DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

ionic balance of the endolymph (Neu and Bendush,
1976). Ototoxicity is largely irreversible and results from
progressive destruction of vestibular or cochlear sensory
cells, which are highly sensitive to damage by aminoglycosides.
The degree of permanent dysfunction correlates
with the number of destroyed or altered sensory hair cells
and is related to sustained exposure to the drug. An ironaminoglycoside
complex is postulated to potentiate reactive
oxygen species–induced cellular degeneration in the
cochlea (Guthrie, 2008).
Accumulation within the perilymph and endolymph occurs
predominantly when aminoglycoside concentrations in plasma are
high. Diffusion back into the bloodstream is slow; the half-lives of
the aminoglycosides are five to six times longer in the otic fluids
than in plasma. Back diffusion is concentration dependent and facilitated
at the trough concentration of drug in plasma Thus, it is generally
thought that ototoxicity is more likely to occur in patients with
persistently elevated concentrations of drug in plasma. However,
studies have not consistently shown an association between ototoxicity
and putative risk factors such as aminoglycoside serum levels,
total dose and duration of aminoglycoside exposure, and renal dysfunction
(including aminoglycoside-induced nephrotoxicity) (de
Jager and van Altena, 2002; Peloquin et al., 2004). Drugs such as
ethacrynic acid and furosemide potentiate the ototoxic effects of the
aminoglycosides in animals, but data from humans implicating
furosemide are less convincing (Moore et al., 1984). Hearing loss
following exposure to these agents also is more likely to develop in
patients with pre-existing auditory impairment.
The description of families where several members experienced
profound deafness from as little as a single dose of aminoglycoside
led to the investigation of a potential genetic predisposition
for this toxicity. Subsequent studies have identified several predisposing
mutations in mitochondrial ribosomal RNA genes (Fischel-
Ghodsian, 2005). The contribution of genetic susceptibility to the
overall incidence of aminoglycoside-induced ototoxicity is unclear,
but surveys of subjects of European origin put the prevalence of one
of these mutations at 1 in 500 (Vandebona et al., 2009).
Although all aminoglycosides can affect cochlear and vestibular
function, there is some preferential toxicity. Streptomycin and gentamicin
produce predominantly vestibular effects, whereas amikacin,
kanamycin, and neomycin primarily affect auditory function;
tobramycin affects both equally. The incidence of ototoxicity is difficult
to determine. Audiometric data suggest that the incidence may
be as high as 25% (de Jager and van Altena, 2002); however, these
data need to be interpreted in the context of the limitations of audiometric
testing in acutely ill patients and day-to-day variability of
audiometric testing (Brummett and Morrison, 1990). The relative
incidence appears to be equal for tobramycin, gentamicin, and
amikacin. Initial studies suggested that netilmicin is less ototoxic than
other aminoglycosides (Lerner et al., 1983); however, the incidence
of ototoxicity from netilmicin is not negligible—such complications
developed in 10% of patients in one clinical trial of netilmicin. The
incidence of vestibular toxicity is particularly high in patients receiving
streptomycin; nearly 20% of individuals who received 500 mg
twice daily for 4 weeks for enterococcal endocarditis developed clinically
detectable irreversible vestibular damage (Wilson et al., 1984).
In addition, up to 75% of patients who received 2 g streptomycin for
>60 days showed evidence of nystagmus or postural imbalance.
Because the initial symptoms may be reversible, patients
receiving high doses and/or prolonged courses of aminoglycosides
should be monitored carefully for ototoxicity; however, deafness
may occur several weeks after therapy is discontinued. Screening
patients for a family history of aminoglycoside-induced deafness
seems reasonable, but the cost effectiveness of genetic screening for
mutations predisposing to aminoglycoside ototoxicity is not yet clear.
Clinical Symptoms of Cochlear Toxicity. A high-pitched tinnitus often
is the first symptom of toxicity. If the drug is not discontinued, auditory
impairment may develop after a few days. The tinnitus may persist
for several days to 2 weeks after therapy is stopped. Because perception
of sound in the high-frequency range (outside the conversational
range) is lost first, the affected individual is not always aware
of the difficulty, and it will not be detected except by careful audiometric
examination. If the hearing loss progresses, the lower sound
ranges are affected, and conversation becomes difficult.
Clinical Symptoms of Vestibular Toxicity. Moderately intense
headache lasting 1-2 days may precede the onset of labyrinthine dysfunction.
This is followed immediately by an acute stage in which
nausea, vomiting, and difficulty with equilibrium develop and persist
for 1-2 weeks. Prominent symptoms include vertigo in the
upright position, inability to perceive termination of movement
(“mental past-pointing”), and difficulty in sitting or standing without
visual cues. Drifting of the eyes at the end of a movement so that
both focusing and reading are difficult, a positive Romberg test, and
rarely, pendular trunk movement and spontaneous nystagmus, are
prominent signs. The acute stage ends suddenly and is followed by
the appearance of manifestations of chronic labyrinthitis, in which,
although symptomless while in bed, the patient has difficulty when
attempting to walk or make sudden movements; ataxia is the most
prominent feature. The chronic phase persists for ~2 months; it is
gradually superseded by a compensatory stage in which symptoms
are latent and appear only when the eyes are closed. Adaptation to
the impairment of labyrinthine function is accomplished by the use
of visual cues and deep proprioceptive sensation for determining
movement and position. It is more adequate in the young than in the
old but may not be sufficient to permit the high degree of coordination
required in many special trades. Recovery from this phase may
require 12-18 months, and most patients have some permanent residual
damage. Although there is no specific treatment for the vestibular
deficiency, early discontinuation of the drug may permit recovery
before irreversible damage of the hair cells.
Nephrotoxicity. Approximately 8-26% of patients who receive an
aminoglycoside for several days develop mild renal impairment that
is almost always reversible. The toxicity results from accumulation
and retention of aminoglycoside in the proximal tubular cells
(Lietman and Smith, 1983). The initial manifestation of damage at
this site is excretion of enzymes of the renal tubular brush border
(Banday et al., 2008). After several days, there is a defect in renal
concentrating ability, mild proteinuria, and the appearance of hyaline
and granular casts. The glomerular filtration rate is reduced after several
additional days (Schentag et al., 1979). The non-oliguric phase
of renal insufficiency is thought to be due to the effects of aminoglycosides
on the distal portion of the nephron with a reduced sensitivity
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CHAPTER 54
AMINOGLYCOSIDES