Pyrimethamine

Pyrimethamine

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 Y
ATC code	P01BD01
PubChem	CID 4993
DrugBank	APRD00599
ChemSpider	4819 Y
UNII	Z3614QOX8W Y
KEGG	D00488 Y
ChEBI	CHEBI:8673 N
ChEMBL	CHEMBL36 Y
Chemical data
Formula	C12H13ClN4
Mol. mass	248.71 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C12H13ClN4/c1-2-9-10(11(14)17-12(15)16-9)7-3-5-8(13)6-4-7/h3-6H,2H2,1H3,(H4,14,15,16,17) Y Key:WKSAUQYGYAYLPV-UHFFFAOYSA-N Y
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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.

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.

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.

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)

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. PMC 415611. PMID 15155209. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=415611. 
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

• Daraprim – Package insert (PDF file)
• Fansidar – sulfadoxine and pyrimethamine