Drug-induced ototoxicity. Pathogenesis and prevention

Ototoxicity is a disabling adverse effect of several widely used classes of drugs, such as diuretics, anti-inflammatory agents, antineoplastic agents and aminoglycoside antibiotics. High-dose therapy with either diuretics or anti-inflammatory agents is primarily associated with acute and transient impairment of hearing or tinnitus. In contrast, long term treatment with antineoplastic agents or aminoglycoside antibiotics is typically associated with delayed and irreversible loss of hearing; lesion in the organ of Corti include the destruction of auditory sensory cells. Vestibular function can also be compromised by ototoxic drugs. Occasional cases of ototoxicity have been reported for a variety of other therapeutic compounds and environmental toxins. In addition, the simultaneous administration of multiple agents which are potentially ototoxic can lead to synergistic loss of hearing. Exposure to loud noise may also potentiate the hearing loss due to cochleotoxic drugs. Ototoxic agents can impair the sensory processing of sound at many cellular or subcellular sites. However, the molecular mechanisms of ototoxicity have not been established for most of these drugs, and structure-toxicity relationships have not been determined. It has therefore been difficult to predict the ototoxic potential of new drugs, and rational approaches to the prevention of ototoxicity are still lacking. The clinical and experimental features of ototoxicity are reviewed for several classes of drugs, with an emphasis on current knowledge of the mechanism and the possibilities for the prevention of ototoxicity for each.