2013Drug-Induced Hearing Impairment

8/12/2019 2013Drug-Induced Hearing Impairment

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Drug-induced Hearing

Impairment

Dr.Datten Bangun MSc,SpFK

&

Dr.Yunita Sari Pane M.SiDept.Farmakologi & Therapeutik

Fak.Kedokteran USU

M E D A N


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I.Ototoxicity;

Stedmans Medical Dictionary:ototoxicity is property of being injuries to

ear -----any side-effect of a drug that

damage the ears,either the outer,middle

or inner ear is ototoxic


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3

Ototoxicity of therapeutic drugs

Antimalarial

Non-steroidal anti-

inflammatory

Aminoglycosides

Antimicrobial

Loop diuretics

AntineoplasticChelating agents

Mostly:

Vastly studied

Effects restricted to cochlea

Use monitored, i.e.,knowledge of intake

Approaches:

Substitution

Antioxidants


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4

Ototoxins

Organic solvents

** Toluene (printing)

** Xylenes (plastics)

** Styrenes (plastics)

** Trichloroethylene (degrease)

* Carbon Disulfide (textile)

* Stoddard/white spirits

* N-hexane

Fuels (JP-8 fuel)

Ethyl benzene

Perchloroethylene

Butyl Nitrite

Methylene chloride

Metals

* Mercury andderivatives

* Lead and derivatives

* Arsenic (atoxyl)

* Manganese

Trimethyltin (organictin)

Cobalt

Asphyxiants

** Carbon Monoxide

* Cyanide

Army ID: * potential ** high-priority

Drugs Aminoglycosides

Loop diuretics

Anti-neoplastic agents

ASA

Quinine compounds

Others

Chem. warfare nerveagents

Organophosphate

(pesticide)

Paraquat (pesticide)


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5

Ototoxicity of environmentalchemical exposures

Mostly:

Relatively few studies

Effects not restricted to the

cochleaUse poorly monitored, i.e., poor

knowledge of exposure history

Confounded by noise

Approaches:

Substitution/control of exposure

Antioxidants

Metals

Solvents Asphyxiants

Pesticides


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6

Schacht J, Hawkins JE. 2006 Sketches of otohistory. Part 11: Ototoxicity:

drug-induced hearing loss. Audiol Neurootol. 2006;11(1):1-6.


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How common are ototoxic side-effect?

= no one really knowsEx.

Cisplatin ( a cytostatic):

- almost anyone who takes the drug

ends up with hearing loss--- almost100 %

- usually irreversible

Aminoglycosides ( an antibiotic)

- in a study--- 25-30 %- other study --- 63 %


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8

Features ofNIHL/Ototoxicity

Bilateral, symmetrical, and irreversible Onset in the high-frequency range,

progress rate determined by riskfactors

Cochlear, or with a cochlearcomponent History of exposure

NIHL=Noise-induced Hearing Loss

General descriptors


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Ototoxic Side-effects

Ototoxic side-effects can damage the ears in

many different ways:

1.Cochlear side-effect:

=tinnitus (ringing in the ears--447 drugs

= hearing loss---230 drugs

- can range from mild----profound

- may be temporary or permanent

Note:ototoxic drugs generally first destroyhearing in the very high frequencies,

(above 8000 Hz,not normally tested),

---patients are not aware.


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= distorted hearing;

- patients do not understand some (or much)

of what they hear

= hyperacusis;

- normal sounds are perceived as being tooloud---- 38 drugs

= feeling fullness in the ears= auditory hallucinations----- 165 drugs


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2.Vestibular Side-effects= dizziness ----588 drugs

= vertigo --- 432 drugs= ataxia

= nystagmus

= labyrinthus

= loss of balance

= oscillopsia

= emotional problems


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3. CNS effects

4. Outer/ middle Ear Side-effects

- ceruminous

- ear pain

- otitis------ :media

:externa


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RISK FACTORS:

1. Age; -very young/even unborn

- over 60 yrs

2. Genetic factors---esp. aminoglycoside

3. Already has hearing problems

4. Previous ear damage

5. Problem with kidney or liver---excretion

of drugs are delayed6. Already had ototoxic reaction before

7. Too much drug,either in amount or doses

8. Dehydration


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Aminoglycoside ototoxicity

= Frequency:- 15-50 % of all cases

= Bilateral vestibulopathy--- oscillopsia= mostly for high frequency (> 8000 Hz----

tidak dikenali segera oleh pasien )

Mechanism of action:

Appear to involve:

= apoptotic (programmed cell death)

= formation of free radicals= reduction of mitochondrial protein synthesis

---- ATP production


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Aminoglycosides

Cochlear toxicity

Amikacin, kanamycin, neomycin, netilmicin

Vestibular toxicity

Streptomycin, gentamicin, sisomycin

Can occur simultaneously


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Aminoglycosides ototoxicities:

- gentamicin

- tobramycin

- amikacin

- streptomycin

---- 6-13 %

- netilmycin---- 2,4 %

Symptoms of ototoxic can be delayed-- 6 weeksafter completion of AG therapy; however 50%

will recover 1 week to 6 months after discontinu-

ation


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Streptomycin

tends to cause more damage to the vestibular portion thanto the auditory portion of the inner ear.

Although vertigo and difficulty maintaining balance tend to

be temporary, severe loss of vestibular sensitivity may

persist, sometimes permanently. Loss of vestibular sensitivity causes difficulty walking,

especially in the dark, and oscillopsia (a sensation of

bouncing of the environment with each step).

About 4 to 15% of patients who receive 1 g/day for > 1 wkdevelop measurable hearing loss, which usually occurs after

a short latent period (7 to 10 days) and slowly worsens if

treatment is continued. Complete, permanent deafness may

follow.


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Neomycin

has the greatest cochleotoxic effect of all

antibiotics.

When large doses are given orally or by colonic

irrigation for intestinal sterilization, enough may beabsorbed to affect hearing, particularly if mucosal

lesions are present.

Neomycin should not be used for wound irrigation

or for intrapleural or intraperitoneal irrigation,

because massive amounts of the drug may be

retained and absorbed, causing deafness.


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Kanamycin

Kanamycin and amikacin are close to neomycin in

cochleotoxic potential and are both capable of

causing profound, permanent hearing loss while

sparing balance. Viomycin has both cochlear and vestibular toxicity.

Gentamicin and tobramycin

have vestibular and cochlear toxicity, causing

impairment in balance and hearing


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Aminoglycosides

Prevention

Pharmacological

Clinical

Consider less ototoxic drugs (netilmicin)

Identify high-risk patients

Audiogram before and weekly after starting

ENG prior if possible

History and physical exam daily (Romberg,

VA)

Adjust doses or switch drugs if toxic


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Macrolides

Discovered erythromycin 1952 (McGuire)

Mintz (1972) first report of ototoxicity

Reversible 50-55 dB losses in two cases

Clinically Hearing loss with/without tinnitus2 days

All frequencies, recovery after stopping

Rarely permanent (hepatic)

Incidence unknown


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Macrolides

Mechanism unknown

Azithromycin and clarithromycin can

cause similar findings in animals


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Other antibiotics

Vancomycin

Believed to be ototoxic (no data)

Penicillin, sulfonamides, cephalosporins

May have topical toxicity in middle ear

Nucleoside analog reverse transcriptase

inhibitors

Poor study


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Cancer Chemotherapeutics

Cisplatinum is a Chemotherapy drug used to

treat cancer patients. The hearing loss is

bilateral and symmetrical, involving the high

frequencies first and the low frequencies.

Severity of hearing loss depends on the type

of tumor, pre-chemotherapy loss, mode of

drug administration, renal function, and age.

Hearing loss is cumulative.


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CISPLATIN OTOTOXICITY

= a platinum based chemotherapeutic drug

Mechanism of ototoxic.-not clearly understood, --probably:

=The Reactive Oxygen Species (ROS)

play a role because cisplatin induce adecrease in plasma antioxidant level

and suppres the formation of endoge-

nous antioxidant

=Cisplatin results in depletion of glutathione

and antioxidant enzymes in cochlear tissue

----malondialdehyde level increased

Otoprotectors:


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Otoprotectors:

Several drugs have been tried as protection to

ototoxic effectof cisplatin.

1. N-acetylcystein ( NAC)----Fluimucil2. Methionine (MET)

-aminoacid

-antioxidant-precursor of gluthatione

3.Vitamin E

4.Ebselen; antiinflammatory antioxidant compound,

acts as a gluthatione peroxidase mimic

5.Sodium Thiosulfat: when given 4hours after carboplatin

----- ototoxicity reduced from 84 to 29 %


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However:

I. These otoprotectors shown to reduce the

antineoplastic effect of cisplatin.

II .Toxic at high doses


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Salicylate Ototoxicity

= firstreported by Muller in 1877

Ex. ASPIRIN

Symptoms:

- tinnitus tends to precede the

deafness

- bilateral

- mostly occurred at serum levels of

35 mg/dl


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Other theory:

= a change in the cochlear blood supply as a result ofsalicylate-induced imbalance of vaso-dilatory

prostaglandin and vasoconstricting leukotriene

= change in the cochlear permeability of the

outer hair cells

Mechanism action: probably by:


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Quinine

Similar clinical findings with aspirin

Usage up for leg cramps---being used a lot lately Clinically

High-pitched tinnitus Reversible, symmetric SNHL

Occasional vertigo

Mechanism

Decreased perfusion, direct damage to outer haircells, biochemical alterations


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QUININE OTOTOXICITY

Effects: - tinnitus

- sensorineural hearing loss (SNHL)

- vertigo

Mechanism of ototoxicity:

- quinine decreased force generation in

cochlear outer hair cells in the lateral

cisternae

-Cells are elongated and diameter

dilated


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Loop Diuretics

Ethacrinic acid, furosemide, bumetaside

Clinically (6-7%)

Usually tinnitus, temporary and reversible SNHL,

rare vertigo within minutes

High doses can cause permanent SNHL

Highest riskcoadministration of

aminoglycosides


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Loop diuretic ototoxicity

Mahler and Schreiner (1965):

= reversible SNHL and vertigo after i.v adm. ofloop diuretic ,i.e ethacrynic acid and furosemide

- high dose

- low dose but rapidly

- existing hearing deficits- severe hypoalbuminemia

- heart or liver failure


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Mechanism of action

= damage the stria vascularis

= damage the outer hair cells of cochlea

Pathologically

Edema of stria vascularis

Ionic gradient changes

Inhibition of adenylate cyclase and G-proteins


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High-Risk Factors

Impaired renal function

Prolonged treatment course

Advanced age (over 65)

Previous aminoglycoside therapy

Sensorineural hearing loss

Occupational noise exposure while takingthese medications


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Prevention of Ototoxicity

1. Ototoxic antibiotic or drugs should be

avoided in pregnant women

2. The elderly and people with pre-existing

hearing loss should not be given ototoxicdrugs.

3. The lowest effective dosage of the drug

should be given and monitored closely.

4. If possible,before giving ototoxic drugs,

hearing should be measured and then

monitored during treatment


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Topical Antimicrobials

Commonly prescribed for otorrhea after

tubes and CSOM

Controversial subject

Agents may enter middle ear and gain access to

membranous labyrinth

Animal testing reveals irrefutable evidence of

severe ototoxicity


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Polymixin B (Brummett)

Chloramphenicol (Patterson)

Neomycin (Brummett)

Gentamicin (Webster)

Ticarcillin (Jakob)

Vasocidin (Brown) Ciprofloxacin (Lenarz)


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Differences in humans

Round window is not exposed

Round window thicker Mucosal membrane protective

Mucosal edema with or withoutexudates typically present

Widespread usage with few sideeffects

One in ten thousand


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Remains a possibility in humans

Patient education important

Prescribe for only necessary duration

Avoid in healthy ear

Caution with prexisting vestibular defects


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I stopped taking the medicine

because I prefer the original disease

to the adverse drug reactions.

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2013Drug-Induced Hearing Impairment