Drug‐induced ototoxicity: Mechanisms, Pharmacogenetics, and protective strategies

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Ototoxic drugs and chemicals cause functional impairment and/or cellular degeneration of tissues of the inner ear. Cochleotoxicity is defined as damage affecting the auditory system and results in tinnitus and/or sensorineural hearing impairment. Vestibulotoxicity is caused by injury to the vestibular system and manifests in dizziness, vertigo, and loss of balance.1 The symptoms can arise during or after the end of therapy. They are typically bilaterally symmetric or asymmetric, with one ear being affected later. More than 150 drugs are currently known to be ototoxic. These include aminoglycosides, glycopeptide and macrolide antibiotics, platinum‐based anticancer drugs, loop diuretics, quinine, and salicylate analgesics.2Table13 presents a selection of known ototoxic drugs.
Ototoxicity is usually permanent, however, a mechanism of reversibility based on animal studies and some cases in humans proposes that initial damage to the marginal cells of the stria vascularis (for example, through cisplatin) may recover if reparative processes are allowed to occur. If not, further accumulation of toxic medication exhausts the chances of recovery, leading to permanent destruction of the outer hair cells (OHCs) and concomitant permanent hearing loss.8
Ototoxicity of loop diuretics, macrolide antibiotics, and quinine usually vanishes when the treatment is stopped.9 The ototoxicity of salicylate analgesics occurs in the event of an overdose and recedes after the medication is discontinued.11 Platinum drugs, especially cisplatin, and aminoglycosides irreversibly damage the inner ear.12 Permanent hearing impairment significantly impacts patients' quality of life and leads to considerable follow‐up costs. Follow‐up costs of $300,000 were estimated per adult who acquired permanent hearing impairment due to ototoxic medication.13 Hearing impairment is especially deleterious for children before and during language acquisition, because it adversely affects their psychosocial development and education.14 For children who experienced permanent hearing impairment before speech acquisition, the estimated follow‐up costs increase to $1,000,000.13 Deaf people or people with hearing impairment are often socially and economically disadvantaged.15 Tinnitus can also be related to considerable distress, anxiety, depression, and reduced quality of life.16 Vestibular disorders are also often comorbid with panic, agoraphobia, and depression.17
So far, research mainly focuses on ototoxicity induced by platinum‐based anticancer drugs, especially cisplatin, and aminoglycosides. In vivo studies on the pathomechanism of drug‐induced ototoxicity were exclusively investigated in animal models and then related to the clinical manifestations of ototoxicity observed in humans.
Information on mechanisms of ototoxicity as well as common and individual risk factors for ototoxicity allows the development of strategies to prevent these life‐long disabling side effects.
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