METHENAMINE MANDELATE, METHENAMINE HIPPURATE
Chemistry - Methenamine is chemically unrelated to other anti-infective agents. It is commerciallyavailable in two salts, methenamine mandelate and methenamine hippurate. Methenamine mandelateoccurs as a white, crystalline powder and contains approximately 48% methenamine and 52%mandelic acid. It is very soluble in water. Methenamine hippurate occurs as a white, crystallinepowder with a sour taste and contains approximately 44% methenamine and 56% hippuric acid. Itis freely soluble in water.
Formaldehyde is a non-specific antibacterial agent that exerts a bactericidal effect. It has activity ona variety of bacteria, including both gram positive (Staphylococcus aureus, S. epidermidis,
Enterococcus) and gram negative organisms (E. Coli, Enterobacter, Klebsiella, Proteus, and Pseudomonas aeruginosa). Reportedly, methenamine also has activity against fungal urinary tractinfections.
Mandelic acid or hippuric acid are added primarily to help acidify the urine, but they also havesome non-specific antibacterial activity. Bacterial resistance to formaldehyde, mandelic acid orhippuric acid does not usually occur.
Within 24 hours, 70-90% of a dose is excreted unchanged into the urine. In an acidic urine, conversion to ammonia and formaldehyde takes place, maximal hydrolysis occurs at urine pH's of5.5 or less. Peak formaldehyde concentrations occur in the urine at about 2 hour post-dose (3-8hours with enteric-coated tablets)
While methenamine crosses the placenta and lab animal studies have not demonstrated any teratogenic effects, it should be used with caution during pregnancy. Methenamine enters milk and canpotentially cause adverse effects; its use in nursing mothers should be carefully considered.
Because methenamine requires an acid urine to be beneficial, urine pH should be kept at or below5.5. Some urea-splitting bacteria (e.g., Proteus and some strains of Staphylococci, Enterobacter and Pseudomonas) may increase urine pH. Addition of a urinary acidification program may be requiredusing dietary modification and acidifying drugs (e.g., ascorbic acid, methionine, sodiumbiphosphate, ammonium chloride).
Overdosage, Acute Toxicity - Dogs have received single IV dosages of up to 600 mg/kg ofmethenamine hippurate without overt toxic effects. Large oral overdoses should be handled usingestablished gut emptying protocols, maintaining hydration status and supporting as required.
Use of methenamine with sulfamethiazole is not recommended. An insoluble precipitate mayform.
Laboratory Considerations - Urinary values of the following compounds may be falsely elevated: catecholamines, vanilmandelic acid (VMA), 17-hydrocorticosteroid. Falselydecreased urinary values of estriol or 5-HIAA may occur.
Storage, Stability, Compatibility
Commercially available methenamine products should bestored at room temperature. As methenamine is hydrolyzed by acids to formaldehyde and ammonia, do not mix with acidic vehicles before administering. Methenamine is also incompatible with mostalkaloids and metallic salts (e.g., ferric, mercuric or silver salts). Ammonium salts or alkalis willdarken methenamine.Pharmacology - METHENAMINE MANDELATE, METHENAMINE HIPPURATE
In an acidic urinary environment, methenamine is converted to formaldehyde.Formaldehyde is a non-specific antibacterial agent that exerts a bactericidal effect. It has activity ona variety of bacteria, including both gram positive (Staphylococcus aureus, S. epidermidis,
Enterococcus) and gram negative organisms (E. Coli, Enterobacter, Klebsiella, Proteus, and Pseudomonas aeruginosa). Reportedly, methenamine also has activity against fungal urinary tractinfections.
Mandelic acid or hippuric acid are added primarily to help acidify the urine, but they also havesome non-specific antibacterial activity. Bacterial resistance to formaldehyde, mandelic acid orhippuric acid does not usually occur.
Uses, Indications
Methenamine is used as an antimicrobial agent for the treatment and prophylaxis of recurrent urinary tract infection.Pharmacokinetics - METHENAMINE MANDELATE, METHENAMINE HIPPURATE
Human data: While methenamine and it salts are well absorbed from the GItract, up to 30% of a dose may be hydrolyzed by gastric acid to ammonia and formaldehyde. Withenteric-coated tablets the amount hydrolyzed in the gut is reduced. While absorbed, plasmaconcentrations of both formaldehyde and methenamine are very low and have negligible systemicantibacterial activity. Methenamine does cross the placenta and is distributed into milk.Within 24 hours, 70-90% of a dose is excreted unchanged into the urine. In an acidic urine, conversion to ammonia and formaldehyde takes place, maximal hydrolysis occurs at urine pH's of5.5 or less. Peak formaldehyde concentrations occur in the urine at about 2 hour post-dose (3-8hours with enteric-coated tablets)
Contraindications, Precautions, Reproductive Safety
Methenamine and its salts are contraindicated in patients known to be hypersensitive to it, with renal insufficiency, severe hepaticimpairment (due to ammonia production) or severe dehydration.While methenamine crosses the placenta and lab animal studies have not demonstrated any teratogenic effects, it should be used with caution during pregnancy. Methenamine enters milk and canpotentially cause adverse effects; its use in nursing mothers should be carefully considered.
Adverse Effects, Warnings
The most likely adverse effect noted is gastrointestinal upset, withnausea, vomiting, and anorexia predominant. Some patients may dysuria probably secondary toirritation secondary to high formaldehyde concentrations. Lipoid pneumonitis has been reported insome humans receiving prolonged therapy with the suspension.Because methenamine requires an acid urine to be beneficial, urine pH should be kept at or below5.5. Some urea-splitting bacteria (e.g., Proteus and some strains of Staphylococci, Enterobacter and Pseudomonas) may increase urine pH. Addition of a urinary acidification program may be requiredusing dietary modification and acidifying drugs (e.g., ascorbic acid, methionine, sodiumbiphosphate, ammonium chloride).
Overdosage, Acute Toxicity - Dogs have received single IV dosages of up to 600 mg/kg ofmethenamine hippurate without overt toxic effects. Large oral overdoses should be handled usingestablished gut emptying protocols, maintaining hydration status and supporting as required.
Drug Interactions
Use of urinary alkalinizing drugs (e.g., calcium or magnesiumcontaining antacids, carbonic anhydrase inhibitors, citrates, sodium bicarbonate, thiazide diuretics) may reduce the efficacy of the methenamine.Use of methenamine with sulfamethiazole is not recommended. An insoluble precipitate mayform.
Laboratory Considerations - Urinary values of the following compounds may be falsely elevated: catecholamines, vanilmandelic acid (VMA), 17-hydrocorticosteroid. Falselydecreased urinary values of estriol or 5-HIAA may occur.