Ototoxicity is a capacity of a drug or therapeutic agent to damage inner ear (auditory and/or vestibular) structure and/or function producing symptoms like hearing loss, tinnitus, dizziness etc. Ototoxicity came into attention when Streptomycin used for the treatment of tuberculosis in 1944 caused the toxicity of the inner ear.
Ototoxic Agents
Aminoglycosides
- Primarily cochleotoxic:- Amikacin, Kanamycin, Neomycin
- Primarily vestibulotoxic:- Streptomycin, Gentamicin, Tobramycin
Anti-neoplastic drugs like Cisplatin and Carboplatin(less toxic).
Loop diuretics like Furosemide, Bumetanide, Ethacrynic acid, Torsemide(less toxicity)
Salicylates like Aspirin
Drugs like Quinines and Deferoxamine(iron-chelating agent)
Other antibiotics like Macrolides and Vancomycin
Agents like Mercury, Ethyl alcohol, Chlorhexidine, Arsenic, Difluoromethylornithine (anti-tumor agent) etc.
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Aminoglycosides
Toxicity depends on the uptake of aminoglycosides facilitated by mechanotransducer channel, Transient Receptor Potential A1(TRPA1).Drugs reaching the hair cells reacts with iron to form ototoxic complex(OC) which reacts with oxygen to form reactive oxygen species(ROS) which causes irreversible destruction of the outer hair cells in the basal turn of the cochlea(apex and inner hair cells have anti-oxidant Glutathione), with progression towards the apex as the dose and duration of the treatment are increased.
In the vestibular apparatus, type I hair cells in the apex of the cristae and striola regions of the macula are affected more.
Risk factors
- Renal insufficiency
- Larger dose and longer duration therapy
- Older age
- Genetic susceptibility: – Mitochondrial 12S rRNA mutation making human RNA similar to bacterial.
Signs and symptoms
- Cochlear: – Tinnitus, high frequency hearing loss initially followed by low frequency.
- Vestibular:- Imbalance, ataxia, visual symptoms like oscillopsia, nystagmus.
Drugs are less cleared from inner ear, so should be monitored for 1-3 weeks after the cessation of the drugs.
Toxicity can be reduced using otoprotective drugs like N-acetyl cysteine, Dexamethasone, given before and after the treatment.
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Anti-neoplastic Drugs
Cisplatin activates the enzyme nicotinamide adenine dinucleotide phosphate oxidase (NOX-3) forming superoxides (ROS) which forms H2O2. H2O2 reacts with iron to form reactive hydroxyl free radical which in turn,
- Damages the cuticular plate of outer hair cells and loss of vestibular sensory cells.
- Degenerates the spiral ganglion cells and cochlear neurons (NOT vestibular).
- Damages the striae vascularis(high doses).
Risk factors
- Children < 5 years and old age
- Renal insufficiency
- Cranial irradiation
- Other ototoxic drugs
Signs and symptoms
- Otalgia
- Transient tinnitus
- Subjective SN hearing loss, usually irreversible and bilateral, first at high frequency followed by low frequency as the therapy continues.
Toxicity can be seen in dose > 1mcg/L. Toxicity can be reduced by slow infusion and dividing the doses rather than bolus injection. Otoprotectants such as Amifostine and Sodium thiosulfate are given during therapy.
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Loop Diuretics
Striae vascularis has sodium/potassium/chloride transporter on which it acts as in kidney. So, loop diuretics cause changes in ionic gradients between perilymph and endolymph which causes edema of the epithelium of striae vascularis affecting fluid transport within inner ear.
These drugs have high GI uptake as 65% in an oral form and long plasma half-life as 3 hours in renal failure, so causes hearing disturbances when >50mg/L.
Signs and symptoms
Hearing loss (mostly temporary and reversible). Hearing loss is permanent in premature infant with furosemide.
Low dose and slow infusion rate prevents toxicity to some extent.
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Salicylates
Salicylates cause only temporary metabolic effect by changes in the stiffness of the lateral membrane of the outer hair cells and changes in the blood flow, without causing death of cells or neurons.
Signs and symptoms
- Tinnitus
- Hearing loss(bilateral and reversible within 24 hours)
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Diagnosis
- Cochleotoxicity: – Diagnosis is made based on patient’s history, symptoms and test results. Clinically, diagnosed by comparing the hearing loss by pure tone audiometry before and after the administration of the ototoxic drugs.
- Vestibulotoxic: – Vestibular testing as caloric testing, VEMP and MNG are performed. Other tests include vestibulo-ocular reflex tests such as dynamic visual acuity testing (eye chart test), head thrust testing etc.
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Management
- Consult an audiologist for assessment of hearing and search alternative drug to minimize further damage.
- Aural rehabilitations such as amplification devices/cochlear implants/assistive listening devices for hearing loss to maintain patient’s communication capabilities.
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References
- Cummings Otolaryngology: Head and Neck Surgery, 6th edition
- Ballenger’s Otorhinolaryngology: Head and Neck Surgery, 15th edition
- Ototoxicity, Wikipedia
- Ototoxicity: A Challenge in Diagnosis and Treatment by Ganesan P, Schmiedge J, Manchaiah V, Swapna S, Dhandayutham S, Kothandaraman PP.
- Research journals by The American Speech-Language-Hearing Association (ASHA)
- Katzung and Trevors’ Basic and Clinical Pharmacology , 13th edition, McGraw-Hill Education
