Pyrimethamine (Daraprim) is the best of a number of 2,4-diaminopyrimidines that were synthesized as potential antimalarial and antibacterial compounds. Trimethoprim (Proloprim) is a closely related compound.

Pyrimethamine is well absorbed after oral administration, with peak plasma levels occurring within 3 to 7 hours. An initial loading dose to saturate nonspecific binding sites is not required, as it is with chloroquine. However, the drug binds to tissues, and therefore, its rate of renal excretion is slow. Pyrimethamine has a half-life of about 4 days. Although the drug does undergo some metabolic alterations, the metabolites formed have not been totally identified.

The only antimalarial drugs whose mechanisms of action are reasonably well understood are the drugs that inhibit the parasite's ability to synthesize folic acid. Parasites cannot use preformed folic acid and therefore must synthesize this compound from the following precursors obtained from their host: p-aminobenzoic acid (PABA), pteridine, and glutamic acid. The dihydrofolic acid formed from these precursors must then be hydro-genated to form tetrahydrofolic acid. The latter compound is the coenzyme that acts as an acceptor of a variety of one-carbon units. The transfer of one-carbon units is important in the synthesis of the pyrimidines and purines, which are essential in nucleic acid synthesis.

Whereas the sulfonamides and sulfones inhibit the initial step whereby PABA and the pteridine moiety combine to form dihydropteroic acid (see Chapter 44), pyrimethamine and trimethoprim inhibit the conversion of dihydrofolic acid to tetrahydrofolic acid, a reaction catalyzed by the enzyme dihydrofolate reductase. The basis of pyrimethamine selective toxicity resides in the preferential binding of the drug to the parasite's reductase enzyme.

The combined use of sulfonamides or sulfones with dihydrofolate reductase inhibitors, such as trimethoprim (Bactrim, Septra) or pyrimethamine (Fansidar), is a good example of the synergistic possibilities that exist in multiple-drug chemotherapy. This type of impairment of the parasite's metabolism is termed sequential blockade. Using drugs that inhibit at two different points in the same biochemical pathway produces parasite lethality at lower drug concentrations than are possible when either drug is used alone.

Pyrimethamine has been recommended for prophylactic use against all susceptible strains of plasmodia; however, it should not be used as the sole therapeutic agent for treating acute malarial attacks. As mentioned previously, sulfonamides should always be coadminis-tered with pyrimethamine (or trimethoprim), since the combined antimalarial activity of the two drugs is significantly greater than when either drug is used alone. Also, resistance develops more slowly when they are used in combination. Sulfonamides exert little or no effect on the blood stages of P. vivax, and resistance to the dihydrofolate reductase inhibitors is widespread.

In addition to its antimalarial effects, pyrimethamine is indicated (in combination with a sulfonamide) for the treatment of toxoplasmosis. The dosage required is 10 to 20 times higher than that employed in malarial infections.

Relatively few side effects are associated with the usual antimalarial dosages. However, signs of toxicity are evident at higher dosages, particularly those used in the management of toxoplasmosis. Many of these reactions reflect the interference of pyrimethamine with host folic acid metabolism, especially that occurring in rapidly dividing cells. Toxic symptoms include anorexia, vomiting, anemia, leukopenia, thrombocytopenia, and atrophic glossitis. CNS stimulation, including convulsions, may follow an acute overdose.The side effects associated with the pyrimethamine-sulfadoxine combination include those associated with the sulfonamide and pyrimethamine alone. In addition, there is evidence of a greater incidence of allergic reactions, particularly toxic epidermal necroly-sis and Stevens-Johnson syndrome, with the combination. This carries an estimated mortality of 1:11,000 to 1:25,000 when used as a chemoprophylactic.

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