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trimethoprim

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trimethoprim
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{{distinguish|Thymidine monophosphate}}{{drugbox| Watchedfields = changed| verifiedrevid = 470615131| drug_name =| IUPAC_name = 5-(3,4,5-Trimethoxybenzyl)pyrimidine-2,4-diamine| image = Trimethoprim.svg| width = 240| alt = Structural formula of trimethoprim| image2 = Trimethoprim-from-hydrochloride-xtal-1984-3D-balls.png| width2 = 250| alt2 = Ball-and-stick model of the trimethoprim molecule
taɪmθpɪ|m}}| tradename =Proloprim, Monotrim, Triprim, othersmonograph|trimethoprim}}| MedlinePlus = a684025| licence_US = Trimethoprim| pregnancy_AU = B3| pregnancy_US = C| legal_AU = S4| legal_CA = Rx-only| legal_UK = POM| legal_US = Rx-only| routes_of_administration = Oral| bioavailability = 90–100%| protein_bound = 44%| metabolism = hepatic| elimination_half-life = 8-12 hours| excretion = Urine (50–60%), faeces (4%)correct|??}}| CAS_number = 738-70-5| ATC_prefix = J01| ATC_suffix = EA01J51|EA01}}| PubChem = 5578correct|drugbank}}| DrugBank = DB00440correct|chemspider}}| ChemSpiderID = 5376correct|FDA}}| UNII = AN164J8Y0Xcorrect|kegg}}| KEGG = D00145correct|EBI}}| ChEBI = 45924correct|EBI}}| ChEMBL = 22| PDB_ligand = TOP H=18 O=3 | molecular_weight = 290.32 g/mol| smiles = Nc1nc(N)ncc1Cc(cc2OC)cc(OC)c2OCcorrect|chemspider}}| StdInChI = 1S/C14H18N4O3/c1-19-10-5-8(6-11(20-2)12(10)21-3)4-9-7-17-14(16)18-13(9)15/h5-7H,4H2,1-3H3,(H4,15,16,17,18)correct|chemspider}}| StdInChIKey = IEDVJHCEMCRBQM-UHFFFAOYSA-N}}Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections.WEB, Trimethoprim,weblink The American Society of Health-System Pharmacists, Aug 1, 2015, no,weblink" title="web.archive.org/web/20150924014936weblink">weblink 2015-09-24, Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for Pneumocystis pneumonia in people with HIV/AIDS.JOURNAL, Masur, H, Brooks, JT, Benson, CA, Holmes, KK, Pau, AK, Kaplan, JE, National Institutes of, Health, Centers for Disease Control and, Prevention, HIV Medicine Association of the Infectious Diseases Society of, America, Prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Updated Guidelines from the Centers for Disease Control and Prevention, National Institutes of Health, and HIV Medicine Association of the Infectious Diseases Society of America., Clinical Infectious Diseases, May 2014, 58, 9, 1308–11, 24585567, 10.1093/cid/ciu094, 3982842, It is taken by mouth.Common side effects include nausea, changes in taste, and rash. Rarely it may result in blood problems such as not enough platelets or white blood cells. May cause sun sensitivity. There is evidence of potential harm during pregnancy in some animals but not humans.WEB, Prescribing medicines in pregnancy database,weblink Australian Government, 22 April 2014, 3 March 2014, no,weblink" title="web.archive.org/web/20140408040902weblink">weblink 8 April 2014, It works by blocking folate metabolism via dihydrofolate reductase in some bacteria which results in their death.
Trimethoprim was first used in 1962.JOURNAL, Huovinen, P, Resistance to trimethoprim-sulfamethoxazole., Clinical Infectious Diseases, 1 June 2001, 32, 11, 1608–14, 11340533, 10.1086/320532, It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.WEB, WHO Model List of Essential Medicines (19th List),weblink World Health Organization, 8 December 2016, April 2015, no,weblink" title="web.archive.org/web/20161213052708weblink">weblink 13 December 2016, It is available as a generic medication and is not very expensive.BOOK, Hamilton, Richart, Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition, 2015, Jones & Bartlett Learning, 9781284057560, 113, In the United States, ten days of treatment costs about $21.

Medical uses

It is primarily used in the treatment of urinary tract infections, although it may be used against any susceptible aerobic bacterial species.BOOK, Rossi, S, 978-0-9805790-9-3, Australian Medicines Handbook, Adelaide, The Australian Medicines Handbook Unit Trust, 2013, 2013, It may also be used to treat and prevent Pneumocystis jirovecii pneumonia. It is generally not recommended for the treatment of anaerobic infections such as Clostridium difficile colitis (the leading cause of antibiotic-induced diarrhea). Trimethoprim has been used in trials to treat retinitis.JOURNAL, Pradhan E, Bhandari S, Gilbert RE, Stanford M, Antibiotics versus no treatment for toxoplasma retinochoroiditis, Cochrane Database Syst Rev, 5, CD002218, May 2016, 27198629, 10.1002/14651858.CD002218.pub2, Resistance to trimethoprim is increasing, but it is still a first line antibiotic in many countries.WEB,weblink Three-day courses of antibiotics for uncomplicated urinary tract infection | Guidance and guidelines | NICE, 2015-12-30, no,weblink" title="web.archive.org/web/20151208004951weblink">weblink 2015-12-08,

Spectrum of susceptibility

Cultures and susceptibility tests should be done to make sure bacteria is treated by trimethoprim.WEB, DailyMed - TRIMETHOPRIM- trimethoprim tablet,weblink dailymed.nlm.nih.gov, 2015-11-04, no,weblink" title="web.archive.org/web/20150930162821weblink">weblink 2015-09-30, WEB, DailyMed - PRIMSOL- trimethoprim hydrochloride solution,weblink dailymed.nlm.nih.gov, 2015-11-04, no,weblink 2015-11-17,

Side effects

Common

  • Nausea
  • Change in taste
  • Vomiting
  • Diarrhea
  • Rash
  • Sun sensitivity
  • ItchinessWEB, PROLOPRIM® (trimethoprim)100-mg and 200-mg Scored Tablets,weblink dailymed.nlm.nih.gov, 2015-11-04, no,weblink" title="web.archive.org/web/20151117015344weblink">weblink 2015-11-17, BOOK, American Hospital Formulary Service- Drug Information 2002., Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger, Williams and Wilkins, Baltimore, MD, 236,

Rare

  • Can cause thrombocytopenia (low levels of platelets) by lowering folic acid levels; this may also cause megaloblastic anemia.BOOK, Drug Information for the Health Care Professional. 22nd ed. Volume 1., MICROMEDEX Thomson Health Care. USPDIpublisher = Thomson Health, CareGreenwood Village, CO. 2002 p. 2849,
  • Trimethoprim antagonizes the epithelial sodium channel in the distal tubule, thus acting like amiloride. This can cause increased potassium levels in the body (hyperkalemia).JOURNAL, Trimethoprim-Induced Hyperkalemia in a Patient with AIDS, New England Journal of Medicine, 1993-03-11, 0028-4793, 8433730, 703–706, 328, 10, 10.1056/NEJM199303113281006, Michael J., Choi, Pedro C., Fernandez, Asit, Patnaik, Brigitte, Coupaye-Gerard, Denise, D'Andrea, Harold, Szerlip, Thomas R., Kleyman,
  • Can compete with creatinine for secretion into the renal tubule. This can cause an artificial rise in the serum creatinine.JOURNAL, Effects of moderate-dose versus high-dose trimethoprim on serum creatinine and creatinine clearance and adverse reactions, Antimicrobial Agents and Chemotherapy, 1997-11-01, 0066-4804, 164146, 9371351, 2466–2470, 41, 11, O., Naderer, A. N., Nafziger, J. S., Bertino, 10.1128/AAC.41.11.2466,
  • Use in EHEC infections may lead to an increase in expression of Shiga toxin.JOURNAL, Kimmitt PT, Harwood CR, Barer MR, Toxin Gene Expression by Shiga Toxin-producing Escherichia coli: The Role of Antibiotics and the Bacterial SOS Response, Emerg Infect Dis, 2000, 6, 5, 458–465, 10998375, 2627954, 10.3201/eid0605.000503,

Contraindications

Liver and kidney problems

10-20% of trimethoprim is metabolized by the liver and the rest is excreted in the urine. Therefore, trimethoprim should be used with caution in individuals with kidney and liver impairments. Dosage adjustment is not needed for liver impairment but should be adjusted for kidney impairment.WEB, DailyMed - TRIMETHOPRIM- trimethoprim tablet,weblink dailymed.nlm.nih.gov, 2015-11-04, no,weblink" title="web.archive.org/web/20150930162821weblink">weblink 2015-09-30,

Pregnancy

Based on studies that show that trimethoprim crosses the placenta and can affect folate metabolism, there has been growing evidence of the risk of structural birth defects associated with trimethoprim, especially during the first trimester of pregnancy.JOURNAL, Trimethoprim-sulfonamide combination therapy in early pregnancy., Canadian Family Physician, 2003-09-01, 0008-350X, 2214286, 14526858, 1085–1086, 49, Anna, Sivojelezova, Adrienne, Einarson, Samar, Shuhaiber, Gideon, Koren, It may be involved in a reaction similar to disulfiram when alcohol is consumed after it is used, in particular when used in combination with sulfamethoxazole.JOURNAL, Edwards DL, Fink PC, van Dyke PO, Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole, J Clinical Pharmacy, 1986, 5, 12, 999–1000, 3492326,weblink no,weblink" title="web.archive.org/web/20090124113327weblink">weblink 2009-01-24, JOURNAL, Heelon MW, White M, Disulfiram cotrimoxazole reaction, J Pharmacotherapy, 1998, 18, 4, 869–870, 9692665,weblink no,weblink" title="web.archive.org/web/20090124113456weblink">weblink 2009-01-24, The trophoblasts in the early fetus are sensitive to changes in the folate cycle. A recent study has found a doubling in the risk of miscarriage in women exposed to trimethoprim in the early pregnancy.JOURNAL, Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen EW, Andersen NL, Afzal S, Torp-Pedersen C, Keiding N, Poulsen HE, Trimethoprim use in early pregnancy and the risk of miscarriage: a register-based nationwide cohort study, Epidemiology and Infection, 2013, 141, 8, 1749–1755, 10.1017/S0950268812002178, 23010291,weblink no,weblink" title="web.archive.org/web/20130929103010weblink">weblink 2013-09-29,

Mechanism of action

(File:Wild-type staphylococcus aureus DHFR in complex with NADPH and trimethoprim.gif|thumb|upright=1.25|Staphylococcus aureus DHFR in complex with NADPH and trimethoprim PDB entry {{PDBe|2W9G}} JOURNAL, Heaslet, H., Harris, M., Fahnoe, K., Sarver, R., Putz, H., Chang, J., Subramanyam, C., Barreiro, G., Miller, J. R., 10.1002/prot.22383, Structural comparison of chromosomal and exogenous dihydrofolate reductase fromStaphylococcus aureusin complex with the potent inhibitor trimethoprim, Proteins: Structure, Function, and Bioinformatics, 76, 3, 706–717, 2009, 19280600, )Trimethoprim binds to dihydrofolate reductase and inhibits the reduction of dihydrofolic acid (DHF) to tetrahydrofolic acid (THF). THF is an essential precursor in the thymidine synthesis pathway and interference with this pathway inhibits bacterial DNA synthesis. Trimethoprim's affinity for bacterial dihydrofolate reductase is several thousand times greater than its affinity for human dihydrofolate reductase. Sulfamethoxazole inhibits dihydropteroate synthase, an enzyme involved further upstream in the same pathway. Trimethoprim and sulfamethoxazole are commonly used in combination due to possible synergistic effects, and reduced development of resistance.JOURNAL, Brogden, RN, Carmine, AA, Heel, RC, Speight, TM, Avery, GS, Trimethoprim: a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections., Drugs, June 1982, 23, 6, 405–30, 10.2165/00003495-198223060-00001, 7049657, This benefit has been questioned.JOURNAL, Brumfitt, W, Hamilton-Miller, JM, Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines, Journal of Chemotherapy, December 1993, 5, 6, 465–9, 8195839,
missing image!
- THFsynthesispathway.png -
Tetrahydrofolate synthesis pathway|none|upright=1.25

History

Trimethoprim was first used in 1962. In 1972, it was used as a prophylactic treatment for urinary tract infections in Finland.

See also

{{Clear right}}

References

{{reflist}}

External links

{{Sulfonamides and trimethoprim}}


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