12 Questions
What is the main characteristic of antimetabolites in terms of their cytotoxic effects?
They are most effective in the S phase of the cell cycle.
How do antimetabolites interfere with DNA or RNA synthesis?
By inhibiting the synthesis of normal nucleotide precursors.
What adverse effect can be prevented or reversed by administering leucovorin?
Hand-foot syndrome
Why should the dose of 6-MP be reduced when used with allopurinol?
To prevent toxicity.
What important action should be taken to prevent conjunctivitis when using high doses of certain antimetabolites?
Administer steroid eye drops.
What factor limits the stability of prepared intravenous antimetabolite drugs?
Time after preparation
What is the mechanism of action of Methotrexate?
Acts as an antagonist of folic acid by inhibiting DHFR
How is the inhibition of DHFR by Methotrexate reversed?
By administration of leucovorin
What is the main role of folic acid in metabolic reactions?
Transferring one carbon units
How does leucovorin help in Methotrexate therapy?
By replenishing the folate pool bypassing MTX inhibition sites
Which vitamin is essential for cell replication and is obtained mainly from dietary sources?
Folic Acid
What is the relationship between Methotrexate and folic acid?
Methotrexate acts as an antagonist to folic acid
Study Notes
Antimetabolites
- Interfere with one or more enzymes or their reactions necessary for DNA synthesis
- Structurally related to normal compounds that exist within the cell
- Generally interfere with the availability of normal purine or pyrimidine nucleotide precursors
- Interfere by inhibiting their synthesis or by competing with them in DNA or RNA synthesis
- Maximal cytotoxic effects are in S phase and are, therefore, cell cycle-specific
Adverse Effects and Interactions
- Some adverse effects can be prevented or reversed by administering leucovorin
- Adjust dose in renal impairment
- Reduce dose of 6-MP by 50%-75% when used with allopurinol to prevent toxicity
- Immunosuppression increases risk of opportunistic infections
- "Hand-foot syndrome"/palmar-plantar erythrodysesthesia is an erythematous desquamation of the palms and soles
Methotrexate
- Acts as an antagonist of folic acid by inhibiting mammalian dihydrofolate reductase (DHFR)
- Inhibition of DHFR can be reversed by a 1000-fold excess of the natural substrate, dihydrofolate (FH2), or by administration of leucovorin
- Folinic acid (leucovorin) can restore MTX inhibition by replenishing THF pool as it bypasses the MTX inhibition sites
Other Antimetabolites
- 6-Mercaptopurine (6-MP): myelosuppression, high-dose: renal damage
- Fludarabine: neutropenia, immunosuppression, fever, N/V, teratogenic, peripheral neuropathy
- Cladribine: myelosuppression, immunosuppression, fever, N/V
- 5-Fluorouracil (5-FU): alopecia, severe mucositis, myelosuppression (bolus), "hand-foot syndrome" (continuous infusion), coronary vasospasm
- Capecitabine: myelosuppression, mucositis, "hand-foot syndrome", chest pain
- Cytarabine: myelosuppression, N/V, conjunctivitis (high dose)
- Azacitidine: myelosuppression, N/V, constipation, hypokalemia, renal toxicity
- Gemcitabine: myelosuppression, N/V, alopecia, rash, flu-like syndrome
Learn about antimetabolites, drugs that disrupt enzymes or reactions required for DNA synthesis by competing with normal nucleotide precursors. These drugs target cells in the S phase of the cell cycle for their cytotoxic effects.
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