Pyrimethamine Folate antagonists

The folate antagonists, pyrimethamine and sulfadiazine, inhibit the parasite s DHFR/TS synthase enzyme complex and the DHPS, respectively (Fig. 4) (see antimalarial drugs). To avoid deficiency of folic acid in patients treated with antifolate antagonists, folinic acid supplementation is recommended to reduce bone-marrow suppression. 

Sulfadoxine-pyrimethamine (Fansidar) Folate antagonist combination Treatment of infections with some chloroquine-resistant P falciparum, including combination with artesunate intermittent preventive therapy in endemic areas... 

In many areas, resistance to folate antagonists and sulfonamides is common for P falciparum and less common for P vlvax. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. At present, resistance seriously limits the efficacy of sulfadoxine-pyrimethamine (Fansidar) for the treatment of malaria in most areas, but in Africa most parasites exhibit only moderate resistance, such that antifolates appear to continue to offer preventive efficacy against malaria. Because different mutations may mediate resistance to different agents, cross-resistance is not uniformly seen. 

Drugs. Antiepilepsy drugs, particularly phenytoin, primidone and phenobarbital, occasionally cause a macrocytic anaemia that responds to folic acid. This may be due to enzyme induction by the antiepileptics increasing the need for folic acid to perform hydroxylation reactions (see Epilepsy) but other factors such as reduced absorption may be involved. Administration of folic acid causes a recurrence of seizures in some patients. Some anti-malarials, e.g. pyrimethamine, may interfere with conversion of folates to the active tetrahydrofolic acid, causing macrocytic anaemia. Methotrexate, another folate antagonist, may cause a megaloblastic anaemia especially when used long-term for leukaemia, rheumatoid arthritis or psoriasis. 

DIHYDROFOLATE REDUCTASE INHIBITORS have as a target the enzyme dihydrofolate reductase, and are known as folate antagonists. These include anttcancer agents ( antimetabolites ) such as methotrexate, antibacterial AGENTS such as trimethoprim, and the antiprotozoals pyrimethamine and proguanil (which are used to treat malaria). Folate is required for synthesis of purine nucleotides, which in turn are essential for DNA synthesis and cell division. In mammals it is necessary to convert body folates, through two separate enzyme-catalysed reduction... 

Most cases of infection with toxoplasma are self-limiting and do not need specific treatment. For treatment of toxoplasma infection of the eye (which can cause blindness) and general infection in the immunocompromized, the preferred treatment is with a combination of pyrimethamine (a folate antagonist) and sulfadiazine (a sulphonamide). 

Uncertain, but a reasonable surmise can be made. Pyrimethamine and trimethoprim are both folate antagonists and both selectively inhibit the actions of the enzyme dihydrofolate reductase, which is concerned with the eventual synthesis of the nucleic acids needed for the production of new cells. The sulfonamides inhibit another part of the same synthetic chain. The adverse reactions seen would seem to reflect a gross reduction of the normal folate metabolism caused by the combined actions of both drugs. Megaloblastic anaemia and pancytopenia are among the adverse reactions of pyrimethamine and, more rarely, of co-trimoxazole taken alone. 

Pyrimethamine is a folic-acid antagonist its therapeutic action is based on differential requirements between host and parasite for nucleic acid precursors involved in growth as it selectively inhibits plasmodial dihydrofolate reductase. Pyrimethamine inhibits the enzyme dihydrofolate reductase that catalyzes the reduction of dihydrofolate to tetrahydro-folate. This activity is highly selective against plasmodia and Toxoplasma gondii. It does not destroy gametocytes but arrests sporogony in the mosquito. Pyrimethamine possesses a blood schizonticidal, and some tissue schizonticidal activity may be slower than that of 4-amino-quinoline compounds. 

Pyrimethamine and trimethoprim are inhibitors of both bacterial and protozoal dihydrofolate reductase (DHFR) enzymes but do not affect the mammalian enzyme. Further specificity is achieved by the use of PABA antagonists, since they are competitive inhibitors of the protozoal dihydropteroate (DHP) synthase reaction, which condenses PABA with hydroxymethyldihydropteridine to form DHP, an intermediate in the tetrahydrofolate (THF) biosynthetic pathway. Protozoa synthesize THF de novo whereas humans require dietary folate. For this reason sulfur drugs are selective and virtually non-toxic to humans. 

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