AMINOGLYCOSIDES

Toxicokinetics:  These drugs are highly water soluble and poorly lipid soluble. They are poorly absorbed from the gastrointestinal tract following oral administration, but they exhibit excellent absorption from intramuscular and subcutaneous injections.

Elimination occurs by renal processes with little protein binding.

Mechanism of Action:

. Aminoglycosides bind to the bacterial 30s ribosomal subunit and inhibit bacterial protein synthesis, which explains the efficacy of these antibiotics on rapidly growing bacteria.

-The mechanism of action of aminoglycoside-induced nephrotoxicity or ototoxicity. In the mammalian kidney and ear, the aminoglycosides are electrically attracted to the charged phospholipids (phosphatidylinositols).

 Aminoglycosides accumulate in the proximal renal tubular epithelial cells and the endolymph of the ear.

Aminoglycosides are sequestered in the lysosomes and interact with ribosomes and mitochondria to cause cellular death.

Clinical Signs:                    

 The primary syndromes of clinical interest are nephrotoxicosis and ototoxicosis.

 Nephrotoxicosis presents as anorexia, vomiting, and depression as a result of acute renal tubular necrosis.

The ototoxicosis involves damage to cranial nerve VIII (vestibulocochlear), which may cause vestibular or auditory dysfunction. Signs of vestibular dysfunction include nystagmus, incoordination, and loss of righting reflex. Signs of auditory dysfunction include permanent damage to the hair cells of the organ of Corti, with an initial loss of the highfrequency auditory function.

Neuromuscular blockade induced by aminoglycosides is expressed as muscular weakness and respiratory arrest, which is more pronounced under general anesthesia.

Clinical Pathology:

. Aminoglycoside-induced nephrotoxicosis is marked by elevation in serum creatinine, increased serum urea nitrogen, and decreased osmolality.

Urinalysis of animals affected by aminoglycoside-induced nephrotoxicosis reveals granular casts, proteinuria, and low urine specific gravity.

In sheep, the concentration of urinary enzymes, gamma-glutamyltransferase, and beta-N-acetylglucosaminidase precedes other indicators of renal damage.

 In dogs, urine gamma-glutamyl transpeptidase (GGT)-tocreatinine ratio increases 3 times above baseline values before azotemia and other abnormalities occur.

 Lesions. Aminoglycoside-induced nephrotoxicosis is characterized by proximal tubular degeneration and necrosis.

 Diagnostic Testing:. Therapeutic monitoring of the serum concentrations of several of the aminoglycosides can be used to prevent intoxication. Auditory brain stem response may be beneficial to determine loss of hearing in intoxicated animals.

 Treatment: At the first indication of clinical signs, aminoglycoside therapy should be discontinued. Attention to the hydration of the patient is essential for elimination of the aminoglycoside and the animal should be monitored for renal function.

Peritoneal dialysis to remove nitrogenous wastes may be necessary for animals with severe renal injury. The use of a renal vascular vasodilator (misoprostol: 3 µg/kg orally every 8 hours) did not maintain renal function in gentamicin-induced nephrotoxicosis in dogs.

Prognosis.: The nephrotoxicosis may be reversible, depending on the severity of damage. The damage to the vestibulocochlear nerve is permanent and irreversible.