Pyrimethamine

PYRIMETHAMINE

It is a directly acting inhibitor of plasmoidal DHFRase (does not require conversion to a cyclic triazine, as is the case with proguanil). Selective antimalarial action depends on high affinity for plasmodial enzyme (~2000 times greater than for the mammalian enzyme). In contrast to trimethoprim, it has very poor action on bacterial DHFRase. Under the influence of pyrimethamine, schizogony of malarial parasite in blood gradually stops. At high doses, it inhibits Toxoplasma gondii.

Pyrimethamine is more potent. It is a slowly acting erythrocytic schizontocide, but does not eliminate the preerythrocytic phase of P. falciparum. It is not a radical curative, but by extended treatment, the secondary tissue phase of P. vivax may be exhausted. If used alone, resistance develops rather rapidly by mutation in the DHFRase enzyme of the parasite. These organisms exhibit cross resistance to proguanil.

Pharmacokinetics

Absorption of pyrimethamine from g.i.t. is good but slow. Certain organs like liver, spleen, kidney and lungs concentrate pyrimethamine. It is metabolized and excreted in urine with a t½ of 4 days. Prophylactic concentrations remain in blood for 2 weeks.

Adverse Effects

Pyrimethamine is relatively safe. The only side effects are occasional nausea and rashes. Folate deficiency is rare; megaloblastic anaemia and granulocytopenia may occur with higher doses, especially in those with marginal folate stores. This can be treated by folinic acid.

Use

Pyrimethamine is used only in combination with a sulfonamide (S/P) or dapsone (see below) for treatment of falciparum malaria.

SULFONAMIDE-PYRIMETHAMINE (S/P) COMBINATION

Sulfonamides/dapsone are not particularly effective antimalarial drugs in their own right; have some inhibitory influence on the erythrocytic phase, especially of P. falciparum. However, they form supra-additive synergistic combination with pyrimethamine due to sequential block (as in case of cotrimoxazole: p. 685). Though, both components are slow acting, the combination acts faster, so that it can be employed as a clinical curative, particularly for P. falciparum. Efficacy against P. vivax is rather low. By the addition of sulfonamide, development of resistance to pyrimethamine is retarded. There is no crossresistance with other groups of antimalarial drugs. The popular combinations are:

Sulfadoxine 500  mg + pyrimethamine 25 mg tab: RIMODAR, FANCIDAR, LARIDOX, MALOCIDE; REZIZ 500 mg + 25 mg tab and per 10 ml susp; REZIZ FORTE 750 mg + 37.5 mg tab.

Sulfamethopyrazine 500 mg + pyrimethamine 25 mg tab: METAFIN,  MALADEX.

Dapsone   100   mg + pyrimethamine 25 mg tab; MALOPRIM.

As clinical curative: Sulfadoxine 1500 mg + pyrimethamine 75 mg (3 tab) single dose (children 9–14 yr 2 tab, 4–8 yr 1 tab, 1–4 yr ½ tab).

Sulfadoxine and sulfametho-pyrazine are ultralong acting sulfonamides — attain low blood concentrations, but are able to synergise with pyrimethamine which also has long t½. The combination has the potential to cause serious adverse effects (exfoliative dermatitis, Stevens-Johnson syndrome, etc.) due to the sulfonamide. Therefore, use is restricted to single dose treatment of uncomplicated chloroquine-resistant falciparum malaria, or in patients intolerant to chloroquine. Prophylactic use, needing multiple unsupervised doses is not approved. It is contraindicated in infants and in individuals allergic to sulfonamide. There is no evidence that single dose of the combination used for treating malaria harms the foetus during pregnancy, but should be avoided if possible.

The major importance of this combination is due to its efficacy against chloroquine-resistant P. falciparum. Compliance is good due to single dose therapy and few acute side effects. Resistance to S/P among P. falciparum was first noted in 1980, and has spread globally now. It is high in South East Asia, South America and Southern Africa, so much as to preclude its clinical use. In India, S/P resistance has not been systematically measured, but appears to be sporadic, except in the North east. A sample study from Aasam found 9% chloroquine-resistant P. falciparum cases to be nonresponsive to S/P as well, while in the area bordering Myanmar 35–44% S/P failures have been recorded. To contain further spread of S/P resistance, the National drug policy on malaria mandates compulsory use of artesunate along with S/P for treatment of chloroquine-resistant falciparum malaria. It is not an effective drug for vivax malaria.

S/P is the first choice treatment for toxoplasmosis, which mainly occurs in immune-compromised patients.