TOXICITY
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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