Pyrimethamine Sulphonamides

Fig. 12.8 Structural relationships between dihydrofolate reductase inhibitors (trimethoprim and pyrimethamine), sulphonamides (sulphamethoxazole and dapsone) and dihydrofolic acid.

Resistance to proguanil, pyrimethamine, sulphonamides, and sulphones, is readily produced in the laboratory and the field, and has seriously compromised the use of these drugs, particularly proguanil which has been withdrawn from the U.S. Pharmacopoeia [16, 324, 330]. Resistance to chloroquine, quinacrine, and quinine, is more difficult to produce both in the laboratory and the field, but it is rapidly becoming a serious problem in the therapy and prophylaxis of falciparum malaria [16, 324, 325]. It is evident that all four... 

Folate metabolism Sulphonamides (also ) Trimethoprim Pyrimethamine Trimetrexate / Inhibit folate synthesis Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Inhibits dihydrofolate reductase Not present in mammalian cells Mammalian enzyme not inhibited Mammalian enzyme not inhibited Toxicity overcome with leucovorin... 

Although inferior to pyrimethamine plus sulphonamides, both puromycin and the aminonucleoside are active against Toxoplasma gondii in vivo [403]. These drugs are also effective against Endamoeba histolytica in vitro [404], and puromycin is active against the infection in man [405]. 

ANTIBIOTICS- SULPHONAMIDES, TRIMETHOPRIM ANTIMALARIALS -PYRIMETHAMINE T antifolate effect Additive effect Monitor FBC closely the effect may take a number of weeks to occur... 

Proguardl (t) 17 h) inhibits dihydrofolate reductase which converts folic to folinic acid, deficiency of which inhibits plasmodial cell division. Plasmodia, like most bacteria and unlike humans, cannot make use of preformed foUc acid. Pyrimethamine and trimethoprim, which share this mode of action, are collectively known as the antifols. Their plasmod-icidal action is markedly enhanced by combination with sulphonamides or sulphones because there is inhibition of sequential steps in folate synthesis (see Sulphonamide combinations, p. 231). 

Considering the drugs in relation to modes of action, dapsone and the sulphonamides block the biosynthesis of tetrahydrofolate by inhibiting di-hydropteroate synthetase, while the 2,4-diamino-pyrimidines (proguanil and pyrimethamine) block the same pathway but at a later step catalysed by dihydrofolate reductase. 

There are few absolute clinical indications for the use of sulphonamides. They have been used extensively in the past for urinary tract infections, though less now. They are used for certain respiratory infections, including that by Pneumocystis carnii, some sexually transmitted diseases (chlamidia. chancroid, trachoma), in drug-resistant malaria (with pyrimethamine), in inflammatory towel disease (sulfasalazine) and as silver sulfadiazine for topical application in infected burns. 

Inhibition of folic acid synthesis in susceptible microorganisms and ultimately the synthesis of nucleic acids. By competing with para-aminobenzoic acid (PABA) for the enzyme dihydropteroate synthetase, sulphonamides prevent the incorporation of PABA into dihydrofolate, while trimethoprin, by selectively inhibiting dihydrofolate reductase, prevents the reduction of dihydrofolate to tetrahydrofolate (folic acid). Animal cells, unlike bacteria, utilize exogenous sources of folic acid. Pyrimethamine inhibits protozoal dihydrofolate reductase, but is less selective for the microbial enzyme and therefore more toxic than trimethoprim to mammalian species. 

Mefloquine is a long-acting blood schizontocide with high efficacy against malarial parasites resistant to quinine, chloroquine and sulphonamide-pyrimethamine combinations [124-129], A single oral dose of the drug of 15 mg/kg (with a maximum of 750-1000 mg/adult) produces cure rates above 90%, Detailed clinical trials carried out in Zimbabwe, Thailand, Burma, Brazil and Europe have established mefloquine as an effective drug both for prophylaxis and treatment of vi-vax and falciparum malaria [125-130],... 

Later as a result of the investigation of Archibold and Ross [33a] and others, it has been shown that dapsone (and its repository forms) could clear the blood from trophozoites of different plasmodium spp. The sensitivity of the different species of parasites varied P. falciparum is very sensitive, while P. vivax is less so. Their action, as with sulphonamides, is mainly against the blood stages with marginal activity against primary (pre-erythrocytic) tissue forms and no activity against sexual and latent tissue forms. It has also been shown that dapsone potentiated the action of pyrimethamine, and a combination of the two markedly delayed the development of... 

A most interesting and useful development concerning DHR inhibitors was the selectivity of inhibition observed between different classes of compounds against dihydrofolate reductases from mammals, protozoa and bacteria, which was found to be due to marked differences in binding affinity to the enzyme methotrexate binds very tightly to all reductases tested and is lethal to any cell it can enter, while trimethoprim and pyrimethamine have selectively strong affinity for bacterial and plasmodial reductases, respectively. This helped to rationalise the clinical use of DHFR inhibitors alone or in combination with sulphonamides and sulphones while trimethoprim is used mainly for bacterial infections, pyrimethamine is used for protozoal infections [58a]. 

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). 

The drug only affects the erythrocytic form of the plasmodia and, therefore, is employed particularly as a suppressive in the management and treatment of severe attacks of/ vivax. P. malariae and P. ovo/e malaria. It may cure upto 50% of infections caused by/ falciparum. The t/n/g maybe employed in combination with pyrimethamine and a sulphonamide, but it seems to be antagonized by chloroquine. 

Sulfadiazine is well absorbed following oral administration. Sulphonamides were used to treat simple urinary tract infectioas but many Escherichia coli t strains are resistant and much less toxic drags are now available. Sulfadiazine in combination with pyrimethamine is used in infectioBs ofTost lasnui gondii. 

Pyrimethamine is usually given in combination with sulfadoxine (Fig. 25.5) which, like many sulphonamide antibacterial compounds, is an inhibitor of the biosynthesis of dihydropteroate which is a precursor of folic acid. Unlike humans, plasmodia synthesise folic acid rather than absorb it from the environment. It is used for prophylaxis rather than treatment. 

An example of sequential blocking is the use of a sulphadiazine with pyrimethamine ( Daraprim ) in the toxoplasmosis of mice and men (Wettingfeld, Rowe and Eyles, 1956). In this sequence, the sulphonamide blocks the incorporation of p-aminobenzoic acid into dihydrofolic acid, and the pyrimethamine (4.7) prevents the reduction of this pteridine to tetrahydrofolic acid (Sections 9.3b and c). In humans, too, pyrimethamine and sulphadiazine have been shown to potentiate one another in the three principal types of malaria. Thus less than o.i m.e.d. (minimal effective... 

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