Dr Mostafa Hashemi
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Ototoxicity refers to the tendency of a drug or
chemical agent to cause inner ear
dysfunction,or Inner ear tissues damage either
temporarily or permanently and induce
symptoms of hearing loss, dizziness, or both.
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Aminoglycoside Antibiotics used to fight gram
negative bacilli and staphylococci
Some Anti‐Neoplastics Used to treat head and
neck, lung, gynecologic and testicular cancers
Loop Diuretics Used to treat congestive heart
failure, renal failure, cirrhosis and hypertension
Quinines Used to treat malaria and
occasionally for nocturnal leg cramps
Salicylates Used in treatment of TIAs, stroke,
unstable angina and myocardial infarction
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The aminoglycoside antibiotics are an
important class of anti-infectious agents.
They were developed to combat tuberculosis
and other life-threatening infections.
The first members of this class of drugs were
streptomycin and dihydrostreptomycin. Initial
clinical trials showed that these compounds
could damage the kidneys and the inner ear.
Since then, many new aminoglycosides have
been developed.
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Neomycin was found to be too toxic for
systemic use and has been relegated to local
application.
Other members of this group of drugs include
kanamycin, gentamicin, tobramycin, amikacin,
netilmicin, and sisomicin.
Some of these agents are more toxic to either
the cochlea or the vestibular apparatus,
although their ototoxicity is not completely
selective
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Toxicity generally occurs only after days or
weeks of exposure.
The overall incidence of aminoglycoside
auditory toxicity is estimated to be
approximately 20%, whereas vestibulotoxicity
may occur in about 15%.
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Aminoglycosides are excreted primarily by the
kidney by glomerular filtration. Impaired renal
function reduces the rate of excretion.
Renal failure is a risk factor for ototoxicity, and
dosing of aminoglycosides must be modified to
compensate for delayed renal excretion.
Measurement of peak and trough serum levels
of aminoglycosides provides rough guidelines
for therapeutic efficacy, but is not an absolute
guarantee for prevention of ototoxicity,
particularly vestibular ototoxicity.
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Aminoglycoside ototoxicity may be detected,
but because of a life-threatening infection and a
lack of suitable alternative antibiotic therapy, it
may be necessary to continue treatment
Antibiotic ototoxicity may continue even after
cessation of aminoglycoside therapy.
Aminoglycosides trigger apoptosis at clinically
relevant doses, whereas higher doses may
trigger necrotic cell death.
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Animal and human temporal bone histopathologic
studies show that the cochlear and vestibular hair
cells serve as primary targets for injury.
In the organ of Corti, the outer hair cells of the
basal turn are damaged first.
As drug treatment is continued, the damage may
spread to more apical regions. Inner hair cells seem
to be more resistant to injury than outer hair cells.
This difference could be a result of the higher
concentration of the natural antioxidant,
glutathione, in the inner hair cells and in the apical
turn outer hair cells compared with in the outer
hair cells of the basal turn..
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High-frequency hearing loss tends to occur first and
may be detectable before it becomes clinically
noticeable. [15] Continued exposure to
aminoglycosides may result in hearing loss that
progresses to lower frequencies, including the
important speech range, interfering with
communication skills.
A hearing loss of 20 dB or more at two or more
adjacent frequencies should be documented to confirm
the diagnosis of drug related hearing loss after
exclusion of other causes of hearing loss.
Delayed ototoxicity may occur after cessation of
treatment with aminoglycoside antibiotics. Delayed
onset of hearing loss usually manifests within 1 to 3
weeks after the end of therapy. [16]
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Rotational vestibular testing in patients
receiving aminoglycoside therapy who were
asymptomatic is normal
When responses to all frequencies were absent,
oscillopsia and severe imbalance were usually
present.
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1- Bacteremia, fever, hepatic dysfunction, and
renal dysfunction have been associated with
ototoxicity
2- Combinations of another ototoxic drug and an
aminoglycoside may increase the risk and severity
of ototoxicity
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Cisplatin is a potent antineoplastic agent that is
used to treat various malignant tumors,
including ovarian,testicular, bladder, lung, and
head and neck carcinomas.
Side effects include nausea and
vomiting,neurotoxicity, ototoxicity, and
nephrotoxicity.
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Hearing loss caused by cisplatin seems to be
highly variable, and seems to be related to
dose; age of the patient; and other factors such
as noise exposure, exposure to other ototoxic
drugs, depleted nutritional state including low
serum albumin and anemia, and cranial
irradiation.
Children seem to be more susceptible than
adults.
Hearing loss tends to be permanent and
bilaterally symmetric.
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Symptoms of ototoxicity include subjective
hearing loss, ear pain, and tinnitus.
Tinnitus has been reported in 2% to 36% of
patients treated with cisplatin, and may be
transient or permanent.
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Although higher frequencies are affected first,
hearing impairment may extend into the middle
frequency range when doses greater than 100
mg/m 2 are used. When ultra-high-frequency
audiometric testing is used, 100% of patients
receiving high-dose cisplatin (150 to 225 mg/m 2 )
may show some degree of hearing loss. [38]
permanent ototoxicity was seen in more than 50%
of patients who received cisplatin in doses of
greater than 400mg/m2 cumulative dose .
Pediatric patients were studied for cisplatin
ototoxicity by use of otoacoustic emissions
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The antioxidant enzymes have been shown to be
decreased in association with cisplatin-induced
ototoxicity in the rat and Increased hydrogen
peroxide formation has been detected in the inner
ear after cisplatin exposure.
The primary target of cisplatin ototoxicity seems to
be the outer hair cells, with the hair cells in the
basal turn being most susceptible.
This increased susceptibility may result from the
relatively low stores of glutathione in the outer
hair cells of the basal turn compared with the inner
hair cells and the outer hair cells in the more apical
turns.
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One concern about the use of systemic
protective agents, such as antioxidants, is the
possible
intratympanic administration of the protective
agent,like dexamethason ,in annimal study was
effectiv.
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A clinical study reported that, contrary to
previous studies in the literature, amifostine
(600 mg/m2 ), given as an intravenous bolus
immediately before and 3 hours after cisplatin
and craniospinal irradiation in children with
medulloblastoma,provided significant
protection against hearing loss.
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Carboplatin is a newer platinum compound
that has been found to be less nephrotoxic than
cisplatin.
Carboplatin may be more ototoxi than initial
studies indicated. High-dose carboplatin (2
g/m 2 total dose) was associated with hearing
loss in 9 of 11 children (82%), with hearing
losses in the speech frequencies that were
sufficiently severe that hearing aids were
recommended.
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DFMO was developed as an irreversible
inhibitor of the enzyme
ornithinedecarboxylase. It was hoped to be
effective in chemotherapy for
hyperproliferative diseases, including cancer
and certain infectious processes.
DFMO was found to cause treatment-limiting,
but reversible ototoxicity at high doses.
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The most commonly used Furosemide Ethacrynic
Acid ,Torsemide Bumetanide,
Seem to have ototoxic effect on Stria Vascularis with
little hair cell damage. Synergistic effect with
aminoglycosides.
Clinical studies suggested that the ototoxicity of
furosemide may be reduced by infusing the drug at
rates of less than 15 mg/min.
Bumetanide and Torsemide are new loop diuretices,
were found to cause reversible hearing loss in cats at a
dose that was similar to that of furosemide No
evidence of ototoxicity has been shown in humans to
date.
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Hydrocodone is a narcotic analgesic. It is often
combined with acetaminophen, and is
frequently prescribed
Common adverse reactions to this
combination analgesic drug include dizziness,
nausea, vomiting, drowsiness, and euphoria
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Hydrocodone abuse was associated with rapidly
progressive SNHL in 12 patients reported from
the House Ear Clinic. In four patients, the initial
presentation was unilateral, and two patients also
experienced vestibular symptoms.
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1. The clinician should document rapidly
progressive SNHL that is bilateral.
2. There should be no vestibular symptoms
(although this is contradicted in a previous
series).
3. There should be no response to steroid
therapy.
Ototoxicity increase by genetic predispose and
hepatitis c
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Toxicity likely due to decreased perfusions of
the inner ear structures.
Ototoxic Effects
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Tinnitus
Hearing Loss.
Vertigo
Nausea
Usually SNHL, with 4kHz notch,and Usually
reversible upon cessation, but can be
permanent.
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Salicylic acid enters the cochlea causing
perilymph levels to equal serum levels.
Toxicity appears to be related to metabolic, not
morphologic, changes in cochlea.
Side Effects:
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. Tinnitus
. Hearing Loss
. Flat, Symmetric mild to moderate SNHL
.. Recovery generally occurs 24‐72 hours after
stopping drug
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Hearing loss in humans may be related to the
concentration of salicylates in blood. Patients
with blood levels
Tinnitus seems to increase continuously with
increasing plasma concentrations of salicylate
over 40 to 320 mg/dL
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Most cases of hearing loss and tinnitus have been
transient recovery of normal hearing usually
occurs within 1 to 2 weeks after stopping
erythromycin. Two cases of permanent
ototoxicity have been reported, however: one
with permanent tinnitus and one with
permanent hearing loss.
Hearing loss from erythromycin has been
reported in liver or kidney transplant patients.
The incidence of hearing loss in these patients
seems to be dose related
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Three patients complained of hearing loss, and
audiograms confirmed mild to moderate SNHL,
which resolved within 2 to 4 weeks after
cessation of treatment. [162]
Another series of patients had reversible
ototoxicity associated with high-dose oral
azithromycin therapy (2400 mg/day). It took an
average of 5 weeks for hearing to recover after
cessation of treatment.
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low-dosage or short-duration treatment
protocol for aminoglycosides with no clinical
risk factors, the use of a pretreatment and posttreatment audiogram with a weekly selfassessment checklist monitoring may be
adequate, but would not provide an early
warning of potential hearing loss. [183]
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For cisplatin treatment protocols, monitoring at
baseline, just before beginning each cycle,
when the patient is less ill and is able to
cooperate better, and after the conclusion of
therapy may be sufficient to document hearing
loss and provide guidelines for rehabilitation
because lifesaving therapy may impossible to
modify
As protective agents progress into clinical use,
high-frequency audiometry may help to
monitor the efficacy of the protective protocols.
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For a high-risk, long-duration course of
therapy with a high-risk agent such as
amikacin, pretreatment and post-treatment
testing with intervening weekly or biweekly
monitoring of conventional audiometry and
high-frequency audiometry may be advisable.
For aminoglycosides, the final audiogram after
treatment should not be performed until a few
weeks after conclusion of therapy because
additional delayed effects on hearing may
occur.
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(1) Pretreatment audiograms should be
obtained in elderly patients and in patients
who have impaired liver or kidney function.
(2) Caution should be used in combining
erythromycin with other potentially ototoxic
drugs.
(3) If the serum creatinine is greater than 180
mol/L, the daily dose of erythromycin should
not be greater than 1.5 g.
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Thanks for your attention!