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DRUG-INDUCED
SPECIAL SENSE IMPAIRMENTS
Dr.Datten Bangun MSc.SpFKDr.Yunita Sari Pane,M.Si
Dept Farmakologi & Therapeutik
Fakultas Kedokteran USU
M E D A N
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I.Ototoxicity;
Stedman s Medical Dictionary: ototoxicity is property of being
injuries to the ear ----- any side-effect of a drug that damage theears,either the outer,middle or inner ear
is ototoxic
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Drug-induced hearing loss,
ototoxicity
Mechanism unclear, possibily related
to drug type, dosage, route, geneticpredisposition, etc
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Ototoxic drug (more than 90)
Aminoglycoside antibiotics
Antitumor drug- cisplatin, carboplatin
Diuretic- furosemide, ethacrynic acid Salicylate-aspirin
antimalarial drug- quinin
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Clinical characteristics of ototoxic
deafness
Bilateral hearing loss
Hearing loss happens at highfrequency
Reversible or progressive
With tinitus, vertigo
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How common are ototoxic side-
effect?= no one really knows
Ex.
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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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 beingtoo loud---- 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 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 vestibularportion than to 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 wk develop 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 maybe absorbed 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 sparingbalance.
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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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
Ot t t
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Otoprotectors:
Several drugs have been tried as protection to
ototoxic effect of cisplatin.
1. N-acetylcystein ( NAC)
2. 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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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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Salicylate Ototoxicity
= first reported 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 aresult of salicylate-induced imbalance of
vaso-dilatory prostaglandin and
vasoconstricting leukotriene
= change in the cochlear permeability of theouter hair cells
Mechanism action: probably by:
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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
by inhibiting Na-KATP-Ase and
Adenyl cyclase in the stria
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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
a e
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Some Drugs that Cause Ototoxicity
Type Examples
Antibiotics Aminoglycosides
Vancomycin
Chemotherapeutic
drugs
Platinum-containing drugs (eg, cisplatin )
Diuretics Ethacrynic acid
Furosemide
Other Quinine
Salicylates
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Drug-induced smell disorders
Usually ,smell disorders----- taste
disorders.
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Can You Smell That?
Anatomy and Physiology of Smell
Baca anatomi & fisiologi
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Many depend upon smell for livelihood or safety:
Cooks
Homemakers
Firefighters
Plumbers
Wine merchants
Perfumers
Cosmetic retailers
Chemical Plant Workers
I sense a hint ofYasmine and roses
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The Sense of Smell
Often downplayed
Vital to our everyday existence
Stop and smell the roses
Has the milk expired?
Essential in our ability to taste
Occasionally the first sign of
other disorders
Rarely tested
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Definitions
Total Anosmia: inability to smell all odorants on
both sides of the nose
Partial Anosmia: inability to smell certain
odorants Specific Anosmia: lack of ability to smell one or
a few odorants
Hyperosmia: abnormally acute smell functionand often interpreted as hypersensitivity to odors
Dysosmia: distorted or perverted smell
perception
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Definitions
Parosmia/Cacosmia: change in quality of an
olfactory cue
Phantosmia: odor sensations in absence of an
olfactory stimulus Olfactory agnosia: inability to recognize odor
sensations despite olfactory processing,
language, and intellectual function intact
Seen in certain stroke and postencephalitic
patients
Presbyosmia: smell loss due to aging
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Olfactory connections to the Brain
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Disorders of Olfaction
Obstructive Nasal and Sinus Disease
Upper Respiratory Infection
Head Trauma
Aging
Congenital Dysfunction
Toxic Exposure
Neoplasms
HIV
Epilepsy and Psychiatric Disorders
Medications
Surgery
Idiopathic Loss
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Medications
Amebicides and antihelmintics: Metronidazole;niridazole
Local Anesthetics: Benzocaine; Procaine; Cocaine;
Tetracaine
Anticholesteremics: Clofibrate
Anticoagulants: Phenindione
Antihistamines: Chlorpheniramine
Antiproliferatives: Doxorubicin; Methotrexate;
Azathioprine; Carmustine; Vincristine Antirheumatic, analgesic-antipyretic, anti-
inflammatory: Allopurinol; Colchichine; Gold;
Levamisole; D-pencillamine; Phenylbutazone; 5-
thiopyridoxine
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Medications (continued)
Antiseptics: Hexetidine
Antithyroid agents: Carbimazole; Methimazole;
Methylthiouracil; Propylthiouracil; Thiouracil
Agents for dental hygeine: Sodium lauryl sulfate
(toothpaste)
Diuretics and antihypertensive agents: Captopril;
Diazoxide; Ethacrynic acid
Hypoglycemic agents: Glipizide; Phenformin
Muscle relaxants and Parkinson treatment drugs:
Baclofen; Chlormezanon; Levodopa
Opiates: Codeine; Hydromorphone; Morphine
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Medications (continued)
Psychopharmacologics: Carbamazepine;
Lithium; Phenytoin; Psilocybin;
Trifluoperazine
Sympathomimetic drugs: Amphetamines;
Phenmetrazine; Fenbutrazate
Vasodilators: Oxyfedrine; Bamifylline
Others: Germine monoacetate;
Idoxuridine; Iron sorbitex; Vitamin D
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Treatment and Management
Conductive Loss vs Receptive Loss
Conductive loss of smell: major olfactory
dysfunction responsive to treatment of
nasal disease
Opening air passageways:
Intranasal steroids
Antibiotics
Allergy therapy
Ethmoid Sinusitis
Intranasal tumors
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Receptive Loss Treatment
Vitamin A:
Necessary in repair of epithelium
White rats become anosmic on Vitamin A
deficient diet
Mammalian olfactory epithelium with
considerable amounts of Vitamin A
Duncan and Briggs studied Vitamin Asupplementation and found successful
restoration of at least partial olfactory ability in
50 of 56 pts
Other authors unable to reproduce benefit
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Receptive Loss Treatment
Zinc
Zinc-deficient adult mice probable anosmia
Severe deficiency rare and difficult to
substantiate
Occasional reports of improvement in
anosmia with zinc therapy
Aminophylline cAMP role in transduction
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Managing Olfactory Loss
Ifno known causes found: reassurance Discuss improving seasoning of diet for
remaining sensory modalities
Emphasize taste, color, texture, viscosityand feel of foods
Smoke and fire detectors are mandatory
Patients should elicit confidential help for
matters of odor
Switch to electric appliances and non-
explosive heating or cooling fuel from
natural gas
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Conclusions
Hearing is one of the most primitive of our
senses
Strong correlation with many of our other
senses, our memories, and quality of life ingeneral
Often not addressed enough with patients
Anosmia may be a marker for certain
conditions and diseases
Many different conditions can lead to
anosmia
Treatment options are often limited
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