Pyrimethamine

Pyrimethamine
Clinical data
Trade names	Daraprim
AHFS/Drugs.com	Monograph
MedlinePlus	a601050
Pregnancy; category	AU: B3; ;
Routes of; administration	Oral
ATC code	P01BD01 (WHO) ;
Legal status
Legal status	In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	well-absorbed
Protein binding	87%
Metabolism	Hepatic
Elimination half-life	96 hours
Excretion	Renal
Identifiers
	IUPAC name 5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine;
CAS Number	58-14-0 ;
PubChem CID	4993;
DrugBank	DB00205 ;
ChemSpider	4819 ;
UNII	Z3614QOX8W;
KEGG	D00488 ;
ChEBI	CHEBI:8673 ;
ChEMBL	ChEMBL36 ;
CompTox Dashboard (EPA)	DTXSID9021217 ;
ECHA InfoCard	100.000.331
Chemical and physical data
Formula	C12H13ClN4
Molar mass	248.71 g/mol g·mol−1
3D model (JSmol)	Interactive image;
	SMILES Clc2ccc(c1c(nc(nc1CC)N)N)cc2;
	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) ; Key:WKSAUQYGYAYLPV-UHFFFAOYSA-N ;
	(verify)

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 derivative that is converted to tetrahydrofolate (the primary active form of 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

^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)
^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)

References

[Gatton2004-1] 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. {{cite journal}}: Explicit use of et al. in: |author= (help)

[Sirichaiwat2004-2] 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. {{cite journal}}: Explicit use of et al. in: |author= (help)

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