cycle.
Many are structural analogs of naturally occurring substances found within the cell.
Anti-metabolites act by either (1) falsely incorporating into DNA or RNA or (2) by competing for binding sites on enzymes involved in DNA synthesis.
Anti-metabolites (4)
- methotrexate
- cytarabine
- 5-fluorouracil
- gemcitabine
Methotrexate (MTX) is a _______ antimetabolite inhibiting DNA synthesis.
It competitively binds to dihydrofolate reductase (DHFR), which is responsible for production of reducted folates necessary for one-carbon transfers and thus _______.
MTX also binds to thymidylate synthetase, inhibiting synthesis of _______.
Methotrexate (MTX) is a folate antimetabolite inhibiting DNA synthesis.
It competitively binds to dihydrofolate reductase (DHFR), which is responsible for production of reducted folates necessary for one-carbon transfers and thus purine synthesis.
MTX also binds to thymidylate synthetase, inhibiting synthesis of thymidylate.
MTX binding to DHFR inhibits conversion of folic acid to _________ leading to _______ pools of purine nucleotides and thymidylate.
MTX binding to DHFR inhibits conversion of folic acid to tetrahydrofolate (FH4), leading to decreased pools of purine nucleotides and thymidylate.
Major pharmacokinetic points to remember:
- MTX binds to _______, leading to drug interactions;
- MTX is very _______ and readily distributes into 3rd space fluid, so it can accumulate in ______ and slowly leak back into the systemic circulation (depot effect);
- MTX at high doses can cross into ____
- MTX binds to albumin, leading to drug interactions;
- MTX is very hydrophilic and readily distributes into 3rd space fluid, so it can accumulate in effusions and slowly leak back into the systemic circulation (depot effect);
- MTX at high doses can cross into CNS.
MTX in active transport vs passive dissuion
- at low concentrations active transport predominates but At high doses the active transport mechanism is overwhelmed, so passive diffusion becomes the main mechanism for cell entry in the CNS.
There are multiple metabolic steps of MTX.
The most important is ___________, leading to the form that is retained in cell for longer periods of time due to slower dissociation from DHFR enzyme.
This form also inhibits ______ synthase and is not easily removed from the cell.
- the formation if DAMPA by intestinal bacteria
There are multiple metabolic steps of MTX.
The most important is polyglutamation, leading to the polyglutamated form that is retained in cell for longer periods of time due to slower dissociation from DHFR enzyme.
This polyglutamated form also inhibits thymidylate synthase and is not easily removed from the cell.
- the formation if DAMPA by intestinal bacteria
Majority of MTX elimination occurs via ______, therefore dose adjustment is necessary in those with ______, however there is some elimination through the _____ and explain that patients with ______ may have increased toxicity because of delayed clearance.
Majority of MTX elimination occurs via kidneys, therefore dose adjustment is necessary in those with reduced renal function. however there is some elimination through the biliary and explain that patients with intestinal obstruction may have increased toxicity because of delayed clearance.
toxicity of MTX include
- low dose:
- High dose:
how can toxicity be prevented?
- low dose: myelosuppression with possible nephrotoxicity
- High dose: myelosuppression and nephrotoxicity from precipitation in renal tubules
A major side effect of MTX is renal toxicity. At high doses, MTX precipitates into renal tubules, causing direct damage, particularly in an acidic environment. This toxicity can be prevented by alkalinization of the urine and hydration.
rescue if there is MTX tox.
leucovorin- administration is based on dosage levels b/c there is competition and at increased doses of MTX, leucovorin also increases but you need to avoid excessive leucovorin doses due its ability to block anti-tumor activity of MTX
In addition to nephrotoxicity, MTX will have other SE including to the GI such as N/V, myelosupression, and hepatoxicity.
there is one that SE that needs to be watched out just in case before starting treatment?
pneumonitis, the effusion must be drained before treatment
can MTX be given into the CSF to clear malignant meningitis?
yep and thus there can be some neurotoxicity associated with leukoencephalopathy
leucovorin
provides reduced folates back into the cellular pool and thus bypasses blockade of DHFR and allowing DNA synthesis to occur
why does leucoveorin given 24 hr after MTX infusion?
MTX affects the bone marrow and GI tract at very low levels and will cause irreversible damage so the timing of of leucovorin is critical
MTX has multiple drug interactions:
- Drugs that are _________ can “knock” methotrexate off albumin, increase plasma levels, and therefore increase toxicity, and vice versa.
- Concomitant _____ drugs should be avoided.
- L-asparaginase prevents cells from entering ___-phase and can therefore _____ effects of methotrexate.
- Drugs that are also highly protein bound can “knock” methotrexate off albumin, increase plasma levels, and therefore increase toxicity, and vice versa.
- Concomitant nephrotoxic drugs should be avoided– affect creatinine clearence
- L-asparaginase prevents cells from entering S-phase and can therefore reduce effects of methotrexate.
