Pyrimethamine

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Pyrimethamine
Pyrimethamine2DACS.svg
Systematic (IUPAC) name
5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine
Clinical data
Trade names Daraprim
AHFS/Drugs.com monograph
MedlinePlus a601050
  • AU: B3
  • US: C (Risk not ruled out)
Oral
Pharmacokinetic data
Bioavailability well-absorbed
Protein binding 87%
Metabolism Hepatic
Half-life 96 hours
Excretion Renal
Identifiers
58-14-0 YesY
P01BD01
QP51AX51 (combinations)
PubChem CID 4993
DrugBank DB00205 YesY
ChemSpider 4819 YesY
UNII Z3614QOX8W YesY
KEGG D00488 YesY
ChEBI CHEBI:8673 YesY
ChEMBL CHEMBL36 YesY
Chemical data
Formula C12H13ClN4
248.71 g/mol
 YesY (what is this?)  (verify)

Pyrimethamine /prɪmɛθmn/ (trade name 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 the sulfonamide antibiotic sulfadiazine) in the treatment of Toxoplasma gondii infections in immunocompromised patients, such as HIV-positive individuals. It is also currently being evaluated[1] in clinical trials as a treatment for amyotrophic lateral sclerosis. In 2011, researchers discovered that pyrimethamine can increase ß-hexosaminidase activity, thus potentially slowing down the progression of late-onset Tay–Sachs disease.[2]

It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[3]

Medical uses[edit]

Pyrimethamine is typically given with a sulfonamide and folinic acid:[4]

  • Sulfonamides inhibit dihydropteroate synthetase, an enzyme that participates in folic acid synthesis from para-aminobenzoic acid. Hence, sulfonamides work synergistically with pyrimethamine by blocking a different enzyme needed for folic acid synthesis.
  • Folinic acid (leucovorin) is a folic acid derivative 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 in the patient.

It is primarily active against Plasmodium falciparum, but it also has activity against Plasmodium vivax.[5] Due to the emergence of pyrimethamine-resistant strains of P. falciparum, pyrimethamine alone is seldom used now, but in combination with a long-acting sulfonamide such as sulfadiazine, it is still widely used, though resistance to this combination is increasing.[5] It has also been used in the treatment of actinomycosis and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.

Mechanism of resistance[edit]

Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness.[6] These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.[7]

Side effects[edit]

Pyrimethamine can cause a rash, and if higher doses are used (such as for toxoplasmosis), it can cause gastrointestinal symptoms such as nausea, vomiting, abdominal cramps, dry mouth, weight loss, and diarrhoea, Central nervous system effects include headache, ataxia, and rarely seizures and haematologic side effects such as leucopenia and anaemia.[4]

Contraindications[edit]

Pyrimethamine is contraindicated in patients with:[4]

  • Folate-deficiency anaemia
  • Epilepsy
  • Pregnancy, especially, during the first trimester due to the possible detrimental effects an antifolate such as pyrimethamine might have on organogenesis

Interactions[edit]

Other antifolate agents such as methotrexate and trimethoprim may potentiate the antifolate actions of pyrimethamine, leading to potential folate deficiency anaemia and other blood dyscrasias.[4]

Physicochemistry[edit]

It is a white, colourless, crystalline powder and is practically insoluble in water and slightly soluble in ethanol, chloroform, and acetone.[5] It is unstable in the presence of air and light.[5] It is chemically a diaminopyrimidine derivative.[5]

Mechanism of action[edit]

Pyrimethamine interferes with tetrahydrofolic acid synthesis from folic acid by inhibiting the enzyme dihydrofolate reductase (DHFR).[8] Tetrahydrofolic acid is needed for DNA and RNA synthesis in many species, including protozoa.[8] It has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.[9][10]

Synthesis[edit]

Condensation of phenylacetonitrile with ethyl propionate in the presence of sodium ethoxide gives the cyanoketone (3). Treatment with diazomethane affords the methyl enol ether of that compound (4). Condensation with guanidine affords pyrimethamine (5).

Notes[edit]

  1. ^ "Pyrimethamine ALS trial". 
  2. ^ Osher, E; Fattal-Valevski, A; Sagie, L; Urshanski, N; Amir-Levi, Y; Katzburg, S; Peleg, L; Lerman-Sagie, T; Zimran, A; Elstein, D; Navon, R; Stern, N; Valevski, A (March 2011). "Pyrimethamine increases β-hexosaminidase A activity in patients with Late Onset Tay Sachs.". Molecular Genetics and Metabolism 102 (3): 356–63. doi:10.1016/j.ymgme.2010.11.163. PMID 21185210. 
  3. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  4. ^ a b c d Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  5. ^ a b c d e Brayfield, A, ed. (13 December 2013). "Pyrimethamine". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 12 April 2014. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ a b "PRODUCT INFORMATION DARAPRIM TABLETS". TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. 5 December 2011. p. 1. Retrieved 12 April 2014. 
  9. ^ Limpert, AS; Mattmann, ME; Cosford, ND (2013). "Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)." (PDF). Beilstein Journal of Organic Chemistry 9: 717–32. doi:10.3762/bjoc.9.82. PMC 3678841. PMID 23766784. 
  10. ^ Lange, DJ; Andersen, PM; Remanan, R; Marklund, S; Benjamin, D (April 2013). "Pyrimethamine decreases levels of SOD1 in leukocytes and cerebrospinal fluid of ALS patients: a phase I pilot study.". Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration 14 (3): 199–204. doi:10.3109/17482968.2012.724074. PMID 22985433. 
  11. ^ Russell, P. B.; Hitchings, G. H. (1951). "2,4-Diaminopyrimidines as Antimalarials. III. 5-Aryl Derivatives". Journal of the American Chemical Society 73 (8): 3763. doi:10.1021/ja01152a060.  edit
  12. ^ Logemann, W.; Almirante, L.; Caprio, L. (1954). "Studien in der heterocyclischen Reihe. I. Mitteil.: Eine neue Synthese der 2.4-Diamino-6-alkyl-5-aryl-pyrimidine ("Daraprim")". Chemische Berichte 87 (3): 435. doi:10.1002/cber.19540870324.  edit

References[edit]