Pyrimethamine
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| Systematic (IUPAC) name | |
| 5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine | |
| Clinical data | |
| Trade names | Daraprim |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a601050 |
| Pregnancy cat. | B3(AU) C(US) |
| Legal status | ℞ Prescription only |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | well-absorbed |
| Protein binding | 87% |
| Metabolism | Hepatic |
| Half-life | 96 hours |
| Excretion | Renal |
| Identifiers | |
| CAS number | 58-14-0  |
| ATC code | P01BD01 |
| PubChem | CID 4993 |
| DrugBank | APRD00599 |
| ChemSpider | 4819 |
| UNII | Z3614QOX8W |
| KEGG | D00488 |
| ChEBI | CHEBI:8673 |
| ChEMBL | CHEMBL36 |
| Chemical data | |
| Formula | C12H13ClN4 |
| Mol. mass | 248.71 g/mol |
| SMILES | eMolecules & PubChem |
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Pyrimethamine (Daraprim) is a medication used for protozoal infections. It is commonly used as an antimalarial drug (for both treatment and prevention of malaria), and is also used (combined with sulfadiazine) in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals.
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[edit] Mechanism of action
Pyrimethamine interferes with tetrahydrofolic acid synthesis from folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR). Tetrahydrofolic acid is needed for DNA and RNA synthesis in many species, including protozoa.
[edit] Mechanism of resistance
Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce the effectiveness of pyrimethamine.[1] These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.[2]
[edit] Clinical use
Pyrimethamine is typically given with a sulfonamide and folinic acid:
- sulfonamides inhibit dihydropteroate synthetase, an enzyme that participates in folic acid synthesis from para-aminobenzoic acid. Hence, sulfonamides work synergistically[citation needed] with pyrimethamine by blocking a different enzyme needed for folic acid synthesis.
- Folinic acid (Leucovorin) is a folic acid precursor that spontaneously forms folic acid in vivo without relying on dihydrofolate reductase. By doing so, folinic acid reduces side effects related to folate deficiency.
[edit] Use in mass drug administrations
Pyrimethamine has been extensively used as monotherapy in mass drug administrations in Asia and South America which is likely to have contributed to the emergence and spread of pyrimethamine resistant Plasmodium falciparum strains.
[edit] Side effects
Pyrimethamine may deplete folic acid in humans, resulting in hematologic side effects associated with folate deficiency.
Side effects include:
- hypersensitivity reactions
- megaloblastic anemia
- leukopenia
- thrombocytopenia
- pancytopenia
- atrophic glossitis
- hematuria
- cardiac arrhythmias
- pulmonary eosinophilia (rare)
- hyperphenylalaninemia (particularly when used with a sulfonamide)
- Stevens–Johnson syndrome (particularly when used with a sulfonamide)
- toxic epidermal necrolysis (particularly when used with a sulfonamide)
[edit] Contraindications
Pyrimethamine is contraindicated in patients with:
- hypersensitivity to pyrimethamine
- megaloblastic anemia – depletion of folic acid may aggravate this condition
[edit] Notes
- ^ Gatton M.L. et al. (2004). "Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum". Antimicrob Agents Chemother 48 (6): 2116–23. doi:10.1128/AAC.48.6.2116-2123.2004. PMC 415611. PMID 15155209.
- ^ Sirichaiwat C. et al. (2004). "Target guided synthesis of 5-benzyl-2,4-diamonopyrimidines: their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from Plasmodium falciparum". J Med Chem 47 (2): 345–54. doi:10.1021/jm0303352. PMID 14711307.
[edit] References
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