OTOTOXICITY

Dr. Ghulam SaqulainHead Of Department of ENT

Capital Hospital

Close to 200 prescription and OTC medications have ototoxic potential.

“Drug-induced hearing loss accounts for most cases of preventable hearing loss worldwide”

Two categories of medications that have the greatest potential for permanent changes in hearing and or balance are:

aminoglycosides and anti-neoplastic agents.

Others Are: Diuretic- furosemide, ethacrynic acid Salicylate-aspirin antimalarial drug- quinine

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Clinical characteristics of ototoxic deafness

Bilateral hearing lossHearing loss happens at high

frequencyReversible or progressiveWith tinnitus, vertigo

Audiometric Monitoring for Ototoxicity

The only way to detect ototoxicity is by audiometric monitoring of extended

high frequencies, above 8 KHz.

Pathophysiology of Ototoxicity

Hair cells in the inner ear are primarily affected.

In the vestibular system type I hair cells of the crista of the semi-circular canals are targeted

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Semicircular canals:

Superior

Posterior

Lateral

Utricle

Saccule

Cochlea

Stapes

Vestibulocochlear nerve

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Incidence of aminoglycoside Ototoxicity

Incidence ranges 20-33% for commonly used

aminoglycosides while balance is affected in 18% of cases.

Risk Factors

Long term treatment i.e. TB patients Impaired renal function – increases drug half-

life Concomitant use of loop diuretics Genetic – mitochondrial mutations (1555

mutation)

Aminoglycoside Ototoxicity

Streptomycin was the first aminoglycosides antibiotic and the first drug effective against TB.

Discovered by Selman Waksman et al in 1944.

Adverse side effects on the kidney and inner ear (vestibular toxicity) were reported in 1945

Aminoglycoside Ototoxicity

In the last 20 years the use of aminoglycosides has declined in industrial societies

In developing countries, their effectiveness and low cost make them popular.

They are often sold OTC and are the most commonly used antibiotics worldwide.

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Aminoglycoside Ototoxicity

With the resurgence of drug resistant TB, there is renewed interest in aminoglycosides specifically streptomycin and amikacin/ kanamycin as part of the World Health Organization recommended multi drug regimen.

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Effect of Aminoglycosides on Auditory/Vestibular Functions

Studies of human temporal bones and experimental animals show inner ear hair cells are the first to be affected followed by outer hair cells..

Outer hair cells are targeted in the cochlea extending from base to apex.

Results in high frequency hearing loss which can extend to frequencies important to understanding speech.

In the vestibular system, its primary effect is loss of vestibular hair cells in the semi circular canals and Utricular macula.

This leads to oscillopsia resulting in postural instability and risk of fall.

It was once believed that maintaining peak and trough serum levels of a drug would mitigate ototoxic effects.

Current evidence shows this not to be the case at least for vestibular toxicity.

Gentamycin and streptomycin are considered more vestibulotoxic.

Amikacin and Neomycin are considered more cochleo-toxic.

Pharmokinetics

Presence of the drug does not necessarily cause toxicity

Concentration of the drug in the inner ear does not exceed the serum level

Half life in cochlear tissue has been measured to exceed one month

Traces can be detected up to 6 months following the end of treatment.

Mechanisms of Aminoglycoside Ototoxicity Reactive Oxygen Species (ROS) formation appears

to be key.

Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. ROS are formed as a natural byproduct of the normal metabolism of oxygen

Depletion of anti oxidant Glutathione (GSH) enhances ototoxicity while dietary supplementation inhibits toxicity.

Is Aminoglycoside ototoxicity preventable?

Medications showing promise are d-methiomine and salicylate.

Two issues need to be solved before protective treatment can be considered. Effective drug levels must be

maintained. Drug must not interfere with the anti-

bacterial activity of the aminoglycosides.

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One clinical study found aspirin was protective reducing incidence of hearing loss by 75%.

Sha, S. H. , Qui, J. H. & Schacht, J. (2006) Aspirin to prevent gentamicin-induced hearing loss. New England Journal of Medicine, 354, 1856-7.

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Chemotheraputic Agents & Ototoxicity - Cisplatin

Introduced in the 1970s and is effective against germ cell, ovarian, endometrial, cervical, urothelial, head and neck, brain and lung cancers.

Highest ototoxic potential and is the most ototoxic drug in clinical use.

Symptoms of ototoxicity begin with tinnitus and high frequency hearing loss.

Incidence of hearing loss has been reported at 11-91% with an overall incidence of 69%.

In patients with head and neck cancer treated with Cisplatin, about 50% develop hearing loss.

Risk Factors for Cisplatin Ototoxicity

Intravenous bolus administration or high cumulative dose

Young children, under 5 years, or older > 46 years

Renal insufficiency Prior cranial irradiation Co-administration of vincristin

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The best predictor of cisplatin ototoxicity is cumulative dose.

The critical dose is 3-4 mg/Kg body weight. Ototoxicity increased dramatically when the

total cumulative dose exceeds 400 mg/m2

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Characteristics of Cisplatin Ototoxicity

Bilateral and permanent. High frequencies affected first.

It can occur suddenly. Speech discrimination may be markedly affected.

Mechanisms of Cisplatin Ototoxicity

Hearing loss affected by free radical formation and anti-oxidant inhibition.

Formation of reactive oxygen radicals produces glutathione depletion in the cochlea and lipid peroxidation.

Induced apoptosis in hair cells causing permanent hearing loss.

Carboplatin

Introduced due to its lower nephrotoxicity than cisplatin.

It is used to treat small cell lung cancer, ovarian and head and neck cancers.

carboplatin is less toxic than cisplatin but higher doses of carboplatin are used increasing ototoxicity

OTOTOXIC MONITORING

Ototoxicity is determined by establishing baseline hearing test data ideally prior to treatment including testing at high frequencies.

Results are compared to serial audiograms allowing the patient to serve as their own control.

The highest frequencies measuring 100 dB or less are monitored with testing ideally occurring just prior to each chemotherapeutic dose

Monitoring 1-2 times per week for patients receiving ototoxic antibiotics.

Post treatment evaluations are conducted as soon as possible after dispensing the drug and repeated at 1, 3 and 6 month post treatment.

The customized test protocol is called the Sensitive Range for Ototoxicity, or SRO and differs for each patient.

It consists of the highest frequencies with thresholds 100 dB or better followed by the next six lower frequencies.

The SRO is established during baseline testing prior to ototoxic drug administration.

Summary Audiometric monitoring using the patient’s

own extended high frequency thresholds as a control, is the most sensitive method to detect ototoxicity.

The test is easily tolerated

High frequency hearing is affected first

Speech perception can degrade if hearing loss extends below 8KHz.