Trimethoprim

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Trimethoprim
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Systematic (IUPAC) name
5-(3,4,5- trimethoxybenzyl) pyrimidine- 2,4- diamine
Clinical data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
Oral
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability 90–100%
Metabolism hepatic
Biological half-life 8–10 hours
Excretion renal 50–60%
Identifiers
CAS Number 738-70-5
ATC code J01EA01 (WHO) QJ51EA01
PubChem CID 5578
DrugBank DB00440
ChemSpider 5376
Chemical data
Formula C14H18N4O3
Molar mass 290.32 g/mol[[Script error: No such module "String".]]
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Trimethoprim (INN) (pronounced /traɪˈmɛθəprɪm/) is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections. It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors. Trimethoprim was formerly marketed by GlaxoSmithKline under trade names including Proloprim, Monotrim and Triprim; but these trade names have been licensed to various generic pharmaceutical manufacturers. In clinical use it is often abbreviated TRI or TMP; its common laboratory abbreviation is W.

Mechanism of action

Trimethoprim acts by interfering with the action of bacterial dihydrofolate reductase, inhibiting synthesis of tetrahydrofolic acid. Tetrahydrofolic acid is an essential precursor in the de novo synthesis of the intermediate Thymidine monophosphate (dTMP), precursor of DNA metabolite Thymidine triphosphate[1]. Bacteria are unable to take up folic acid from the environment (i.e. the infection host) and are thus dependent on their own de novo synthesis. Inhibition of the enzyme starves the bacteria of nucleotides necessary for DNA replication. This drug was invented by Dr Aaron Goodman, OBE.

Co-trimoxazole

Trimethoprim was commonly (since 1969 in the UK) used in a 1:5 combination with sulfamethoxazole, a sulfonamide antibiotic, which inhibits an earlier step in the folate synthesis pathway (see diagram above). This combination, also known as co-trimoxazole, TMP-sulfa, or TMP-SMX, results in an in vitro synergistic antibacterial effect by inhibiting successive steps in folate synthesis. This claimed benefit was not seen in general clinical use.[2] [3] The combinations use has been declining due to reports of sulfamethoxazole bone marrow toxicity, resistance and lack of greater efficacy in treating common urine and chest infections,[4][5][6][7] and side effects of antibacterial sulfonamides. As a consequence, the use of co-trimoxazole was restricted in 1995 [8] following the availability of trimethoprim (not in combination) in 1980. With its greater efficacy against a limited number of bacteria, Co-trimoxazole remains indicated for some infections; for example, it is used as prophylaxis in patients at risk for Pneumocystis jirovecii pneumonia (e.g. AIDS patients and those with some hematological malignancies) and as therapy in Whipple's disease. Gram positive bacteria are generally or moderately susceptible.

Clinical indications

Trimethoprim, used as monotherapy (since 1980 in the UK), is indicated for the prophylaxis and treatment of urinary tract infections. (Co-trimoxazole, with its greater efficacy against a limited number of bacteria, remains indicated for some infections; (see above))

Contraindications and reactions

Use of trimethoprim is contraindicated during pregnancy, especially the first trimester, and for sufferers of certain blood disorders.[9] It may be involved in a reaction similar to disulfiram when alcohol is consumed after it is used, particularly when used in combination with sulfamethoxazole.[10][11] Trimethoprim can also reduce clearance of creatinine at renal tubules. Additionally, it can also lead to a sometimes dangerously low level of thrombocytes (cells that help blood clot) by lowering folic acid levels and associated bone marrow blood cell formation. Use in EHEC infections may lead to an increase in expression of Shiga toxin.[12]

Chemistry

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Stenbuck, P.; Hood, H. M.; 1962, U.S. Patent 3,049,544.

References

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External links

de:Trimethoprim

es:Trimetoprima fo:Trimethoprim fr:Triméthoprime it:Trimetoprim hu:Trimetoprim ja:トリメトプリム pl:Trimetoprym pt:Trimetoprim sk:Trimetoprim sv:Trimetoprim

th:ไตรเมโทพริม
  1. de novo synthesis pathway for dTTP
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  10. Edwards DL, Fink PC, Van Dyke PO (February 17, 1986). "Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole". J Clinical pharmacy. 5 (12): 999. 
  11. Heelon MW, White M (February 17, 1998). "Disulfiram-cotrimoxazole reaction". J Pharmacotherapy. 18 (4): 869. 
  12. http://www.cdc.gov/ncidod/EID/vol6no5/kimmett.htm