Overview of ototoxic drug Investigation Management and prevention

17/10/55
Overview of ototoxic drug
Investigation
Management and prevention
Beta-adrenoceptor blocking drugs : propanolol,
atenolol, metoprolol, oxprenolol, labetalol
Sedative & tranquilizers : barbiturate, thalidomide
Narcotic drugs : hydrocodone, marijuana (),
alcohol
Antibiotics : aminoglycosides, erythromycin, vancomycin
Loop diruretics : ethacrynic acid, furosemide, Bumetanide,
Piretanide, Indacrinone, ozolinone, Azosemide,
Toresemide
Antiinflamatory : Salicylates, aspirin, NSAIDs
Quinine delivates : quinine, chloroquin
Chemotherapeutic agents : cisplastinum,carboplatin,
nitrogen mustard(cyclophosphamide), 6-Amino
nicotinamide, vincristine sulfate&vinblastine sulfate,
misonidazole, DL- alpha difluromethyl ornithine (DFMO)
Organic sovents : carbon disulfide, toluene,
trichloroethylene, styrene, xylene, hexane
Gas : carbon monoxide, butyl nitrite
Heavy metal : arsenic, mercury, lead, manganese , tin
Muscle relaxant : dantrolene sodium
Topical ototopic drugs : aminoglycoside,
chloramphenical, polymyxin B
1
17/10/55
Hematogenous
CSF
Direct : round window membrane, annular ligament
Drug or chemical agent to cause IE dysfunction
IE dysfunction : cochleotoxicity or vestibulotoxicity
IE tissues damage
temporary or permanent
Impaired renal & hepatic function
High dose
Inappropriate route
Infant & elderly
Cofactor (exp. Noise)
Previous HL
Prolong used/ exposured
Dehydration/ fever
Bacteremia
Anemia
Depleted nutrition state, hypoalbuminemia
genetic
Cochleotoxicity
(usually damage at basal turn
apex )
tinnitus : earliest symptom of cochleotoxicity
hearing loss(bilateral) : usually high ƒ SNHL
Vestibulotoxicity
› Vertigo
› Oscillopsia
› Impairment of balance in the dark
Streptomycin, Kanamycin,Gentamicin
Neomycin , Amikacin, Tobramycin,
Netilmicin, and Sisomicin
Toxicity occurs only after days or weeks of
exposure
Incidence of auditory toxicity is 20%
Incidence of vestibulotoxicity is15%
Poorly absorbed orally ( 3% of orally dose is absorb from GI )
Poorly penetrate to BBB
Conc. in tissue = 1/3 of serum
Aminoglycosides in plasma
pass spiral lig.&stria vascularis to perilymph
endolymph organ of corti
Maximun aminoglycosides in perilymph = 2-3 hrs
Ototoxicity related to aminoglycosides level in
endolymph
Excrete by renal high conc. in urine
Renal failure is risk factor for ototoxicity
2
17/10/55
Cochlear &vestibular hair cells primary targets for inj.
cristae and in the striola regions of the maculi
Damage first The OHC of the basal turn
(except neomycin
first at apical turn)
If continued
spread to apical regions
resistant to injury( high antioxidant : glutathione) :
IHC > apical turn OHC > basal turn OHC
Progressive destruction of spiral ganglion cells
The stria vascularis become thinner as a result of
marginal cell death
HC destruction extend to the periphery of the
vestibular sensory epithelium
Type I hair cells primary affect
Mechanoelectrical transduction channel and act as a
blocker :
Competition between the AG & Ca entry into OHC
AG combine Iron form ototoxic complex
complex reacts with O2
produce reactive oxygen species (ROS)
ROS react with cell components (phospholipids in the
cell membrane, proteins, and DNA)(primary in OHC)
disrupt the function
Trigger programmed cell death
apoptosis
Vestibular ototoxicity
In the vestibular system
Hair cell damage begin in the apex of the
The organ of Corti
Auditory ototoxicity
Tinnitus first symptom
Hearing loss
First at High ƒ progresses to lower ƒ
include speech ƒ
Dx.
HL ≥ 20 dB at ≥ 2 adjacent ƒ
Must exclude other causes
Delayed ototoxicity : within 1-3 wks after the end of Tx.
Recruitment
Poor SD
Unpredictable, relate to AUC,but not correlate with
cumulative dose
Imbalance and ataxia
Dramatically worsened by movement
Oscillopsia
risk factor of ototoxicity
› Bacteremia
› Fever
› Hepatic dysfunction
› Renal dysfunction
› Combine with another ototoxic drug : furosemide
Reversible & irreversible
3
17/10/55
Potent antineoplastic agent
Used to treat various malignant tumors :
ovarian, testicular, bladder, lung, and H&N CA
S/E : N/V, neurotoxic, ototoxic, nephrotoxic
Degeneration of OHC in lower turns of the cochlea,
spiral ganglia, and cochlear nerve
Damage first OHC of basal turn of cochlea
If continue extend to apical of cochlea
Normal vestibular ganglion cells, vestibular nerve
Scanning electron microscopic of inner ear
› fusion of steriocilia of OHC
› damage cuticular plate
› decreased number of IHC ,OHC and spiral gg. cells
› The stria vascularis atrophic
Dose-related ototoxicity (relate to cumulative dose)
Cochleotoxicity
Permanent and bilateral symmetric HL
Symptoms
tinnitus(2-36% of pt. treat with cisplatin)
(transient or permanent)
Subjective HL
ear pain
Affected first at High ƒ
extend to middle ƒ when doses > 100 mg/m2
17 % +/- 2.7% of dose administered
excrete in urine within 24 hrs.
Free cisplatin half life 8 min.
Total platinum half life 40-50 hrs.
Liver rapid converts cisplatin into nontoxic
metabolites within 1 hr after administation
CP entry into OHC through mechanotransducer
channels
form the monohydrate complex (MHC)
activate NOX-3, nicotinamide adenine
dinucleotide phosphate (NADPH) oxidase enz
produce ROS/RNS
ROS/RNS react with cellular lipids, proteins, DNA
produce toxic aldehyde, 4-hydroxynonenal
cell damage
• reactive
oxygen species (ROS) :
superoxide
anion, hydrogen peroxide
• reactive nitrogen species (RNS) : NO
Cochleotoxicity ()
Ultra-high-frequency audiometric testing :
100% of pts receiving high-dose cisplatin (150 to 225 mg/m2)
some degree of HL
More than 50% of pts receiving cisplatin > 400 mg/m2
cumulative dose permanent HL
Vestibulotoxicity
Esp. in pts with preexisting vestibular problems
4
17/10/55
Risk facter
› Age : Children<5 yrs & elderly
› Renal insuff.
› Noise exposure
› Combine with other ototoxic drugs
› Poor nutritional state , low serum albumin
› Anemia
› Cranial radiation
Protective agents
No successful clinical trials
but, successful experiments protection in animal models
Intratympanic dexamethasone
Amifostine
Sodium thiosulfate
D-Methionine
Fosfomycin
Free oxygen radical scavengers : glutathione, gingko
biloba extract etc.
Aminoglycoside
Less nephotoxic & ototoxic than cisplatin
High dose ( >2g/m2 total dose)
HL in the speech ƒ
Cisplatin
mechanism
Ethacrynic acid( 0.7%)
Furosemide(6.4%)
Bumetanide(rare)
Toresemide ( New)
Piretanide
Indacrinone
ozolinone
Azosemide
Have data of study
Renal
blocking Na/K/2Cl transporter at ascending loop of Henle
inhibit reabsorption of Na, K, Cl
Ear
Primary target : stria vascularis
blocking Na/K/2Cl transporter at tria vascularis
abnormal endolymphatic ion concentration
swelling
of stria vascularis
reduce of endocochlear potential HL
Disturb oxidative metabolism of OHC
stereocillia tear
5
17/10/55
Usually reversible ( may be permanent )
Bilateral symmetrical
Flat SNHL (may be profound )
Symptoms : HL, tinnitus, vertigo, ataxia
› Ethacrynic acid
permanent SNHL, more at mid-high ƒ
› Furosemide
reversible SNHL, tinnitus, vertigo
› Bumetanide
rare
Aminoglycoside & loop diuretic
Severity of ototoxicity
Combine drugs > AG then LD > LD then AG
Prevention
Avoid to combine with other ototoxic drugs
IV furosemide : control rate ≤ 15 mg/min
Furosemide plasma concentration not more
than 50 mg/L
Bilateral HL , tinnitus
HL related to Plasma salicylate conc.
Salicylate induces tinnitus
Plasma salicylate conc. > 40-320 mg/ml
activated of N-methyl-d-aspartate (NMDA)
receptors in the cochlea perilymph blocked the
increase in pole-jumping behavior tinnitus
Histopatho. in temperal bone : not show significant
damage of hair cell/stria vascularis/spiral ganglion
cell/myelin sheath of CN VIII
reversible SNHL (within 24-72 hrs after stop salicylates)
Risk factor
Renal failure
Rapid infusion
Combind with other ototoxic drugs
Drug interaction
Combine with aminoglycoside potentiate toxicity of
aminoglycoside by increase permeability of tria bl
vessel
increse concentration of aminoglycoside in
scala media organ of corti damage faster & easily
Other ototoxic drugs : spiral organ damage easily
Derivatives of benzoic acid anti-inflammatory
drugs and analgesic effect
Salicylates rapidly enter the perilymph
The effects on cochlea
Inhibit cyclooxygenase
vasoconstrict reduce blood flow
change cellular permeability of HC
electrolyte imbalance
abnormal cochlea potentials HL
Changes in stiffness of the lateral membrane of
OHC
Non-steroidal anti-inflammatory drugs (NSAIDs)
used as analgesic agents
inhibit activity of cyclooxygenase (COX)
COX-1, COX-2
COX-1 enz. : protect your stomach lining
Traditional NSAIDs (Diclofenac, Ibuprofen,
Indomethacin, Mefenamic Acid, Naproxen)
inhibit both COX-1 and COX- 2 enz.
Selective COX-2 inhibitors (celecoxib)
only inhibit COX-2 enz.
6
17/10/55
S/E gastritis, renal insuff., allergic reactions,
cardio-vascular complications, ototoxicity
(including tinnitus & HL)
mild to moderate hearing loss
usually reversible
mechanisms : decreased cochlear blood flow
impaired of the OHC function
In animal studies
protective effects of NSAIDs on cochlear Inj.
(acoustic injury)
COX-1 & COX-2 are expressed in several types of
inner ear cell
non-selective NSAID : can protected the cochlear
hair cells against acoustic injury
semi-selective & selective COX-2 inhibitor : did not
protective effect
Mechanisms
› Inhibit inflammatory metabolites (PGs, TXs and LTs)
› Block ROS production
Nacrotic analgesic
Often combine with acetaminophen
S/E : dizziness, N/V, drowsiness, euphoria, RS
depression, mood disturbances,
drugs dependent
Reported a few case of HL but severe
Unknown mechanism
Clinical manifestations
Prolong daily use (months to yrs)/ high dose
Bilateral rapid progressive SNHL
No vestibular symptom
No response to steroid therapy
May be associated with hepatitis C
Erythromycin, Azithromycin, clarithromycin
Reversible ototoxicity
Risk factor : high dose, elderly, impair
liver/renal function
Ototoxic symptoms
› “Blowing” tinnitus
› Bilateral HL
› Vertigo : some cases
› Visual changes
› Slurred speech
› Some patients complained of confusion,
fear, psychiatric disturbances
Hearing loss
› 16% of patients receiving 2 g daily
› 53% in patients treated with 4 g daily
unknown mechanisms
7
17/10/55
audiometric pattern in erythromycin ototoxicity
› Early : High-frequency SNHL
› Late : A flat type of SNHL
ABR testing : absence of waves I to III
HL & tinnitus Transient
Recovery of normal hearing in 1-2 wks after
stopping erythromycin
Iron overload chelation
38% significant SNHL at high ƒ with recruitment
more effect in younger pts received high dose
( > 50 mg/kg sc.)
Pts with ferritin level > 2000 ng/ml
recommended Deferoxamine dose< 50 mg/kg
Pts with symptomatic HL
stopped drugs for 4 wks
repeat audiograms until improve/stable
restarted at 10-25 mg/ kg / dose
Audiometric screening for ototoxicity
› Pure-tone thresholds at 6 kHz : most affect
› DPOAE testing : more sensitive and
superior to pure-tone audiometry
fluoroquinolones drugs antibiotic
topical ciprofloxacin
› no increase risk of HL
systemic ciprofloxacin
› HL (1%)
› Can pass through placenta & lactation
› In pregnancy : increase risk for abortion
Recommended for audiologic monitoring
Mild to moderate SNHL and involved the high
ƒ (3 to 12.5 KHz)( most common at 6 kHz)
Asymptomatic
Serial audiograms q 6 mo
More frequent in young patients with normal
serum ferritin values and audiogram shown HL
Quinine, chloroquine, hydroxychloroquine
Tx. Malaria, rheumatoid arthritis, connective tissue dz.
Ototoxic : 20% of pt. receive≥ 200-300 MKD for long time
Maximum perilymph concentration at
› 8 hrs after IM
› 2 hrs after intra round window membrane
Mechanism :
Block Ca-dependent-K-channels
cell swelling
narrow vascular
decrease bl. Supply
abnormality OHC function
8
17/10/55
Symptoms & sign
reversible symmetrical bilateral SNHL
( if high dose or HL at speech ƒ
may be permanent)
High ƒ loss, notch at 4 kHz
SD score ≤30 %
Tinnitus
Vertigo
Other : headach, N/V, Disturb vision
1st trimester of pregnancy
may be congenital deafness, cochlear hypoplasia,
marked vestibular paresis
Antibiotic : aminoglycoside, chloramphenical,
polymyxin B,
Antiseptic : acetic acid, alcohol, chlorhexidine,
cresylate, povidone-iodine, potassium iodide
solution : propylene glycol, polyethylene glycol
•Drug
•Mechanism
•Auditory
toxicity
Aminogly
coside
•ROS formation
OHC
degenerstion from
basal turn
apical turn
•HF SNHL LF
SNHL
•Tinnitus
•Reversible •Vestibular
and
toxicity
irreversible ataxia,
imbalanced,
ossilopsia
Cisplatin
•Generate ROS in
cochlear
OHC at
basal turn,Organ of
Corti, spiral gg
•Activated apoptotic
cell death
induced
cell death
•Mild tinnitus
•HF SNHL
•Irrevesible •Impaired
VOR
bilateral
SNHL
•“Blowing “
tinnitus
•SNHL :flat
type
•HF SNHL
•ABR :absense
wave I-III
•Transient
Macrolide •Not clear
•Character
istic of HL
•Vestibular
toxicity
•Vertigo
•Confusion
•Slur speech
High dose
Combine with other ototoxic drugs
use in elderly pts, renal/hepatic failure
In animal experimental : Controversy
reported
Hearing loss
Ototoxic : 3.4 % of pts. Receive topical ototopic
drugs in USA)
Not recommend for TM perforation with normal
middle ear mucosa
•Drug
•Mechanism
•Auditory
toxicity
•Characteri
stic of HL
Loop
diuretic
drug
•Extensive edema of
•HF SNHL
striar vascularis
loss of •Tinnitus
auditory function
•Decrease of
endocochlear potential
•Increase theshold for
compound AP
Transient
or
permanent
Salicylate
•Change of blod flow of
striar vascularis
•Change stiffness of lat
membrane oof OHC
•Activation of NMDA
rec increase pole
jumping
Reversible
•HF SNHL
•Tinnitus
•Vestibular
toxicity
•Vertigo
9
17/10/55
Organic solvents
Gas : Carbon monoxide, butyl nitrite (
)
Heavy metals
Trichlorethylene : ;
high ƒ loss (2-3 kHz)
Xylene : )*&+,
Styrene : )* plastic,
, &'(
, !"#$%
,
#'#, *
#
,
&#-,
Hexane : )*#
prolong latency of wave V, I-V
Carbo disulfide : )*, .
high ƒ loss
Toluene : )*&#+, &+, &#'#,
Mercury
Lead
Arsenic
Manganese
Tin
, , #&*"
Begin damage at inner ear
› Both cochleotoxicity & vestibulotoxicity
› Symptoms : HL, virtigo
later brain damage ataxia, paresthesia, weakness,
dysarthria, dysplagia, blure vision death
Mechanism of HL
› Acute : mostly affected both afferent and efferent n., hair cells
( block potassium currents )
› Chronic : damage the stria vascularis
Mechanism : unclear ( in guinea pig )
Block Ca-dependent-K-channels
suppression of potassium currents of OHC
abnormality OHC function
Delayed latency of wave III
Permanent high ƒ loss
Vertigo
High ƒ HL
#'/
*
Study in animal temporal bone
› Change in marginal & intermediate of stria vascularis
Then degeneration of OHC & IHC
› Damage at apex
base
All ƒ loss but, mid ƒ are better than other
10
17/10/55
cochleotoxicity
more sensitive and superior to
Conventional Audiogram because can
detect early HL that loss at ƒ > 8000
› High-frequency audiometry
› Distortion-Product Otoacoustic Emissions (DPOAEs)
› Electrocochleography (sens. But, long duration &cost)
› ABR (sens. But, long duration &cost)
Vestibulotoxicity
› Electro nystagmography
› Rotation test
› Dynamic posturography
Distortion-Product Otoacoustic Emissions
(DPOAEs)
more sensitive and superior to pure-tone
audiometry in detecting early HL
Limitation : low specificity
Stop the ototoxic drugs/agent
Behavioral change
› slow movement
› use rubber shoes
› avoid discotheque
Rehabilitation
› cooksey-Cawthorne exercise
Medication
› supportive symptoms tinnitus, virtigo
hearing aid
Surgery
› cochlear implant ( profound HL)
Thank you
Cummings otolaryngology head&neck surgery, 5th edition,
chapter 154 vestibular & auditory ototoxicity
Scott-Brown’s Otorhinolaryngology, H&N surgery,chapter 238 d
ototoxicity
012
,, .4.42
*, +( 6 ototoxicity
for your attention
11