Ototoxic drugs

Ototoxicity includes:
A. Cochlea toxicity
B. Vestibular toxicity
Definition of drug induced hearing loss:
1. hearing loss of 20 dB or more
2. at two or more adjacent frequencies
3. exclusion of other causes of hearing loss

high frequency sounds are detected at the basal turn

So the ototoxic drugs that affect the basal turn will cause high
frequency hearing loss
A. Ototoxic drugs that cause high frequency hearing loss:
1. aminogylcoside
2. cisplatin
3. Salicylate
4. Loop diuretic
B. ototoxic drugs causing low frequency hearing loss:
1. arsenic
2. erythromycin ( speech frequency)
Temporary vs permenant hearing loss:
a) permanent (hearing loss/vestibular dysfunction):
1. Amingogylcoside
2. Anti-neoplastic: cistaplatine/carboplatine
3. vancomycin
b) temporary (hearing loss):
1. Aspirin
2. Macolide: erythromycin
3. Quinine
c)

temporary/permenant:
1. Diuretics:
can cause both
in neonates it cause permanent hearing loss

The main drug that cause vestibulotoxicity is:

1- streptomycin 2- gentamicin 3-minocylcline ( tetracycline)

potentiator of the ototoxic effect of other ototoxic

drugs:

1. vancomycin
these drugs alone if given at the therapeutic level are not
ototoxic
but when they are given in combination with other ototoxic
drugs, they will potentiate their effect
2. diuretics:
they are ototoxic alone when used in high doses
but more dangerous as potentiator of the effect of other
ototoxic drugs

Aminoglycoside:
Suffix mycin/micin

A. Cochleotoxicity (mainly):

amikacin
kanamycin:
usually cause unilateral hearing loss

B. Vestibulotoxicity( mainly)
streptomycin
gentamicin
both cause severe damage to sensoryepithelium of cristae of all SCC
C. Cochleotoxicity = vestibulotoxicity
tobramycin
D. the least toxic drug of all aminoglycoside
arbekacin
E. The most tocix drugs:
streptomycin
neomycin: the 2nd toxic

General information
Toxicity generally occurs only after days or weeks of exposure
Antibiotic ototoxicity may continue even after cessation of
aminoglycoside therapy due to the long half life of the
aminogylicosside in the cochlear tissue
They are excreted by the kidney therefore renal failure is a risk
factor for ototoxicity
Toxicity may occur following:
1. Systemic use
2. Peritoneal lavage
3. Topical tympanic cavity use:
but it is considered negligible when compared with
the risk of inner ear due to infection

Most affected:
Cochlea:
outer hair cells
Basal turn
Note:
outer hair cells are more venerable than inner hair cells
So the primary effect of aminoglycoside is on the OHC from
the base to the apex
And after the damage of all OHC,IHC are damaged in
reversed direction from the apex into the basal turn
Vestibule: type 1 hair cells
Crista ampulla of ssc more than macule of saccule & utricle
Auditory toxicity vs vestibular toxicity:
Some of these agents are more toxic to either the cochlea or the
vestibular apparatus, although their ototoxicity is not completely
selective.
auditory toxicity 20%
vestibular toxicity may occur in about 15%
Auditory toxicity:
gradual progressive SNHL
High-frequency hearing loss tends to occur first
Continued exposure to aminoglycosides may result in hearing loss
that progresses to lower frequencies
This is why High frequency audiometery is a sensitive method for
early detection of ototoxicity
Vestibular toxicity:
onset is unpredictable
may not correlate with cumulative dose of ototoxic medication
Patients change from being normal to being symptomatic during an
easily identifiable 1- or 2-day period
symptoms are always present during motion or ambulation
clinical improvement can be seen beginning 2 months after onset of
symptoms, it is rarely complete
Gentamycin:
extremely toxic to the vestibule (this is why it is used in
intratympanic injection in case of meneier disease = medical
labyrinthectomy)
significantly but less sever toxic to the cochlea
streptomycin and kanamycin

 both the are extremely toxic to both the cochlea and vestibule.

Risk factors increasing the likelihood of ototoxicity:

1.
2.
3.
4.
5.
6.
7.

cumulative dose
duration of treatment
Bacteremia
Fever
Hepatic Dysfunction
renal dysfunction
Combinations of another ototoxic drug and an aminoglycoside may
increase the risk and severity of ototoxicity:

Ethacrynic acid exacerbate the ototoxicity of aminoglycosides in

patients with uremia.

Furosemide (it makes the drug more consentrated in the sacla

media) result in severe sensorineural hearing loss in a patient
who had received only 5 doses of gentamicin for pneumonia.
8. mitochondrial RNA mutation:
may sensitize a patient to even a single dose of
aminoglycoside.
It follows a maternal inheritance pattern
Up to 17% of patients with aminoglycoside-induced hearing loss
may have this mutation.[33]
For some unknown reason, only the auditory system, but not
the vestibular part of the inner ear, is sensitized to the toxic
effects of aminoglycosides in patients with this mutation
Pathophysiology of amnioglycoside ototoxicity:
1. Depletion of glutathione
2. Reactive oxygen species (ROS).
The drug in its inactive form + iron= ototoxic complex.
ototoxic complex + oxygen = reactive oxygen species (ROS).
ROS react with various cell components primarily in the
outer hair cell.

Anti-neoplastic:
Cisplatin
It Has the same features as aminoglycoside
Caroplatin:
Less cocheotoxic than cisplatin
May cause cochleotoxic at high dose
Affect IHC more than OHC

Minocycline:

Tetracycline
Reversible vestibular symptoms

 Do not cause nystagmus

Diuretics:
Cause reversible/permenant bilateral hearing loss
Mediated via stria vascularis metabolic alteration:
1. edema & damage in the strai vascularis
2. which leads to decrease in the endocochlear potential
3. which leads to raise in the threshold of the compound
action potential
Potentiates the ototoxic effect of the aminoglycoside
Note: ethacrynic acid is a loop diuretic

Salicylate:
Tinnitus more than loss of hearing
Cause reversible hearing loss, complete recovery into the base
line after 2-3 days of discontinuation of the aspirin
Infiltrate into the perilymph
Dose dependent (linear relation between the hearing loss & serum
level)
Affects the outer hair cells ( loss of otoacoustic emission)

Macrolide: erythromycin:
Cochleotoxic when given IV in high dose
Note outer hair cell death occurs:
1. Aminoglycoside
2. Cisplatine
3. Acoustic trauma