ACETOHYDROXAMIC ACID

Chemistry - An inhibitor of urease, acetohydroxamic acid (also known as AHA, Acetic acid oxime,
N-Acetylhydroxylamide, or N-Hydroxyacetamide) occurs as a white crystal having a pKa of 9.32-9.4 and a pH of about 9.4. In one ml of water, 850 mg is soluble and 400 mg is soluble in one ml of alcohol.

Storage, Stability, Compatibility

Tablets should be stored in tight containers.

Pharmacology - ACETOHYDROXAMIC ACID

AHA inhibits urease, thereby reducing production of urea and subsequent urinaryconcentrations of ammonia, bicarbonate and carbonate. While the drug does not directly reduceurine pH, by reducing ammonia and bicarbonate production by urease-producing bacteria, itprevents increases in urine pH. The drug may act synergistically with several antimicrobial agents(e.g., carbenicillin, gentamicin, clindamycin, trimethoprim/sulfa or chloramphenicol) in treatingsome urinary tract infections. The drug's effects on urinary pH and infection also indirectly inhibitthe formation of urinary calculi (struvite, carbonate-apatite ).
Uses, Indications - Acetohydroxamic acid is used as adjunctive therapy in some cases of recurrentcanine urolithiasis (see pharmacology above) or in the treatment of persistent urinary tractinfections caused by the following bacteria: E. coli, Klebsiella spp., Morganella morganii, Staphylococci spp., Pseudomonas aeruginosa.

Pharmacokinetics - ACETOHYDROXAMIC ACID

No canine specific data was located. In humans, the drug is rapidly absorbedafter PO administration. Absolute bioavailability "in animals" is reported to be 50-60%. AHA iswell distributed throughout body fluids. It is partially metabolized to acetamide which is active. 36-65% of a dose is excreted in the urine unchanged, and 9-14% excreted in the urine as acetamide.
The remainder is reportedly excreted as CO2 via the respiratory tract. It is unknown if AHA isexcreted into milk.

Contraindications, Precautions, Reproductive Safety

AHA is contraindicated in patients with poor renal function (e.g., serum creatinine >2.5 mg/dl) or when it is not specifically indicated (see Indications).
AHA use is considered contraindicated during pregnancy. In pregnant beagles, doses of 25mg/kg/day caused cardiac, coccygeal, and abdominal wall abnormalities in puppies. At high doses(>750 mg/kg), leg deformities have been noted in test animals. Higher doses (1500 mg/kg) caused significant encephalopathologies.

Adverse Effects, Warnings

Potential adverse effects include CNS disturbances (anxiety, depression, tremulousness), GI effects (anorexia, vomiting), hematologic effects (reticulocytosis,
Coombs negative hemolytic anemia, bone marrow depression), phlebitis, and skin rashes/alopecia.
Effects on bilirubin metabolism have also been reported.

Overdosage, Acute Toxicity

In humans, mild overdoses have resulted in hemolysis particularlyin patients with reduced renal function after several weeks of treatment. Acute overdoses would beexpected to cause symptoms such as anorexia, tremors, lethargy, vomiting and anxiety. Laboratoryfindings that would be expected include increased reticulocyte counts, and a severe hemolyticreaction. Treatment for an acute overdose may include intensive hematologic monitoring withadjunctive supportive therapy, including possible transfusions.

Drug Interactions

AHA may chelate iron salts in the gut if given concomitantly. AHA may havea synergistic effect with methenamine in inhibiting the urine pH increases caused by ureaseproducing Proteus spp. AHA may also potentiate the antibacterial effect of methenamine againstthese bacteria. In humans, AHA taken with alcohol has resulted in a rash.
Laboratory Considerations - Although AHA is a true urease inhibitor, it apparently does notinterfere with urea nitrogen determination using either the urease-Berthelot, urease-glutamate dehydrogenase or diacetyl monoxime methods.