DRUG-INDUCED

SPECIAL SENSE IMPAIRMENTS

Dr.Datten Bangun MSc.SpFK

Dept Farmakologi & Therapeutik

Fakultas Kedokteran UHN

MEDAN
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
 Ototoxins

Organic solvents Metals Drugs

** Toluene (printing) * Mercury and derivatives Aminoglycosides
** Xylenes (plastics) * Lead and derivatives Loop diuretics
** Styrenes (plastics) * Arsenic (atoxyl) Anti-neoplastic agents
** Trichloroethylene * Manganese ASA
(degrease) Trimethyltin (organic
Quinine compounds
* Carbon Disulfide (textile) tin)
Cobalt
* Stoddard/white spirits
* N-hexane
Asphyxiants Others
Fuels (JP-8 fuel)
** Carbon Monoxide Chem. warfare nerve
Ethyl benzene
* Cyanide agents
Perchloroethylene
Organophosphate
Butyl Nitrite
(pesticide)
Methylene chloride
Paraquat (pesticide)
Army ID: * potential ** high-priority 3
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--- almost
100 %
- usually irreversible

Aminoglycosides ( an antibiotic)
- in a study--- 25-30 %
- other study --- 63 %
 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 destroy
hearing in the very high frequencies,
(above 8000 Hz,not normally tested),
--- patients are not aware.
= distorted hearing;
- patients do not understand some (or
much) of what they hear

= hyperacusis;
- normal sounds are perceived as being
too loud---- 38 drugs

= feeling fullness in the ears

= auditory hallucinations----- 165 drugs
2.Vestibular Side-effects
= dizziness ---- 588 drugs
= vertigo --- 432 drugs
= ataxia
= nystagmus
= labyrinthus
= loss of balance
= oscillopsia
= emotional problems
3. CNS effects
4. Outer/ middle Ear Side-effects
- ceruminous
- ear pain
- otitis------ :media
:externa
 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 delayed
6. Already had ototoxic reaction before
7. Too much drug,either in amount or doses
8. Dehydration
 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<<,--- cellular
disruption
Aminoglycosides ototoxicities:
- gentamicin
- tobramycin
---- 6-13 %
- amikacin
- streptomycin
- netilmycin---- 2,4 %

Symptoms of ototoxic can be delayed-- 6 weeks

after completion of AG therapy; however 50%
will recover 1 week to 6 months after discontinu-
ation
 Streptomycin
tends to cause more damage to the vestibular portion 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.
 Neomycin
has the greatest cochleotoxic effect of all
antibiotics.
When large doses are given orally or by colonic
irrigation for intestinal sterilization, enough may be
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.
 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
 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 a
decrease 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:
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 %
However:

I. These otoprotectors shown to reduce

the antineoplastic effect of cisplatin.
II .Toxic at high doses
 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
 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
Mechanism action: probably by:
= change in the cochlear permeability of the
outer hair cells

Other theory:

= a change in the cochlear blood supply as a

result of salicylate-induced imbalance of
vaso-dilatory prostaglandin and
vasoconstricting leukotriene
 Loop diuretic ototoxicity
Mahler and Schreiner (1965):
= reversible SNHL and vertigo after i.v adm. of
loop diuretic ,i.e ethacrynic acid and
furosemide
- high dose
- low dose but rapidly
- existing hearing deficits
- severe hypoalbuminemia
- heart or liver failure
Mechanism of action
= damage the stria vascularis
= damage the outer hair cells of cochlea

by inhibiting Na-K ATP-Ase and

Adenyl cyclase in the stria
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 ototoxic
drugs.
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
 Table 1

Some Drugs that Cause Ototoxicity

Type Examples
Antibiotics Aminoglycosides
Vancomycin

Chemotherapeutic Platinum-containing drugs (eg, cisplatin )

drugs

Diuretics Ethacrynic acid

Furosemide

Other Quinine

Salicylates
 Drug-induced smell disorders
Usually ,smell disorders----- taste
disorders.
 Can You Smell That?

Anatomy and Physiology of Smell

Baca anatomi & fisiologi

 I sense a hint of Yasmine and roses
Many depend upon smell for livelihood or safety:
Cooks
Homemakers
Firefighters
Plumbers
Wine merchants
Perfumers
Cosmetic retailers
Chemical Plant Workers
 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
 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 function and
often interpreted as hypersensitivity to odors
Dysosmia: distorted or perverted smell perception
 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
Olfactory connections to the Brain
 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
 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
 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
 Medications (continued)
Psychopharmacologics: Carbamazepine;
Lithium; Phenytoin; Psilocybin;
Trifluoperazine
Sympathomimetic drugs: Amphetamines;
Phenmetrazine; Fenbutrazate
Vasodilators: Oxyfedrine; Bamifylline
Others: Germine monoacetate;
Idoxuridine; Iron sorbitex; Vitamin D
 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
 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 A
supplementation and found successful restoration
of at least partial olfactory ability in 50 of 56 pts
Other authors unable to reproduce benefit
 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
 Managing Olfactory Loss
If no known causes found: reassurance
Discuss improving seasoning of diet for
remaining sensory modalities
Emphasize taste, color, texture, viscosity and
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
 Otic Medications
Must be at room temperature or body
temperature
heated drops may cause rupturing of the
eardrum
cold drops can cause vertigo and discomfort
Old medication should be removed along with
any drainage before applying fresh medication
Alcohol causes pain and burning sensation
should not be used if the patient has a
ruptured tympanic membrane (eardrum)
 Otic Medications
Tilt head to side with ear
facing up
2 to 5 minutes
Cotton swabs placed in the
Patients under 3
should have lobes
pulled down and
back.

ear after administration of

drops will prevent excess
medication from dripping
out of the ear
swabs will not reduce Patients over 3
should should have
drug absorption lobes pulled up and
back
 Nasal Medications
Applied by:
drops (instillation)
sprays
aerosol (spray under pressure)

Used for:
relief of nasal congestion or allergy
symptoms
administration of flu vaccine
 Nasal Medications
Patient should:
tilt head back
insert dropper or spray or aerosol tip into the
nostril pointed toward the eyes
apply prescribed number of drops or sprays in
each nostril
Breathing should be through mouth to
avoid sniffing medication into the sinuses
Important not to overuse nasal
decongestants
follow label instructions carefully
 Ophthalmic Medications

Ear drops can never be used in the eye, but eye

drops can be used in the ear.
 Conclusions
One of the most primitive of our senses
Strong correlation with many of our other
senses, our memories, and quality of life in
general
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