Antifolate

Dihydrofolate reductase 1DRF

Folic acid

Methotrexate skeletal

Pemetrexed

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Raltitrexed

Antifolates are a class of antimetabolite medications that inhibit the actions of folic acid (vitamin B9) within the body. Folic acid is essential for the synthesis of nucleotides, which are the building blocks of DNA and RNA. By inhibiting the production or function of folic acid, antifolates interfere with the growth of rapidly dividing cells, making them particularly effective in the treatment of cancers and some autoimmune diseases.

Mechanism of Action

Antifolates work by inhibiting enzymes involved in the folic acid pathways. The primary target of most antifolates is dihydrofolate reductase (DHFR), an enzyme critical in the conversion of dihydrofolate to tetrahydrofolate. Tetrahydrofolate is necessary for the synthesis of purine nucleotides and thymidylate, which are essential for DNA and RNA synthesis. By inhibiting DHFR, antifolates prevent the formation of tetrahydrofolate, leading to a reduction in nucleotide synthesis and, consequently, inhibition of cell division.

Clinical Uses

Antifolates are used in the treatment of a variety of conditions, including:

• Cancer: Certain cancers, such as leukemia, lymphoma, and osteosarcoma, are treated with antifolates due to their ability to inhibit rapidly dividing cells.
• Autoimmune diseases: Diseases like rheumatoid arthritis and psoriasis can be treated with lower doses of antifolates, which help control the rapid cell division associated with these conditions.
• Ectopic pregnancy: Methotrexate, a common antifolate, is sometimes used to treat ectopic pregnancies by inhibiting the growth of the embryo.

Examples of Antifolates

• Methotrexate: One of the most widely used antifolates, methotrexate is used to treat cancer, autoimmune diseases, and ectopic pregnancy.
• Pemetrexed: Used primarily in the treatment of lung cancer, pemetrexed inhibits multiple enzymes in the folic acid pathway.
• Pyrimethamine: Often used in combination with other drugs to treat malaria, pyrimethamine inhibits dihydrofolate reductase in parasitic protozoa.

Side Effects

The use of antifolates can lead to a range of side effects due to their impact on normal cell division as well as cancerous cells. Common side effects include nausea, vomiting, fatigue, and an increased risk of infections. More severe side effects may include liver toxicity, kidney damage, and suppression of bone marrow activity, leading to conditions such as anemia, leukopenia, and thrombocytopenia.

Conclusion

Antifolates are a critical component of the pharmacological arsenal against cancer and certain autoimmune diseases. Their ability to inhibit folic acid pathways and interfere with cell division makes them effective in treating conditions characterized by rapid cell growth. However, their use must be carefully managed to balance therapeutic benefits with the potential for significant side effects.