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Pyrimethamine: Wikis

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Pyrimethamine
Systematic (IUPAC) name
5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine
Identifiers
CAS number 58-14-0
ATC code P01BD01
PubChem 4993
DrugBank APRD00599
Chemical data
Formula C12H13ClN4 
Mol. mass 248.71 g/mol
Pharmacokinetic data
Bioavailability well-absorbed
Protein binding 87%
Metabolism Hepatic
Half life 96 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. B3(AU) C(US)
Legal status Prescription only
Routes Oral
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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.

Contents

Mechanism of action

Pyrimethamine interferes with folic acid synthesis by inhibiting the enzyme dihydrofolate reductase (DHFR). Folic acid is needed for DNA and RNA synthesis in many species, including protozoa.

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].

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.

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.

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Side effects

Pyrimethamine may deplete folic acid in humans, resulting in hematologic side effects associated with folate deficiency.

Side effects include:

Contraindications

Pyrimethamine is contraindicated in patients with:

  • hypersensitivity to pyrimethamine
  • megaloblastic anemia – depletion of folic acid may aggravate this condition

Notes

  1. ^ 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. PMID 15155209. 
  2. ^ 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. 

References


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