o to Toxicity

7/30/2019 o to Toxicity

http://slidepdf.com/reader/full/o-to-toxicity 1/37

Ototoxicity



Ototoxicity is chemical injury to the labyrinthoccurring as a side effect of pharmacotherapy.

An ototoxic insult may affect the hearing,

vestibular function or both.

Irreversible ototoxicity drugs are the

aminogIycosides and the chemotherapeutic

agent, cisplatin.

Salicylates and the loop diurectics, tend to causea temporary hearing loss when used at

therapeutic doses.





Audiometric Monitoring for

Ototoxicity The only way to detect ototoxicity is by

audiometric monitoring of extended high

frequencies, above 8 KHz.



Aminoglycosides

Mechanism of action:

act on bacterial ribosomes to stop synthesis of

bacterial cell protein

bactericidal against gram-negative aerobic bacilli.



Within the cochlea, the outer hair cells are moresusceptible than the inner hair cells.

Within the vestibule, the type I hair cells are more

susceptible than type II hair cells, and the crista

ampullae are more sensitive to toxicity than the

utricular or saccular maculi.

Loss of the cochlear hair cells results in a

secondary degeneration of the auditory nerve.



Cellular injury depends upon aminogIycosidesbinding with iron to form a toxic metabolite which

generates hydroxyl radicals (reactive oxygen

species and free radicals) that place the cell

under oxidative stress.



As drug treatment is continued, the damage mayspread 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..



Continued exposure to aminogIycosides mayresult 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.



GENETIC SUSCEPTIBILITY

There exists a genetic susceptibility to aminoglycoside ototoxicity, by a nucleotide 1555 A to G

substitution on the mitochondrial 125 rRNA.



POTENTIATORS

Loop diuretics (ethacrynic acid or frusemide)potentiate the otoxicity of aminogIycosides by

increasing the permeability of strial blood vessels

which leads to an increased concentration of

aminogIycosides within the scala media.

cisplatin

flagyl



vestibulotoxic:

streptomycin and gentamicin

manifested by vertigo or disequilibrium

overall incidence of 15% for gentamicincochleotoxic:

amikacin, neomycin, kanamycin, tobramycin

onset heralded by tinnitus



Aminoglycoside ototoxicity may occur followingeither systemic administration, peritoneal dialysis

or topical application to the tympanic cavity.

Aminoglycoside ototoxicity is a classical cause of

bilateral vestibular impairment or failure.

Vestibulopathy may become apparent by the

development of gait ataxia and, if extreme,

oscillopsia.



Labyrinthine injury will usually be gradual,progressive, symmetrical bilaterally and

permanent, but unilateral hearing loss and cases

of partial recovery have been reported.

The ototoxic injury and associated hearing loss

may continue to progress for weeks following the

cessation of amino glycoside treatment, probably

due to the long half-life of aminogIycosides in

cochlear tissues.



Although ototoxicity is usually gradual, a suddenprofound sensorineural hearing loss may follow a

short duration of treatment, or even single dose,

of aminoglycoside administered systemically or

topically to the round window.

On the other hand, the presence of genes

associated with high antioxidant activity has been

shown to protect patients against aminoglycoside

ototoxicity.



Risk factors

Risk factors for ototoxicity include the Cumulative drug dose,

Duration of treatment,

Seriously ill patients with bacteraemia

Debilitated malnourished are all at increased risk of ototoxicity.

Patients‘ generally poorer metabolic reserves and

Renal failure

Liver failure. preexisting SNHL Genetic susceptibility and family history,



Premature babies treated in a neonatal intensivecare are at a higher risk than normal children of

developing a sensorineural hearing loss.

Interactions between aminogIycosides and

hyperbilirubinaemia or the coadministration of

Loop diuretics, cisplatin and flagyl has been

shown to increase the risk of hearing loss.



Infants less affected, once daily dosing



CISPLATIN

Etiopathology

Cisplatin is a chemotherapeutic agent effective

against solid tumours, including head and neck

carcinoma.

Therapeutic doses are limited by its ototoxicity.

The most frequent pattern of hearing loss is a

bilateral, symmetric, progressive, high frequency

sensorineural loss, caused by a loss of cochlear outer, and to a lesser extent inner hair, cells



The cellular mechanism for ototoxicity is oxidativestress, via an increased intracellular production of

reactive oxygen species and free radicals.

The mammalian vestibule appears to be less

sensitive to cisplatin toxicity than aminoglycosidetoxicity,

Animal study evidence] and the ampullary crista

are more susceptible to damage than the utricle



Natural history

The extent of cisplatin ototoxicity depends uponthe cumulative dose.

Transient tinnitus and hearing loss are commonly

observed for cumulative doses greater than 200

mg/m2.

A progressive, bilateral and symmetric, high

frequency SNHL, reflecting a cochleotopic

gradient of susceptibility, is the expectation from

cisplatin chemotherapy.



Detection of the earliest signs of toxicity requiresultra-high frequency audiometry or otoacoustic

emission testing.

A sudden sensorineural hearing loss is

occasionally observed following higher cumulativedoses,' and there are reports of spontaneous

recovery following this pattern of hearing.



Vestibulotoxicity may be detected on balancetesting following cumulative doses of cisplatin

exceeding 400 mg/m2.

->50% receiving > 400 mg/m2 permanent

ototoxicity.



Risk Factors for Cisplatin Ototoxicity

Intravenous bolus administration or highcumulative dose

Young children, under 5 years, or older > 46

years

Renal or liver insufficiency

Prior cranial irradiation

Co-administration of vincristine

Previous noise exposure.



Mechanisms of Cisplatin

Ototoxicity

Hearing loss affected by free radical formationand 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.



Carboplat in

Introduced due to its lower nephrotoxicity thancisplatin.

It is used to treat small cell lung cancer, ovarian

and head and neck cancers.



Loop diuretics

Potentiation of aminoglycoside ototoxicity by theloop diuretics ethacrynic acid and frusemide has

already been discussed, but these diuretics can

cause a hearing loss when used as sole agents.

The hearing impairment is usually a reversible,flat sensorineural hearing loss, but a permanent

profound loss can occur.

The auditory symptoms may be associated with

ataxia.



Mechanism Of Action:

The primary pathology is an oedema and injury tostria vascularis which causes a loss of the

endocochlear potential.

disturbance of K-ion transport with subsequent

reduction of endocochlear potential



SNHL, tinnitus and vertigo Transient and permanent loss reported

Incidence of ototoxicity ~ 6%



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 hearingloss in cats at a dose that was similar to that of

furosemide No evidence of ototoxicity has been

shown in humans to date



Salicylates

characteristic toxicity was described manifestingas reversible tinnitus, hearing impairment, nausea

and transient vomiting.

limited to cochlea.

serum Salicylates levels > 30 mg/100L.

The auditory symptoms correspond with a flat,

reversible sensorineural hearing, which has been

attributed to an effect on the ionic conductance'sthrough the outer hair cells.



Mechanism Normal histology (no hair cell loss)

Decreased blood flow, decreased enzymes

Clinically

Tonal, high frequency tinnitus (7-9 kHz)Reversible mild to moderate SNHL (usually high

frequency) – rarely permanent



Side Effects: . Tinnitus

. Hearing Loss

. Flat, Symmetric mild to moderate SNHL

.. Recovery generally occurs 24‐72 hours after

stopping drug



Quinine

Quinine is antimalarial drugs. Toxicity presents as a reversible sensorineural

hearing loss and tinnitus, associated with nausea

and vomiting.

The hearing loss results primarily from effects of

the quinine on the motility of outer hair cells.

chloroquine, a synthetic drug resembling quinine,

may also lead to a permanent sensorineuralhearing.



Clinically High-pitched tinnitus

Reversible, symmetric SNHL

Occasional vertigo

Mechanism Decreased perfusion, direct damage to outer hair

cells, biochemical alterations



Erythromycin

Erythromycin can cause a transient ototoxicitywhen used in high doses systemically.

macrolides cause a transient reduction of the

transient-evoked otoacoustic emission,

suggesting that the ototoxicity may occur at thelevel of the outer hair cell.



others

chlorhexidine, chloramphenicol,

bromides, mercurials.

Vinblastine Vincristine

Vancomycine

Date post:	14-Apr-2018
Category:	Documents
Upload:	abouzr
View:	221 times
Download:	0 times

o to Toxicity

Documents