2013Drug-Induced Hearing Impairment
Transcript of 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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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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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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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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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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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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Topical Antimicrobials
Polymixin B (Brummett)
Chloramphenicol (Patterson)
Neomycin (Brummett)
Gentamicin (Webster)
Ticarcillin (Jakob)
Vasocidin (Brown) Ciprofloxacin (Lenarz)
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Topical Antimicrobials
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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Topical Antimicrobials
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.