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Drug-induced Ototoxicity

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Abstract

Organ specific toxicity of drugs is now recognised to be a serious problem. This type of toxicity is known to affect the eye, liver, kidney, heart, blood, and bone marrow, as well as the ear. Organ specific toxicity to the ear is usually referred to as ototoxicity. There are many different classes of drugs reported to produce ototoxicity, and the effect ranges from production of permanent deafness to temporary tinnitis. The drugs that are most well known in this regard are the aminoglycoside antibiotics, the salicylate analgesics and quinine and related antimalarials.

Ototoxicity resulting from all of the aminoglycoside drugs is qualitatively similar. However, there are quantitative differences. Aminoglycoside-induced ototoxicity is often complicated by factors related to their absorption and elimination. Because this class of drugs is poorly absorbed from the gastrointestinal tract it is sometimes mistakenly assumed that they are without danger from this route of administration. In fact, the 3 % of the large doses administered orally that is absorbed represents about one-third of the dose that might be administered parenterally. This route of administration can result in ototoxicity, especially in patients with renal disease. Another related problem occurs when these drugs are used to irrigate wounds. It is assumed that, because the drugs are poorly absorbed from intact skin, they are also poorly absorbed when used topically on wounds. In fact, aminoglycoside antibiotics are rapidly absorbed from wounds, and blood levels that are ototoxic can easily be achieved. The sole mechanism for the elimination of the aminoglycoside antibiotics is by renal excretion. Their renal clearance is the same as the renal clearance of creatinine, and thus any impairment of renal excretion of creatinine will be reflected in impaired excretion of the aminoglycoside antibiotic, necessitating appropriate dosage adjustment. Aminoglycoside antibiotic ototoxicity results from rather selective destruction of the sensory hair cells of the organ of Corti. The most sensitive cells are those in the basal turn of the cochlea because high frequency sounds are processed in this region. The initial hearing loss involves high frequency sound. The hair cells are incapable of regeneration so that the ototoxicity is permanent. In general the magnitude of the ototoxicity is related to both the daily dosage and the duration of therapy. A unique feature of the ototoxicity is that it might not be detected during the period of drug administration, but can occur days to weeks after therapy has terminated. Another unique feature of aminoglycoside ototoxicity is that it can be unilateral. Ototoxicity is known to occur in utero when women are given aminoglycoside antibiotics while they are pregnant. Ototoxicity is also reported to occur in experimental animals after the drugs are placed in the middle ear space.

Aminoglycoside antibiotics have been shown to interact with loop-inhibiting diuretics such as ethacrynic acid. This interaction is reported to occur in both man and experimental animals, and can occur with all of the aminoglycoside antibiotics and all of the loop-inhibiting diuretics. (Although such an interaction appears to occur only with loop-inhibiting diuretics, a similar interaction can occur with non-aminoglycoside antibiotics such as viomycin, capreomycin, polymyxin B and even cis-platinum.) This interaction results in the destruction of cochlea hair cells. It appears that there is no such effect on the vestibular portion of the inner ear.

In laboratory animals it has been clearly demonstrated that excessively loud noise, and concurrent administration of aminoglycoside antibiotics, results in augmented ototoxicity. The relationship of these findings to the clinical use of the drugs is not known at this time, but it would seem prudent to keep the noise exposure of patients receiving these drugs to a minimum.

Non-steroidal anti-inflammatory drugs such as aspirin are reported to produce a temporary hearing loss and tinnitis in patients receiving large doses. In most cases both the hearing loss and the tinnitis disappear when drug therapy has been terminated. There are a few cases of permanent ototoxicity reported, but the data are not very convincing. There are no well controlled animal studies that demonstrate permanent cochlea lesions following the administration of these drugs.

Many other types of drugs are reported to be ototoxic. Of these the most serious toxicity appears to be produced by drugs such as quinidine and other antimalarial drugs, and cisplatinum. Other drugs such as nitrogen mustard, 6-aminonicotinamide, viomycin and vancomycin have been reported to produce permanent ototoxicity. Erythromycin, in very large doses, has been reported to produce a temporary hearing loss, and minocycline has been reported to produce temporary unsteadiness.

The iatrogenic nature of drug-induced ototoxicity should be borne in mind by physicians prescribing drugs with such a propensity.

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  1. Kresge Hearing Research Laboratory, University of Oregon Health Sciences Center, Portland, Oregon, 97201, USA

    R. E. Brummett (Associate Professor of Otolaryngology and Pharmacology)

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  1. R. E. Brummett
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Brummett, R.E. Drug-induced Ototoxicity. Drugs 19, 412–428 (1980). https://doi.org/10.2165/00003495-198019060-00002

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