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Aminoglycosides cause nephrotoxicity, and the relative toxicity of the various aminoglycosides can be corre-lated with the number of constituent amine groups that each contains; neomycin is the most nephrotoxic and streptomycin is the least. Although their polycationic structure prevents their entry into most cells, aminogly-cosides can diffuse from the tubular lumen across the apical membrane of proximal renal tubular cells follow-ing drug filtration through the glomerulus. Passage of the aminoglycosides across the apical membrane occurs via a saturable process of adsorption of polycationic aminoglycoside molecules to the proximal renal tubular lumen’s anionic brush border and subsequent endocy-tosis and accumulation in lysosomes.
Once the drug is within the lysosomes, it will bind to anionic phospholipids, inhibiting lysosomal phospholi-pase A2. This leads to lysosomal distension, rupture, and release of acid hydrolases and the aminoglycoside into the cytosol. Free aminoglycoside then binds to other cellular organelles. Gentamicin accumulation in mito-chondria displaces Ca++ , leading to mitochondrial de-generation and cell necrosis. The necrotic cellular debris then sloughs off and is passed in the urine, leaving a de-nuded basement membrane. The development of toxicity depends upon the duration of aminoglycoside therapy and the mean trough blood plasma drug con-centration. Nephrotoxicity is more likely in aminogly-coside-treated patients with gram-negative bacillary bacteremia than in those with staphylococcal bac-teremia. Nephrotoxicity is most common and most se-vere in patients with extrahepatic biliary obstruction, hepatitis, or cirrhosis.
The severity of aminoglycoside nephrotoxicity is ad-ditive with that of vancomycin, polymixin, gallium, furosemide, enflurane, cisplatin, and cephalosporins. Aminoglycoside nephrotoxicity is synergistic with that of amphotericin B and cyclosporine.
Even quite severe aminoglycoside-induced nephro-toxicity is nearly always reversible upon prompt discontinuation of the drug. Verapamil and Ca++ can lessen the nephrotoxicity, but the latter may also inhibit the antibacterial effect of the aminoglycosides. Polyaspartic acid is a promising new agent that lessens aminoglyco-side nephrotoxicity, although it also may partially in-hibit the drug’s antibacterial activity.
Aminoglycosides accumulate in otolymph and can cause both vestibular and auditory ototoxicity, both of which can be irreversible. Uptake is driven by the con-centration gradient between blood and the otolymph; this process is saturable. Sustained high concentrations in otolymph first destroy hair cells that are sensitive to high-frequency sounds. Streptomycin is more likely to cause vestibular toxicity than ototoxicity. The severity of aminoglycoside-induced ototoxicity is worsened by the coadministration of vancomycin, furosemide, bumetanide, and ethacrynic acid. Ca++ may lessen the ototoxic effect.
Aminoglycosides can cause neuromuscular junction blockade by displacing Ca++ from the neuromuscular junction, inhibiting the Ca++ -dependent prejunctional release of acetylcholine and blocking postsynaptic acetylcholine receptor binding. This is usually clinically significant only in patients with myasthenia gravis, hypocalcemia, or hypermagnesemia or when the amino-glycoside is given shortly after the use of a neuromuscu-lar blocking agent. The neuromuscular blockade can be reversed by administration of intravenous calcium
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