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

1510 wounds, burns, or cutaneous ulcers, particularly if there is renal
insufficiency.
All the aminoglycosides are absorbed rapidly from intramuscular
sites of injection. Peak concentrations in plasma occur after
30-90 minutes and are similar to those observed 30 minutes after
completion of an intravenous infusion of an equal dose over a 30-minute
period. These concentrations typically range from 4-12 μg/mL following
a 1.5-2 mg/kg dose of gentamicin, tobramycin, or netilmicin
and from 20 to 35 μg/mL following a 7.5 mg/kg dose of amikacin or
kanamycin. In critically ill patients, especially those in shock,
absorption of drug may be reduced from intramuscular sites because
of poor perfusion.
There is increasing use of aminoglycosides administered via
inhalation, primarily for the management of patients with cystic
fibrosis who have chronic Pseudomonas aeruginosa pulmonary
infections. Amikacin and tobramycin solutions for injection have
been used, as well as a commercial formulation of tobramycin designed
for inhalation (TOBI, others). Studies of this formulation indicate
that high sputum concentrations are obtained (mean of 1200 μg/g),
but serum concentrations remain low (mean peak concentration
of 0.95 μg/mL) (Geller et al., 2002).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Distribution. Because of their polar nature, the aminoglycosides do
not penetrate into most cells, the CNS, or the eye. Except for streptomycin,
there is negligible binding of aminoglycosides to plasma
albumin. The apparent volume of distribution of these drugs is 25%
of lean body weight and approximates the volume of extracellular
fluid. The aminoglycosides distribute poorly into adipose tissue,
which must be considered when using weight-based dosing regimens
in obese patients. Approaches using ideal or adjusted body
weight are recommended in conjunction with drug-level monitoring
to avoid excessive serum concentrations.
Concentrations of aminoglycosides in secretions and tissues
are low. High concentrations are found only in the renal cortex and
the endolymph and perilymph of the inner ear; the high concentration
in these sites likely contribute to the nephrotoxicity and ototoxicity
caused by these drugs. As a result of active hepatic
secretion, concentrations in bile approach 30% of those found in
plasma, but this represents a very minor excretory route for the
aminoglycosides. Penetration into respiratory secretions is poor
(Panidis et al., 2005). Diffusion into pleural and synovial fluid is
relatively slow, but concentrations that approximate those in the
plasma may be achieved after repeated administration.
Inflammation increases the penetration of aminoglycosides into
peritoneal and pericardial cavities.
Concentrations of aminoglycosides achieved in CSF with
parenteral administration usually are subtherapeutic. In patients, concentrations
in CSF in the absence of inflammation are <10% of those
in plasma; this value may approach 25% when there is meningitis
(Kearney and Aweeka, 1999). Given the limit on dosage escalation
due to the toxicity of aminoglycosides, treatment of meningitis with
intravenous administration is generally suboptimal. Intrathecal or
intraventricular administration of aminoglycosides has been used to
achieve therapeutic levels, but the availability of third- and fourthgeneration
cephalosporins has made this unnecessary in most cases.
Penetration of aminoglycosides into ocular fluids is so poor that
effective therapy of bacterial endophthalmitis requires periocular and
intraocular injections of the drugs.
Administration of aminoglycosides to women late in pregnancy
may result in accumulation of drug in fetal plasma and amniotic
fluid. Streptomycin and tobramycin can cause hearing loss in
children born to women who receive the drug during pregnancy.
Insufficient data are available regarding the other aminoglycosides;
it is therefore recommended that they be used with caution during
pregnancy and only for strong clinical indications in the absence of
suitable alternatives.
Elimination. The aminoglycosides are excreted almost entirely by
glomerular filtration, and urine concentrations of 50-200 μg/mL are
achieved. A large fraction of a parenterally administered dose is
excreted unchanged during the first 24 hours, with most of this
appearing in the first 12 hours. The half-lives of the aminoglycosides
in plasma are similar, 2-3 hours in patients with normal renal
function. Renal clearance of aminoglycosides is approximately twothirds
of the simultaneous creatinine clearance; this observation suggests
some tubular reabsorption of these drugs.
After a single dose of an aminoglycoside, disappearance from
the plasma exceeds renal excretion by 10-20%; however, after 1-2 days
of therapy, nearly 100% of subsequent doses eventually is recovered in
the urine. This lag period probably represents saturation of binding sites
in tissues. The rate of elimination of drug from these sites is considerably
longer than from plasma; the t 1/2
for tissue-bound aminoglycoside
has been estimated to range from 30 to 700 hours. For this reason, small
amounts of aminoglycosides can be detected in the urine for 10-20 days
after drug administration is discontinued. Aminoglycoside bound to
renal tissue exhibits antibacterial activity and protects experimental animals
against bacterial infections of the kidney even when the drug no
longer can be detected in serum (Bergeron et al., 1982).
The concentration of aminoglycoside in plasma produced by
the initial dose depends only on the volume of distribution of the
drug. Because the elimination of aminoglycosides depends almost
entirely on the kidney, a linear relationship exists between the concentration
of creatinine in plasma and the t 1/2
of all aminoglycosides
in patients with moderately compromised renal function. In anephric
patients, the t 1/2
varies from 20-40 times that is determined in normal
individuals. Because the incidence of nephrotoxicity and ototoxicity
is likely related to the overall drug exposure to aminoglycosides, it
is critical to reduce the maintenance dosage of these drugs in
patients with impaired renal function.
Aminoglycosides can be removed from the body by either
hemodialysis or peritoneal dialysis. Approximately 50% of the
administered dose is removed in 12 hours by hemodialysis, which
has been used for the treatment of overdosage. As a general rule, a
dose equal to half the loading dose administered after each hemodialysis
should maintain the plasma concentration in the desired range;
however, a number of variables make this a rough approximation at
best. Continuous arteriovenous hemofiltration (CAVH) and continuous
venovenous hemofiltration (CVVH) will result in aminoglycoside
clearances approximately equivalent to 15 and 15-30 mL/min of
creatinine clearance, respectively, depending on the flow rate. The
amount of aminoglycoside removed can be replaced by administering
~15-30% of the maximum daily dose (Table 54–2) each day.
Frequent monitoring of plasma drug concentrations is again crucial.
Peritoneal dialysis is less effective than hemodialysis in
removing aminoglycosides. Clearance rates are ~5-10 mL/min for
the various drugs but are highly variable. If a patient who requires