Lecture 06 ototoxicity

Workshop on Pharmacology of hearing and speech sciences

1. OTOTOXICITY
Dr. Ghulam Saqulain
Head Of Department of ENT
Capital Hospital

2. Close to 200 prescription and OTC medications have
ototoxic potential.
“Drug-induced hearing loss accounts for most cases of
preventable hearing loss worldwide”

3. 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

4. X

5. X

6. Clinical characteristics of ototoxic deafness
Bilateral hearing loss
Hearing loss happens at high
frequency
Reversible or progressive
With tinnitus, vertigo

7. Audiometric Monitoring for
Ototoxicity
The only way to detect ototoxicity is by
audiometric monitoring of extended high
frequencies, above 8 KHz.

8. 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
X

9. Semicircular canals:
Superior
Posterior
Lateral
Utricle
Saccule
Cochlea
Stapes
Vestibulocochlear
nerve

10. X

11. X

12. Incidence of aminoglycoside
Ototoxicity
Incidence
ranges 20-33% for commonly used
aminoglycosides while
balance is affected in 18% of cases.

13. 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)

14. 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

15. 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.
X

16. 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.
X

17. 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.

18. 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.

19. Gentamycin and streptomycin are considered
more vestibulotoxic.
Amikacin and Neomycin are considered more
cochleo-toxic.

20. 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.

21. 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.

22. 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.
X

23. 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.
X

24. 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.

25.  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.

26. 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
X

27. 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
X

28. Characteristics of Cisplatin
Ototoxicity
Bilateral and permanent. High frequencies affected
first.
It can occur suddenly. Speech discrimination may be
markedly affected.

29. 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.

30. 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

31. 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.

32. 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.

33. 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.

34. 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.