70 Ototoxicity

Ototoxicity is the term used to describe damage to the vestibulocochlear apparatus reducing function and caused by the interaction of chemicals, most commonly pharmacotherapeutic agents, with the sensory structures of the vestibule and/or cochlea.

Although there are many ototoxic substances, only a small group of drugs, in common therapeutic use, are regularly associated with ototoxicity:

• Aminoglycoside antibiotics (e.g., gentamicin).

• Chemotherapy agents (e.g., cisplatin).

• Loop diuretics (e.g., frusemide).

• β-Blockers (e.g., propranolol).

• Salicylates (e.g., aspirin).

• Quinine.

• Anticonvulsants (e.g., phenytoin and ethosuximide).

The most frequent agents causing permanent damage are the aminoglycoside antibiotics and the chemotherapeutic agent, cisplatin. Rates of ototoxicity vary from 20 to 50% depending on definitions (particularly the frequencies affected and the amount of hearing loss), duration of use, dose used and the agent in question, with some series quoting a prevalence of 90% for some degree of hearing loss with cisplatin use! This chapter will therefore focus primarily on these agents.

70.1 Aminoglycosides

Since their discovery in the late 1940s, aminoglycoside antibiotics have found widespread use in medicine because of their effectiveness against gram-negative bacteria and mycobacteria, relatively low incidence of bacterial resistance and cost. They exert their antibacterial effect by binding with the 30S ribosomal subunit of prokaryotic cells causing a misreading of the genetic code and an interruption of bacterial protein synthesis. Cell death follows. They are poorly absorbed by the gut and so are usually administered parenterally, or topically as eardrops.

The severity of ototoxicity varies amongst the aminoglycosides: neomycin is considered highly toxic; gentamicin, kanamycin and tobramycin somewhat less; and amikacin and netilmicin are regarded as the least toxic. Aminoglycoside antibiotics tend to be either predominantly cochleotoxic (e.g., neomycin and amikacin) or vestibulotoxic (e.g., gentamicin and tobramycin). The former may relate to the number of free amino groups (−NH₂), the latter to the number of free methyl-amine groups (−NHCH₃). It is not related to any site-specific uptake mechanism or to drug levels in the cochlear and vestibular tissues. Indeed, the severity of gentamicin-induced vestibulotoxicity is the basis of vestibular ablation therapy for the treatment of Ménière’s disease.

Aminoglycosides are excreted by the kidney and the administered dose must be reduced in renal failure. Hypoproteinemia, anaemia, pyrexia and increasing age all increase the chances of ototoxicity. The risk of aminoglycoside ototoxicity is greatly enhanced by the synchronous use of a loop diuretic.

Mutations in the mitochondrial genome are also well-defined risk factors; quite striking is the effect on aminoglycoside ototoxicity of the A1555G mutation in the 12S ribosomal RNA whose carriers may sustain profound deafness after a single injection. This mutation, which is passed on by the mother, pervades all geographic and ethnic groups and may account for deafness in about 20% of patients with aminoglycoside ototoxicity.

70.2 Cisplatin

Cisplatin is a chemotherapeutic agent effective in treating many solid tumours including head and neck cancer. Its anti-tumour effects were discovered serendipitously in the 1960s and appear to be due to its ability to bind to cellular DNA, thereby blocking transcription and cell replication. Cell death usually follows. Unlike the aminoglycosides, cisplatin appears to be exclusively cochleotoxic. Its ototoxic effects are potentiated by hypoproteinemia and anaemia.

70.3 Mechanism of Damage

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