Pyrimethamine

Absorption

Well absorbed with peak levels occurring between 2 to 6 hours following administration

Chemical properties

White Solid

The Uses of Pyrimethamine

For the treatment of toxoplasmosis and acute malaria; For the prevention of malaria in areas non-resistant to pyrimethamine.
Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum malaria with pyrimethamine alone is therefore not recommended. Most strains of Plasmodium vivax have remained sensitive. Pyrimethamine is also used in combination with a sulfonamide for the treatment of Toxoplasmosis. It is slowly absorbed from the gastrointestinal tract with peak plasma levels 4–6 hours after dosing. Pyrimethamine is bound to plasma proteins and is extensively metabolized before excretion. Its elimination half-life is 3–5 days.

The Uses of Pyrimethamine

Dihydrofolate reductase inhibitor; generally used in combination with other antimicrobial agents. Antiprotozoal (Toxoplasma); antimalarial

The Uses of Pyrimethamine

This powerful inhibitor of dihydrofolate reductase is used for preventing and treating malaria caused by plasmodia P. vivax, P. malariae, P. ovale, including P. falciparum.
Pyrimethamine, an antagonist of folic acid, exhibits antimicrobial action against causative agents of malaria and simultaneously possesses sporontocide action. It is also effective with respect to the causative agent of toxoplasmosis. It is used for preventing malaria and treating toxoplasmosis. It can only be used for preventative measures; however, because resistance develops quickly and because of the fact that the maximal effect is achieved by using it in combination with sulfadoxine, a combined drug which is prescribed under the name fansidar, which contains a pyrimethamine–sulfadoxine ratio of 1:20. A combination of pyrimethamine, sulfonamide, and quinine is the drug of choice for acute attacks of malaria and its chloroquine-resistant forms.
Pyrimethamine in combination with sulfadiazine or trisulfapyrimidine is the drug of choice for toxoplasmosis. A synonym of this combined drug is daraprim.

Background

One of the folic acid antagonists that is used as an antimalarial or with a sulfonamide to treat toxoplasmosis.

Indications

For the treatment of toxoplasmosis and acute malaria; For the prevention of malaria in areas non-resistant to pyrimethamine

Definition

ChEBI: An aminopyrimidine that is pyrimidine-2,4-diamine which is substituted at position 5 by a p-chlorophenyl group and at position 6 by an ethyl group. It is a folic acid antagonist used as an antimalarial or with a sulfonamide to treat toxoplasmo is.

Indications

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.

brand name

Daraprim (GlaxoSmithKline).

General Description

Odorless white crystalline powder. Tasteless. An antimalarial drug.

Air & Water Reactions

Pyrimethamine is a diaminopyrimidine which is structurally related to trimethoprim. It is effective against erythrocytic stage of Plasmodium (P) falciparum and less so against P. vivax, P. ovale and P. malariae. Pyrimethamine also inhibits the sporogony in the mosquito, resulting in a decrease of transmission of the infection within the community^[1].
The mechanism of action of pyrimethamine is related to its inhibition of dihydrofolic reductase necessary for the folic acid synthesis in the parasite. Pyrimethamine acts slowly and is not recommended as monotherapy for acute malaria attacks. Resistance to pyrimethamine developed soon when the drug was used on a large scale as monoprophylaxis ^[1]. In resistant strains, the enzyme dihydrofolic reductase binds to pyrimethamine several hundred times less than in sensitive strains ^[2]. This high grade resistance is probably a onestep mutation and cannot be overcome by increasing the dose. However, when combined with long-acting sulphonomides (sulphadoxine), the effect of pyrimethamine is potentiated and the risk of developing resistant strains is far less.

Reactivity Profile

Pyrimethamine together with sulphadoxine (Fansidar) is used in the treatment of P. falciparum malaria (cf. Sulphadoxine: Indications). Pyrimethamine is also valuable in the treatment of toxoplasmosis.

Fire Hazard

Pyrimethamine in combination with sulphadoxine (Fansidar) can cause severe cutaneous adverse reactions (cf. Sulphadoxine: Side effects). Agranulocytosis occurs quite frequently (1/2000) and fatalities have been reported when pyrimethamine is combined with dapsone ^[3]. When given alone, life-threatening adverse reactions are very rare and the drug is generally well tolerated. Megaloblastic anaemia may, however, occur during long-term treatment with high doses (i.e. for toxoplasmosis) and can be prevented by folinic acid supplementation ^[4].

Biological Activity

During long-term treatment with high doses, folinic acid supplement is usually given.

Mechanism of action

The combination of pyrimethamine with a long-acting sulfonamide, sulfadoxine, which blocks dihydrofolate synthesis by blocking incorporation of PABA into the dihydrofolate, is called Fansidar, which produces sequential blockage of tetrahydrofolate synthesis similar to that reported for treatment of bacterial infections. Plasmodium enzymes catalyzing folic acid synthesis differ from those enzymes found in other organisms. A single bifunctional protein present in Plasmodium sp. catalyzes the phosphorylation of 6-hydroxymethyl-7,8-hydropterin (a pyrophosphokinase) and the incorporation of PABA into dihydropteroic acid. A second bifunctional enzyme catalyzes the reduction of dihydropteroic acid and thymidylic acid synthesis. As a result, the drug combination (Fansidar) appears to have improved drug-mediated disruption of folic acid in Plasmodium sp.. This combination has been used with quinine for the treatment and prevention of chloroquine-resistant malaria (Plasmodium falciparum, Plasmodium ovale, Plasmodium vivax, and Plasmodium malaria). The combination therapy (Fansidar) has the added advantage of being inexpensive, which is essential for successful therapy in developing countries. When used on its own, pyrimethamine is a blood schizonticide without effects on the tissue stage of the disease.

Pharmacokinetics

Pyrimethamine is an antiparasitic compound commonly used as an adjunct in the treatment of uncomplicated, chloroquine resistant, P. falciparum malaria. It possesses blood schizonticidal and some tissue schizonticidal activity against malaria parasites of humans. However, the 4-amino-quinoline compounds are more effective against the erythrocytic schizonts. It does not destroy gametocytes, but arrests sporogony in the mosquito. The action of pyrimethamine against Toxoplasma gondii is greatly enhanced when used in conjunction with sulfonamides.

Clinical Use

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 coadministered 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.

Side Effects

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 necrolysis 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.

Safety Profile

Poison by ingestion, subcutaneous, and intraperitoneal routes. Experimental teratogenic and reproductive effects. Questionable carcinogen. Human mutation data reported. When heated to decomposition it emits very toxic fumes of Cland NOx. Used as an antimalarial drug for humans and to treat toxoplasmosis in hogs.

Synthesis

Pyrimethamine, 2,4-diamino-5-(4
-chlorophenyl)-6-ethylpyrimidine (33.1.60), is synthesized from 4-chlorobenzycyanide, which upon condensation with methyl ester of propionic acid in the presence of sodium methoxide gives the |?-ketonitrile (33.1.58). Reacting this with ethyl orthoformate gives a methoxymethylene derivative (33.1.59), which upon heterocyclization in pyrimidine using guanidine as the binucleophile forms the desired pyrimethamine (33.1.60).

Veterinary Drugs and Treatments

In veterinary medicine, pyrimethamine is used to treat Hepatozoon americanum infections, and toxoplasmosis in small animals (often in combination with sulfonamides). In horses, it is used to treat equine protozoal myeloencephalitis, sometimes called equine toxoplasmosis.
In humans, pyrimethamine is used for the treatment of toxoplasmosis and as a prophylactic agent for malaria.

Drug interactions

Potentially hazardous interactions with other drugs
Increased antifolate effect with sulphonamides, trimethoprim, methotrexate and pemetrexed.
Antiepileptics: anticonvulsant effect of fosphenytoin and phenytoin antagonised, also increased antifolate effect.
Antimalarials: avoid concomitant use with artemether/lumefantrine; increased antifolate effect with proguanil.

Side Effects

Common side effects include gastrointestinal upset, severe allergic reactions, and bone marrow suppression.

Metabolism

Hepatic

Metabolism

Pyrimethamine is metabolised in the liver and slowly excreted via the kidney, with up to 30% recovered in the urine as parent compound over a period of several weeks. Several metabolites have also been detected in the urine, although data are lacking on the nature of these metabolites, their route, rate of formation and elimination, and any pharmacological activity, particularly after prolonged daily dosing.

storage

Store at RT