Gentamicin Ototoxicity

and Exam Review

Gentamicin
• Gentamicin is the most common single identifiable cause of bilateral
vestibular loss that we encounter in our practice (Chicago Dizziness
and Hearing).
• The majority of cases are "idiopathic" -- meaning not an identifiable
source.
• updated: 2014.
Gentamicin
• Gentamicin is a member of the family of antibiotics called
aminoglycosides.
• All aminoglycosides are ototoxic.
• This includes kanamycin, tobramycin, streptomycin, neomycin
• Significant hearing ototoxicity reportedly occurs about 5-10% of the
time that gentamicin is given intravenously or during peritoneal
dialysis.
• However hearing in humans is generally affected only for high
frequencies (e.g. 8 and 12,000 Hz) or not at all.
Gentamicin Toxicity
• In pathologic studies, severe aminoglycoside toxicity is associated
with death of inner ear hair cells (Plogar et al, 2001).
• Doses that are not enough to kill hair cells may damage their motion
sensitive hairs (sterocilia), making them unable to respond to motion,
at least for some months.( Oei, Segenhout et al. 2004).
• In humans, pathologic and clinical data suggests that the otolithic hair
cells are less sensitive than the canal hair cells to gentamicin.
• In rodents however, it appears that both otoliths and canals are
affected equally (Oei, Segenhout et al. 2004).
Gentamicin Toxicity
• More temporal bone studies with humans are sorely needed !
• If you have gentamicin ototoxicity, please consider donating your
inner ear to the temporal bone registry, in the event of your death.
• The mechanism of aminoglycoside ototoxicity remains unknown but it
appears to involve both apoptotic (programmed cell death) pathways
as well as formation of free radicals (for a review see Forge and
Schacht, 2000).
• Some authors suggest that the mechanism of toxicity is through
reduction of mitochondrial protein synthesis (Guan et al, 2000).
Gentamicin Toxicity
• Nephrotoxicity (kidney damage) is more common than ototoxicity.
• In the Hartford hospital trial, it occurred in 1.2% of patients, roughly an order
of magnitude more frequently than ototoxicity.
• When the kidneys are damaged, gentamicin can build up and cause more
damage -- a very dangerous situation. For this reason kidney function is
usually monitored during courses of gentamicin, with serum creatinine levels.

• Certain serious infections are conventionally treated with a prolonged dose of

gentamicin or other drugs. These include osteomyelitis, and endocarditis as
well as serious and overwhelming infections.
Gentamicin Toxicity in Children
• Little is known about toxicity in children. Aust (2001) suggested that children are
less prone to develop vestibulotoxicity from gentamicin than adults.
• Fjalstad (2013) suggested that neonates are also less prone due to a higher volume
of distribution.
• This is not certain, however, as most animal data suggests the opposite. In mice,
newly born mice accumulate gentamicin sooner than adults (Steyger and Dai,
2003).
• In cat, neonates are also more sensitive to gentamicin than adults (Bernard 1981).
• Gentamicin is probably also toxic to the ear of the developing fetus as related
drugs (e.g. streptomycin) have been shown to have this problem (see Boradori et
al, 1997).
Diagnosis of Gentamicin Ototoxicity
• Diagnosis is generally not difficult.
• What is required is exposure to gentamicin, documentation of bilateral
vestibular reduction, and exclusion of reasonable alternatives.
• Although there are sporadic reports of individuals developing gentamicin
toxicity after a single ordinary dose (e.g. Halmagyi et al, 1994; Ahmed et
al, 2012), practically this is extremely rare and very unlikely.
• It probably requires the person to have a susceptibility mutation in their
mitochondria -- not a common situation at all.
• Most patients with significant and persistent gentamicin ototoxicity have
an exposure for 2 weeks or longer.
Why not all people given gentamicin develop
ototoxicity
• As discussed above, gentamicin toxicity is certainly not the rule, even
for month long courses of gentamicin. Why do some people get
toxicity and others don't ?
• dose and kidney function, especially "area under curve" of blood gentamicin
level.
• potentiating medications such as vancomycin
• susceptibility
• Age (In general, older people are more susceptible than younger people to
gentamicin toxicity)
Safe situations:

• Conventional doses of gentamicin, given for 1-3 days are highly

unlikely to cause toxicity (although there are occasional reports of
toxicity after a single dose)
• Gentamicin or other aminoglycosides administered as ingredients in
cement used for prosthetic joints or used to irrigate wounds are also
highly unlikely to cause toxicity. (Friberg et al, 2003)
• Gentamicin-impregnated beads, used for osteomyelitis, do not appear
to be a significant source of ototoxicity (Haydon et al, 1993).
Pharmacology Exam Review
 The Exam
• CA -
• MCQs
• Essay (-Long, and -Short)
• Viva (10 - 20 mins per candidate)
 MCQ
• Select on Best answer
• There is no negative marking
• review before submitting your booklet.
• keep an eye on time
 HOW TO STUDY
• Be able to identify main drug classes,
• Classification scheme, e.g., chemical; by main
mechanism(s) of action; by clinical use;
• Be able to cite a prototype drug for each. Conversely,
• Be able to work backward and
• know the rest of the most relevant information.
• relevant information are: MOA, PK, Clinical Indications,
and Adverse effects
• then add extras
 Adverse Drug Effects
• Be able to recognize the most common and/or most
important (e.g., serious or life-threatening) side effects or
adverse responses for the main drugs or drug classes.
• The more common and important ones are often
“extensions” of expected effects of the drug or class.
• For example, most antihypertensive drugs can cause
hypotension (when blood levels are excessive), and many
drugs cause nephrotoxicity and/or hepatotoxicity because
the kidneys or liver are the main sites of elimination of the
drugs, or their metabolites.
• Beta-adrenergic blockers can reduce cardiac rate,
contractility, and electrical impulse conduction velocity
(especially through the AV node), and sometimes these
drugs are used specifically to cause one or more of those
effects. You should then realize that excessive doses may
cause unwanted degrees of suppression of those cardiac
parameters.
 What are the factors that affect drug
absorption?
• pH and pKA
• Blood flow at the site of absorption
• Surface area at site of absorption
• Contact time
• Expression of P-glycoprotein (A transporter)
• Physico-chemical properties of the drug
 Factors affecting Bioavailability
• Route of administration
• Oral: Factors affecting drug absorption
• First pass effect
• Physico-chemical properties of the drug
 Factors affecting Drug Distribution
• Blood flow
• pH and pKA
• Capillary permeability
• Binding to plasma proteins
• Binding to tissue proteins
• Vd
 Short Essay
• LIST, Describe, mention
– Actions of
– Therapeutic uses/Clinical Indications
– Adverse effect
 Long Essay
• Mostly Systems Pharmacology
• Lecture Notes
• Classify the drugs in systems taught
• eg Dr Michael, Anti-DM (major drug is?), Anti-thyroid
(major drug is?), Calcium Metabolism (Drug Classes?)
 VIVA
• Be calm
• All is well
• Review your essay paper
• Remeber drug classes and major adverse effects
Other General tips

Preferably answer questions in the format given by the

lecturer who treated the subject, especially long essays
Usually two-three examples are enough
Use tables to simply your responses
Avoid abbreviations and “short hand”
Do not write on your question paper
Classifications are usually based of MOA or chemical classes
Short answer questions

ANSWER ALL QUESTIONS IN THE SECTION

Be very direct
Read the command word
Keep your answers short.
Use bullet points or tables.
Draw figures if necessary
“List” questions are common
 Acknowledgements
• Gentamicin Ototoxicity, by Timothy C. Hain, MD
• Various textbooks of Pharmacology