Trimethoprim inhibition

Procainamide 12-1 7 mg/kg, no faster than 20 mg/minute 1-4 mg/minute Cimetidine, ranitidine, and trimethoprim inhibit procainamide elimination... 

Trimethoprim Trimethoprim Inhibits folic acid synthesis by Used in combination with... 

The answer is c. (Hardman, pp 1058-1059. Katzung, pp 793-795.) Trimethoprim inhibits dihydro folic acid reductase. Sulfamethoxazole inhibits p-aminobenzoic acid (PABA) from being incorporated into folic acid by competitive inhibition of dihydropteroate synthase. Either action inhibits the synthesis of tetrahydrofolic acid. 

Trimethoprim inhibits bacterial DHF reductase, the human enzyme being significantly less sensitive than the bacterial one (rarely bone marrow depression). A 2,4-diaminopyrimidine, trimethoprim, has bacteriostatic activity against a broad spectrum of pathogens. It is used mostly as a component of co-trimoxazole. 

Both the sulfonamides and trimethoprim interfere with bacterial folate metabolism. For purine synthesis tetrahydrofolate is required. It is also a cofactor for the methylation of various amino acids. The formation of dihydrofolate from para-aminobenzoic acid (PABA) is catalyzed by dihydropteroate synthetase. Dihydrofolate is further reduced to tetrahydrofolate by dihydrofolate reductase. Micro organisms require extracellular PABA to form folic acid. Sulfonamides are analogues of PABA. They can enter into the synthesis of folic acid and take the place of PABA. They then competitively inhibit dihydrofolate synthetase resulting in an accumulation of PABA and deficient tetrahydrofolate formation. On the other hand trimethoprim inhibits dihydrofolate... 

Lamivudine is associated with an increased risk of pancreatitis in children and should be used with great caution in children who have had pancreatitis or are at high risk for it. Dosage adjustment is necessary in patients with renal impairment. Lamivudine should not be used in combination with zalcitabine, because they inhibit each other s activation by phosphorylation. Trimethoprim inhibits the renal elimination of lamivudine. 

Whereas the sulfonamides and sulfones inhibit the initial step whereby PABA and the pteridine moiety combine to form dihydropteroic acid (see Chapter 44), pyrimethamine and trimethoprim inhibit the conversion of dihydrofolic acid to tetrahydrofoUc acid, a reaction... 

As indicated earher, sulfonamides are effective in both gram-positive and gramnegative bacteria. Mostly prescribed for humans in the United States, in this class is sulfamethoxazole, mostly in combination with trimethoprim (SMZ-TMP) in a 5 1 ratio. Trimethoprim inhibits dihydropholic acid reductase and this, just like sulfonamides, also interferes with the synthesis of folic acid (Fig. 1.8). As a matter of fact, use of the combined SMZ-TMP has been steadily increasing recently as is displayed by the number of prescriptions (Fig. 1.7). Oral doses of sulfonamides are absorbed well and eliminated by the liver and kidney with 20-60% excreted as the parent compound (Queener and Gutierrez, 2003). 

Oxidation of acetaldehyde is inhibited by disulfiram, a drug that has been used to deter drinking by alcohol-dependent patients undergoing treatment. When ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache. Several other drugs (eg, metronidazole, cefotetan, trimethoprim) inhibit ALDH and can cause a disulfiram-like reaction if combined with ethanol. 

FIGURE 33-2 Folic acid metabolism in bacterial cells. Certain antibacterial drugs [e.g., sulfonamides and trimethoprim] inhibit the dihydrofolate synthetase and reductase enzymes, thus interfering with DNA biosynthesis. 

METHOTREXATE SULFAMETHOXAZOLE/ TRIMETHOPRIM t plasma concentrations of methotrexate and risk of toxic effects of methotrexate, e.g. myelosuppression, liver cirrhosis, pulmonary toxicity Sulfamethoxazole displaces methotrexate from plasma protein-binding sites and also 1 renal elimination of methotrexate. Trimethoprim inhibits dihydrofolate reductase, which leads to additive toxic effects of methotrexate Avoid concurrent use. If concurrent use is necessary, monitor clinically and biochemically for blood dyscrasias and liver, renal and pulmonary toxicity... 

A widely available fixed combination is co-trimoxazole (Bactrim, Eusaprim, Septrin), which contains trimethoprim and sulfamethoxazole in a ratio of 1 5. Both trimethoprim and sulfamethoxazole have favorable and comparable pharmacokinetics and the combination is bactericidal (4). Synergy between trimethoprim and sulfonamides has conventionally been ascribed to sequential inhibition of dihydropteroate synthetase by sulfonamides (in competition with pora-aminobenzoic acid) and of dihydrofolate reductase by trimethoprim (in competition with dihydrofolate). However, sulfonamides in high concentrations also inhibit dihydrofolate reductase. Thus, an initial partial sequential blockade by trimethoprim (inhibition of dihydrofolate reductase) and sulfonamides (inhibition of dihydropteroate synthetase) leads to defective protein synthesis and cytoplasmic damage, which in turn results in marked increases in the uptake of both agents and double strength inhibition of dihydrofolate reductase (5). 

Trimethoprim inhibits the active tubular secretion of procainamide (198). 

SchlangerLE, KleymanTR, Ling BN. K(+)-sparlng diuretic actions of trimethoprim Inhibition of Na+channels In A6 distal nephron cells. Kidney International. 1994 Apr 45(4) l 070-6. 

Co-trimoxazole is a mixture of sulphamethoxazole (five parts) and trimethoprim (one part). The reason for using this combination is based upon the in vitro finding that there is a sequential blockade of folic acid synthesis, in which the sulphonamide is a competitive inhibitor of dihydropteroate synthetase and trimethoprim inhibits DHFR (see Chapter 12). The optimum ratio of the two components may not... 

Sequential biochemistry interactions also fall within this category. Sulfamethoxazole and trimethoprim inhibit different stages of the folate metabolism pathway. Concomitant administration reduces the probability that a bacterial strain can mutate in any single step to evade the antibiotic effects of both drugs. 

D. Bacteria must synthesize the folate that is required for their biosynthetic processes they do not have a transporter to bring folate into the cell. Trimethoprim inhibits prokaryotic DHFR (eukaryotic is not affected) and sulfamethoxazole is an analog of p-aminobenzoic acid (PABA), a precursor to folic acid. Bacteria will use this analog instead of PABA and produce a nonfunctional folate. 

Co-trimoxazole (Septrin) is a well-known combination of a sulfonamide (sulfamethoxazole) with trimethoprim. This combination inhibits enzymes at two points of folic acid (32.2) utilisation - the sulfonamide inhibits incorporation of p-aminobenzoic acid during bacterial folic acid synthesis, and trimethoprim inhibits its conversion into tetrahydrofolate. The overall result is synergistic, i.e. there is a greater activity than the sum of the two components. 

Schlanger LE, Kleyman TR, Ling BN. K-F-sparing diuretic actions of trimethoprim inhibition of Na-F channels in A6 distal nephron cells. Kidney Int 1994 45 1070-1076. 

Trimethoprim inhibits another enzyme, dihydrofolate reductase, in the same folic acid metabolic pathway. Folic acid is converted into folate, which then has to be converted into an activated form by dihydrofolate reductase. In this way, trimethoprim interferes with the conversion of folate into its activated form, which is a cofactor in the synthesis of bacterial DNA. Dihydrofolate reductase also occurs in host cells, but it is less sensitive to trimethoprim. Trimethoprim is used to treat urinary tract infections. It is also formulated in combination with a sulphonamide, when it is known as co-trimoxazole, to treat pneumonia in patients with HIV (see page 170). Due to the synergistic effect of the two drugs, this combination is more effective than either drug alone. 

Figure 7.15 Sulfonamides and trimethoprim inhibit different sites in the folate pathway. This results in decreased tetrahydrofolic acid cofactors which are essential in the formation of DNA, RNA and protein.

Sulfamethoxazole displaces methotrexate from plasma protein-binding sites and also i renal elimination of methotrexate. Trimethoprim inhibits dihydrofolate reductase, which leads to additive toxic effects of methotrexate... 

The manufacturer of dofetilide notes that trimethoprim 160 mg (in combination with sulfamethoxazole 800 mg) twice daily given with dofetilide 500 micrograms twice daily for 4 days increased dofetilide peak levels by 93% and AUC by 103%. Trimethoprim inhibits the active renal tubular secretion mechanism by which dofetilide is eliminated, so reducing its loss from the body (see also Dofetilide + H2-receptor antagonists , p.255). There is a linear relationship between plasma dofetilide concentrations and prolongation of the QT interval, which increases the risk of torsade de pointes arrhythmia. For this reason, the manufacturer contraindicates the use of trimethoprim in patients on dofetilide. This would seem to be a prudent precaution. 

ML. Trimethoprim inhibition of the renal clearance of procainamide N-acetylprocaina-... 

A likely reason is that the trimethoprim inhibits the secretion of both zidovudine and its glucuronide by the kidney tubules. It is not known why the half-life of co-trimoxazole is increased. The other NRTTs that interact are likely to do so by the same mechanism. 

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