Ototoxic Drugs

Complete Classification (Table 59.1, Scott-Brown's Otorhinolaryngology)

Pathophysiological Classification (3 Groups)

Group 1 - Stria Vascularis Agents (Temporary Threshold Shift)

• Examples: Loop diuretics (furosemide, ethacrynic acid), erythromycin
• Mechanism: Disrupt ion transport in the stria vascularis, altering endolymph composition and the endocochlear potential (EP)
• Effect: Temporary hearing loss - usually reversible upon stopping the drug
• Furosemide produces a selective, dose-dependent reduction in EP; ethacrynic acid produces more severe strial damage and can occasionally cause permanent injury

Group 2 - Outer Hair Cell (OHC) / Tinnitus-Producing Agents (Reversible)

• Examples: Salicylates (aspirin), quinine/chloroquine
• Mechanism:
  • Salicylate blocks the OHC motor protein prestin, which is packed in the basolateral membrane of OHCs and drives electromotility (cochlear amplification). This is completely reversible
  • Quinine at therapeutic doses (200-300 mg/day) causes threshold shifts at all frequencies, likely acting at IHC synapses and blocking nicotinic acetylcholine receptors (alpha9/alpha10 subunits) on hair cells
• Effect: Tinnitus + hearing loss that fully resolves on drug withdrawal

Group 3 - Hair Cell Death (Permanent Damage)

• Examples: Aminoglycosides, cisplatin, organic solvents
• Mechanism: Cause irreversible death of cochlear and vestibular hair cells
• Effect: Permanent sensorineural hearing loss (SNHL) and/or vestibular dysfunction
• In mammals, the organ of Corti does not regenerate hair cells (unlike birds), so damage is permanent

Aminoglycosides - Key Features

• Enter perilymph slowly (peak ~4 hours after systemic injection vs. 15-30 minutes in serum)
• Half-life in the inner ear exceeds 30 days - far longer than serum half-life
• This explains why hearing loss can progress even after the drug is stopped
• Cochleotoxicity typically begins at the basal turn (high-frequency region) and progresses apically, producing a characteristic high-frequency hearing loss first

• Aminoglycosides are taken up specifically into hair cells via cation channels in their apical (endolymphatic) surface
• Inside the cell they generate reactive oxygen species (ROS) and activate caspase-mediated apoptosis pathways
• Supporting cells are largely spared; they expand to close the lesion left by dead hair cells
• Both cochlear and vestibular hair cells are affected - cochleotoxicity (hearing loss) and vestibulotoxicity (oscillopsia, imbalance) can occur together or separately depending on the drug and dosing

• Streptomycin, gentamicin - predominantly vestibulotoxic
• Amikacin, kanamycin, neomycin - predominantly cochleotoxic
• Tobramycin - both

• Renal impairment (reduces drug clearance, raises serum and perilymph levels)
• Concomitant use of other ototoxic drugs (especially loop diuretics - synergistic damage)
• Malnutrition, infection (increase sensitivity)
• Genetic predisposition: Mitochondrial 12S rRNA mutation A1555G (adenosine→guanosine at position 1555) confers profound sensitivity - even a single parenteral injection can cause severe hearing loss. Prevalence ~0.19% in the UK, up to 1% in Chinese, Arab-Israeli and Japanese populations

Cisplatin - Key Features

• Causes severe, often irreversible cochleotoxicity - bilateral, symmetric, high-frequency SNHL
• Damages primarily the outer hair cells (OHCs) and stria vascularis in the basal cochlear turn
• Mechanism: generates intracellular ROS and activates apoptosis; also forms platinum-DNA adducts in hair cells
• Carboplatin is less ototoxic than cisplatin in adults but can be significantly ototoxic in children
• Vestibular damage is less prominent than with aminoglycosides

Loop Diuretics - Key Features

• Ethacrynic acid > furosemide in ototoxic potential
• Cause acute reduction in the endocochlear potential by inhibiting ion transport in the stria vascularis
• Usually reversible, but synergistic with aminoglycosides - concurrent use dramatically increases the risk of permanent damage
• Rapid IV bolus dosing is more dangerous than slow infusion

Vancomycin

• Evidence for independent ototoxicity is limited; most clinical reports involve concurrent use with aminoglycosides
• IV vancomycin is potentially ototoxic; oral vancomycin is not (not absorbed systemically)
• Experimental studies at standard doses show no hair cell loss

Routes of Entry to the Inner Ear

1. Systemic blood supply - the blood-labyrinth barrier (analogous to blood-brain barrier); most drugs enter this way after IV/IM administration
2. Round window membrane - drugs applied to the middle ear (e.g., topical aminoglycosides) can diffuse across the round window into the perilymph; this is also deliberately used clinically (intratympanic gentamicin) to ablate vestibular hair cells in Meniere's disease

Clinical Monitoring

• Baseline and serial pure-tone audiometry (especially high-frequency testing 8-20 kHz, which is affected first)
• Otoacoustic emissions (OAEs) can detect early OHC damage before standard audiogram changes
• Vestibular function testing (caloric, rotational tests) for vestibulotoxic drugs
• Serum drug levels to minimize peak concentrations
• Screen for A1555G mutation before aminoglycoside use where feasible

Cochleotoxic vs Vestibulotoxic Drugs

Aminoglycosides - Spectrum from Most Vestibulotoxic to Most Cochleotoxic

"SGT KAN" - listed from most vestibulotoxic to most cochleotoxic:

• Dihydrostreptomycin also falls in the cochleotoxic group
• Netilmicin is notable for a delayed cochleotoxic effect

Memory tip: "Some Girls Take Knee-length And Neck" - Streptomycin, Gentamicin (vestibulo) → Tobramycin, Kanamycin, Amikacin, Neomycin (cochleo)

Complete Classification Table

Primarily COCHLEOTOXIC

Primarily VESTIBULOTOXIC

Key Points to Remember

• Toxicity is rapid and profound. Rarely used systemically for this reason.

• This is deliberately exploited clinically: intratympanic gentamicin is used to perform a "chemical labyrinthectomy" in disabling Meniere's disease - ablating vestibular hair cells to stop vertigo attacks.

• Causes bilateral, symmetric, high-frequency SNHL. Minimal vestibular damage compared to aminoglycosides.

• Act on the stria vascularis. Effect is temporary unless combined with aminoglycosides, in which case damage becomes synergistic and permanent.

• Cause tinnitus + high-frequency hearing loss that resolves on stopping the drug.

• Falls in the middle of the spectrum; has both properties but cochleotoxicity is slightly dominant.

Why the Difference?

• It is not related to site-specific accumulation of the drug (concentrations are similar in both organs)
• Differences in the intrinsic properties of cochlear vs vestibular hair cells, and possibly differences in antioxidant defenses, likely account for the selective vulnerability
• The pattern is species-independent - the same selectivity is seen across different animal models