important ent topic for ug and pg students

1. z
OTOTOXICITY
DR SUDHA BALASUBRAMANIAN

2. z
DEFINITION
 THE TENDENCY OF CERTAIN THERAEUTIC AGENTS AND
OTHER CHEMICAL SUBSTANCES TO CAUSE FUNCTIONAL
IMPAIRMENT AND CELLULAR DEGENERATION OF TISSUE
OF THE INNER EAR AND ESPECIALLY END ORGANS AND
NEURONS OF EIGHTH NERVE

3. z
It can cause
 Auditory symptoms
 Vestibular symptoms
 Both
Duration
 Temporary
 Permanent
TYPES

4. z

5. z
PATHOPHYSIOLOGY
 • Access to perilymph is possible from the middle ear cavity via the
membrane covering the round window at the base of the cochlea and that
filling the oval window over the vestibule.

 • Access to the perilymphatic compartment of the inner ear via the cochlear
aqueduct from (CSF) is possible and this may be a route of entry for
bacterial toxins, such as those associated with meningitis.

6. z
• The occurrence and extent of ototoxicity is to some extent dependent upon
the dosing regime (or exposure conditions) .
• Stress produced by infection may increase sensitivity as may malnourishment;
the effects of aminoglycosides are more pronounced in nutritionally deprived
• Individuals under similar conditions and with similar drug-dosing regimes differ in
their sensitivity to ototoxic side effects.

7. z
• Multi Drug interactions can also result in much greater damage than would be
expected from single drug regimes.
• A number of ototoxic agents, including aminoglycosides, polypeptide antibiotics
and anti-neoplastics, are also nephrotoxic. So that possible damage to the
kidney may result in reduced drug clearance and higher serum levels potentially
increasing the risk to the inner ear.

8. z
AGENT AFFECTING THE ION TRANSPORTING
EPITHELIA
LOOP DIURETICS
 primary site of action is on the iontransporting epithelia - the stria vascularis (SV) in
the cochlea and the vestibular dark cells
• The SV has one the highest rates of oxidative metabolism in the body, with oxygen
delivered from the intraepithelial blood supply so agents that induce anoxia or ischaemia
will affect strial activity.

9. z
• Those diuretics whose principal site of action is in the ascending limb of the
loop of Henle, including ethacrynic (etacrynic) acid, furosemide(frusemide),
bumetanide and piretanide, produce a transient hearing loss across most of the
frequency range.
• The effects are rapid in onset, within minutes or hours, and persist for some
hours but are usually completely resolved within a day if the drug is
discontinued.

10. z
 However, a single dose of diuretic
when administered closely with a
single dose of an ototoxin such as
aminoglycoside or cisplatin which
has the potential to cause hair cell
loss only after chronic repeated
treatment, results in rapid
devastatingly extensive hearing loss
and hair cell death.
 Histo – Extensive odema and
swelling of stria vascularis

11. z
• Potassium cyanide, along with its other actions in the body, causes TTS with a
symptomatology similar to that of loop diuretics, thought to result from inhibition of
marginal cell Na+/K+-ATPase.
• Macrolide antibiotics such as erythromycin also produce effects similar to
those of diuretics.

12. z
SALICYLATE
 COMPLETELY REVERSIBLE
 Develops only at high dose level – penetrates the
blood- perilymph barrier readily
 Outer hair cells – primary target .
 Affects all frequency range with tinnitus &
dizziness.
 Affects the motor protein of OHC’S –PRESTIN by
inhibiting the ANIONS at anion binding site.
AGENTS CAUSING REVERSIBLE EFFECT ON
HAIR CELLS

13. z
QUININE
 The ototoxic effects of salicylate and quinine thus derive from an ability to
cross the blood-perilymph barrier freely.
 Initial site – inner hair cell and spiral ganglion/ outer hair cell only at higher
concentration
 Causes reversible vasculitis and ischaemia leading to degenerative changes in
stria vascularis and organ of corti
 Affects entire frequency range

14. z
AGENTS THAT CAUSES PERMANENT HEARING
LOSS AND BALANCE DISORDER
AMINOGLYCOSIDES ANTIBIOTICS
• Although all aminoglycosides are potentially both cochleotoxic and vestibulotoxic,
the different aminoglycosides exhibit differences in their toxic potential and organ
preference.
• These have indicated that neomycin is the most toxic, gentamicin, kanamycin and
tobramycin less so, and amikacin and netilmicin least toxic, but such differential
toxicity.
• Streptomycin and gentamicin are considered more vestibulotoxic than cochleotoxic
to humans, whereas amikacin and neomycin are primarily cochleotoxic in the human
inner ear.

15. z
 Single systemic administration are not normally damaging to the ears byt
Topical application of a single dose of the drug to the middle ear cavity can
almost immediately initiate the progressive damage observed after chronic
systemic treatment.

 • The severity of the effects increases progressively with time, continuing after
drug, administration has been stopped.

16. z
 Hair cells in the basal (high-frequency) coil are affected first, damage
spreading progressively apical wards with time and with increasing dosage.
• Outer hair cells are more sensitive than inner hair cells.
• IHCs do not usually appear to die until all the OHCs in their immediate vicinity
and may persist for months after there has been complete loss of all OHCs.

17. z
• similarly , The type 1 hair cells predominate on those regions where damage is
initiated and are thought to be more susceptible to aminoglycoside induced
damage than the type 2 vestibular hair cells.
• The death of each hair cell is accompanied by expansion of the supporting
cells around them to close the lesion and effect tissue repair/are not usually
affected by aminoglycosides (or other ototoxins.
• After hair cell loss and ultimately the crest of cells that normally constitutes the
organ of Corti can become replaced by an apparently simple cuboidal-like
epithelium across the basilar membrane.

18. z
 • A programmed cell death pathway in which particular enzymes called caspases
play the crucial roles.

 • Gentamicin-induced hair cell death can be prevented by pan-caspase inhibitors

 • One significant initiator of programmed cell death leading to apoptosis is
generation of reactive free radicals.Damage to mitochondria releases not only
ROS but also a number of factors normally resident within mitochondria that
regulate the cascade of reactions leading to apoptosis.

19. z
GENETIC RELATED AMINOGLYCOSIDES TOXICITY
• Mutations in the gene that encodes 12s ribosomal RNA of mitochondria.
• The ‘A1555G’ missense mutation an adenosine to guanosine substitution at
base position 1555
• Mutations appear to affect only the cochlea’s sensitivity t aminoglycoside; there
is no enhanced effect on the vestibular system.

20. z
 NOISE AND AMINOGLYCOSIDES- more transduction channel opens up, leading
to increased entry of aminoglycosides
 LOOP DIURETICS-AND AMINOGLYCOSIDES- Co-administration causes hair cell
loss produces significant cochlear damage , as loop diuretics increases
penetration of aminoglycosides into endolynph

21. z
CISPLATIN
 Like aminoglycosides, it is nephrotoxic as well as ototoxic.
 Used to treat various tumours of soft tissue.

 Cisplatin induces a progressive loss of hair cells, the extent of which correlates
with the dose of drug administered.
 Hair cells in the basal coil of the cochlea are affected with damage spreading
progressively apicalwards.

22. z
 Cisplatin may have direct effects upon the spiral ganglion cells and Strial
atrophy develops several days or weeks after the end of the chronic
treatment.
 Once inside a cell , cisplatin leads to
1. cross-linking of nuclear DNA,
2. Inhibits DNA synthesis,
3. induces cell cycle arrest,
4. suppresses transcription ultimately leads to apoptosis.

23. z
 NOISE AND CISPLATIN- increased susceptibility of hearing loss in patient
who received cisplatin even some years prior , Due to long persistence of
platinum in the body and prolonged suppression of antioxidant mechanisms

 LOOP DIURETICS-AND CISPLATIN- causes rapid hearing loss and death of
outer haircells

24. z ORGANIC SOLVENT
 • Exposure to high concentrations of organic solvents induce acute, reversible
narcosis and neurotoxicity and ototoxic damage.

 • Workers in the chemical Industry and solvent abusers showed a high
incidence of hearing loss.
 • Trichroethylene has also been reported to be ototoxic- The cell bodies of the
afferent neurones are the target of trichloroethylene.

25. z
 TOLUENE - • It is the mid-frequency ranges of hearing that are affected
Rather than the high frequencies, with HC loss in the middle and apical
turns of the organ of Corti
 • There is a distinct spread of damage from the third (outermost) row of
OHCs inwards to involve subsequently the second and maybe the first row
of OHCs.
 Additionally, the supporting cells, especially the third (outermost) row of
Deiters cells, are affected

26. z
 • Since organic solvents are minimally water-soluble their distribution in the
inner ear is unlikely to be determined by entry into the fluid spaces.
 • It is their distribution in the tissue that is significant.

 • The pattern of damage across the organ of Corti, from outside to in, has
suggested that the solvents reach the inner ear from the vasculature of the
SV or the spiral prominence region just below it and then pass through the
tissues to the organ of Corti.

27. z
 • The cuboidal cells of the outer sulcus,epithelia of lateral wall to the organ of
Corti along the basilar membrane may be a major transport route.

 • Upon reaching the organ of Corti, the supporting cells of the organ of Corti,
the Hensen’s cells that form the outer ridge of the sensory epithelium and the
Deiters’ cells that surround the hair cells, may then become injured
 • Loss of membrane integrity and cell swelling- as a consequence of
membrane damage.

28. z
OTHER OTOTOXIC AGENTS
• VIOMYCIN
Reported to be predominantly vestibulotoxic following chronic treatment
regimes,Repeated systemic injections of relatively high doses, viomycin causes
hair cell death in the vestibular sensory organs.
• VANCOMYCIN :
has been reported to cause transient hearing loss and/or Tinnitus.
.POLYMYXIN B :
When perfused through the perilymphatic spaces caused an almost immediate
decline in cochlear microphonic (CM)

29. z
 • CHLORAMPHENICOL: in animals causes irreversible hearing loss following
infusion into the middle ear cavity- gaining access to the perilymph following
uptake across the round window membrane.
 • DESFERRIOXAMINE (DFO) binds iron and is used in patients with b-
thalassaemia to remove excess iron from the serum
 • repeated highdose systemic administration of DFO – cause high-frequency
hearing loss in about 20-40% receiving long-term therapy

30. z
INVESTIGATIONS
 PTA
 OAE
 BERA
 MONITORING OF COCHLEAR POTENTIAL
 ENG

31. z
TREATMENT
 PREVENTION PLAYS A KEY ROLE
 Permanent hearing loss – hearing aid / cochlear implant
 Tinnitus maskers
 Multivitamins & vasodilators
 Cooksey Cawthrone vestibular rehabilitation exercise – to built up a
tolerance mechanism to compensate unequal balance

32. z