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The aminoglycoside antibiotics are the first ototoxic agents which
highlighted the problem of drug-induced hearing and vestibular loss. They
are highly water soluble compounds and their charge prevents entry into
cells via diffusion across the plasma membrane. The incidence of clinical
and functional hearing loss due to aminoglycosides has been significantly
diminished because some of the newer derivatives have lower ototoxic
potential and perhaps efficient monitoring of serum levels of drugs have
allowed for better dosing schedules. However, the problem is a significant
one as they are still widely used in the treatment of serious gram-negative
infections as pointed out by Schacht.69 The concentration of
aminoglycoside in plasma produced by the initial or loading dose is
dependent only on the volume of the distribution of the drug. Since the
elimination of aminoglycosides is almost entirely dependent on the kidney, a
linear relationship exists between the concentration of creatinine in plasma
and the half-life of all aminoglycosides in patients with moderately
compromised renal function. In anephric patients, the half-life varies from
20 to 40 times that determined in normal individuals. Because the incidence
of nephrotoxicity and ototoxicity is related to the concentration to which
an aminoglycoside accumulates, it is critical to reduce the maintenance
dosage of these drugs in patients with impaired renal function.2
The mechanism of oto- and vestibular toxicity has been elusive. Mechanisms for acute and chronic toxicity may be different. It appears that there is an antagonistic relationship between aminoglycosides and calcium which can block the acute aminoglycoside-induced depression of microphonic potentials experimentally.70 A number of potential synaptic mechanisms are postulated.69 For example, streptomycin blocks the postsynaptic actions of excitatory amino acids on primary afferents in the vestibular system, blocks the glutamate-gated ionophore at the crayfish neuromuscular junction, and antagonizes quisqualate-induced excitation of cortical neurons. The chronic toxicity of aminoglycosides appears to target exclusively the kidney, cochlea, and the vestibular system. Aminoglycosides have been reported to affect a wide variety of intracellular reactions which are probably responsible for the permanent deficits of chronic toxicity. DNA, RNA, and protein synthesis, energy metabolism and ion transport are affected as well as synthesis or degredation of prostaglandins, gangliosides, mucopolysaccharides, and lipids. An important feature is the delayed onset of auditory and vestibular damage in almost all cases of chronic glycoside toxicity, both in experimental animals and as in patients. Early studies of aminoglycoside pharmacokinetics gave rise to the hypothesis that the toxicity of these drugs was based upon their Aaccumulation@ in inner ear fluids. This early hypothesis has been questioned.69,71 It may well be that a metabolite of the aminoglycoside is involved in the toxic action of such drugs. This hypothesis is reviewed in detail by Schacht.69 Drug metabolism may also explain the selective toxicity toward kidney and the inner ear as well as why some aminoglycosides preferentially damage the cochlea, and others the vestibular system. For example, although the vestibular system may have a preference to metabolize vestibulotoxic drugs, it may conversely have a greater capacity to detoxify those aminoglycosides that spare the vestibular system.
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