Trimethoprim


Trimethoprim
Trimethoprim
Systematic (IUPAC) name
5-(3,4,5- trimethoxybenzyl) pyrimidine- 2,4- diamine
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a684025
Pregnancy cat. B3(AU) C(US)
Legal status Prescription Only (S4) (AU) POM (UK)
Routes Oral
Pharmacokinetic data
Bioavailability 90–100%
Metabolism hepatic
Half-life 8–10 hours
Excretion renal 50–60%
Identifiers
CAS number 738-70-5 YesY
ATC code J01EA01 QJ51EA01
PubChem CID 5578
DrugBank DB00440
ChemSpider 5376 YesY
UNII AN164J8Y0X N
KEGG D00145 YesY
ChEBI CHEBI:45924 N
ChEMBL CHEMBL22 YesY
Chemical data
Formula C14H18N4O3 
Mol. mass 290.32 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Trimethoprim (INN) (play /trˈmɛθəprɪm/) 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.

Contents

Mechanism of action

Tetrahydrofolate synthesis pathway

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 causing, in certain circumstances, cell lethality due to thymineless death. This drug was developed by George H. Hitchings and collaborators, who shared the Nobel Prize for Physiology or Medicine in 1988 for the discovery of antifolates.[2]

Co-trimoxazole

Trimethoprim was commonly (from 1969 to 1980 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 below). 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.[3][4]

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,[5][6][7][8] and side effects of antibacterial sulfonamides. As a consequence, the use of co-trimoxazole was restricted in 1995 [9] 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, and parasites remains indicated for some infections, see above.)

Contraindications and reactions

Trimethoprim can cause thrombocytopenia (low levels of platelets) by lowering folic acid levels; this may also cause megaloblastic anemia. Trimethoprim antagonises the epithelial sodium channel (ENaC) in the distal tubule, thus acting like amiloride, this can cause hyperkalemia. Trimethoprim also competes with creatinine for secretion into the renal tubule, this can cause an artefactual rise in the serum creatinine. Use in EHEC infections may lead to an increase in expression of Shiga toxin.[10] Due to the fact that it crosses the placenta and can affect folate metabolism, trimethoprim is relatively contraindicated during pregnancy, especially the first trimester.[11] 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.[12][13]

Chemistry

Trimethoprim syn.png

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

References

  1. ^ de novo synthesis pathway for dTTP
  2. ^ http://nobelprize.org/nobel_prizes/medicine/laureates/1988/press.html
  3. ^ Brumfitt W, Hamilton-Miller JM (December 1993). "Reassessment of the rationale for the combinations of sulphonamides with diaminopyrimidines". J Chemother 5 (6): 465–9. PMID 8195839. 
  4. ^ Brumfitt W, Hamilton-Miller JM (February 1993). "Limitations of and indications for the use of co-trimoxazole". J Chemother 6 (1): 3–11. PMID 8071675. 
  5. ^ Bean DC, Livermore DM, Papa I, Hall LM (November 2005). "Resistance among Escherichia coli to sulphonamides and other antimicrobials now little used in man". J Antimicrob Chemother 56 (5): 962–4. doi:10.1093/jac/dki332. PMID 16150859. http://jac.oxfordjournals.org/cgi/content/full/56/5/962. 
  6. ^ Felmingham D, Reinert RR, Hirakata Y, Rodloff A (September 2002). "Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and compatative in vitro activity of the ketolide, telithromycin". J Antimicrob Chemother 50 (Suppl S1): 25–37. doi:10.1093/jac/dkf808 (inactive 2010-03-20). PMID 12239226. http://jac.oxfordjournals.org/cgi/reprint/50/suppl_2/25. 
  7. ^ Johnson JR, Manges AR, O'Bryan TT, Riley LW (June 29 2002). "A disseminated multidrug-resistant clonal group of uropathogenic Escherichia coli in pyelonephritis". Lancet 359 (9325): 2249–51. doi:10.1016/S0140-6736(02)09264-4. PMID 12103291. 
  8. ^ Lawrenson RA, Logie JW (December 2001). "Antibiotic failure in the treatment of urinary tract infections in young women". J Antimicrob Chemother 48 (6): 895–901. doi:10.1093/jac/48.6.895. PMID 11733475.  - suggest some small advantage in UTIs
  9. ^ "Co-trimoxazole use restricted". Drug Ther Bull 33 (12): 92–3. December 1995. doi:10.1136/dtb.1995.331292. PMID 8777892. 
  10. ^ http://www.cdc.gov/ncidod/EID/vol6no5/kimmett.htm
  11. ^ "Trimethoprim". netdoctor.co.uk. 
  12. ^ 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. http://cat.inist.fr/?aModele=afficheN&cpsidt=8287529. 
  13. ^ Heelon MW, White M (February 17, 1998). "Disulfiram-cotrimoxazole reaction". J Pharmacotherapy 18 (4): 869. http://cat.inist.fr/?aModele=afficheN&cpsidt=2340043. 

External links


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Look at other dictionaries:

  • Trimethoprim — Strukturformel Allgemeines Freiname Trimethoprim Andere Namen …   Deutsch Wikipedia

  • trimethoprim — An antimicrobial agent that potentiates the effect of sulfonamides and sulfones; usually used in combination with sulfamethoxazole. * * * tri·meth·o·prim trī meth ə .prim n a synthetic antibacterial drug C14H18N4O3 used alone esp. to treat… …   Medical dictionary

  • trimethoprim — n. an antibacterial drug that is active against a range of microorganisms; taken by mouth, it is used mainly in the treatment of chronic urinary tract infections and respiratory tract infections. Long term treatment may cause anaemia due to… …   The new mediacal dictionary

  • trimethoprim — noun Etymology: tri + meth + prim (by shortening & alteration from pyrimidine) Date: 1964 a synthetic antibacterial and antimalarial drug C14H18N4O3 used alone or in combination with sulfamethoxazole …   New Collegiate Dictionary

  • trimethoprim — A drug that inhibits the reduction of dihydrofolate to tetrahydrofolate (a later step than that inhibited by sulphonamides). Selective for some bacterial DHF reductases and often used in conjunction with sulphonamides …   Dictionary of molecular biology

  • trimethoprim — /truy meth euh prim/, n. Pharm. a synthetic crystalline compound, C11H18N4O3, usually combined with a sulfonamide as an antibiotic preparation in the treatment of urinary tract infections and pneumocystis pneumonia. [1960 65; trimetho(xyphenyl) + …   Universalium

  • trimethoprim — noun An antibiotic, 5 (3,4,5 trimethoxybenzyl)pyrimidine 2,4 diamine, used against, among other infections, those of the urinary tract …   Wiktionary

  • trimethoprim — [trʌɪ mɛθə(ʊ)prɪm] noun Medicine a synthetic antibiotic used to treat urinary infections. Origin 1960s: from trimeth(yl) + o(xy ) + p(y)rim(idine) …   English new terms dictionary

  • trimethoprim — tri·meth·o·prim …   English syllables

  • trimethoprim — tri•meth•o•prim [[t]traɪˈmɛθ ə prɪm[/t]] n. pha a synthetic crystalline compound, C11H18N4O3, usu. combined with a sulfonamide as an antibiotic preparation in the treatment of urinary tract infections and pneumocystis pneumonia • Etymology:… …   From formal English to slang


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