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

Aminoglycosides
Conan MacDougall
and Henry F. Chambers
The aminoglycoside group includes gentamicin,
tobramycin, amikacin, netilmicin (not available in the
U.S.), kanamycin, streptomycin, paromomycin, and
neomycin. These drugs are used primarily to treat infections
caused by aerobic gram-negative bacteria; streptomycin
is an important agent for the treatment of
tuberculosis, and paromomycin is used orally for intestinal
amebiasis and in the management of hepatic coma.
In contrast to most inhibitors of microbial protein synthesis,
which are bacteriostatic, the aminoglycosides are bactericidal
inhibitors of protein synthesis. Mutations
affecting proteins in the bacterial ribosome, the target for
these drugs, can confer marked resistance to their action.
However, most commonly resistance is due to acquisition
of plasmids or transposon-encoding genes for aminoglycoside-metabolizing
enzymes or from impaired transport
of drug into the cell. Thus, there can be cross-resistance
between members of the class.
These agents contain amino sugars linked to an
aminocyclitol ring by glycosidic bonds (Figure 54–1).
They are polycations, and their polarity is responsible
in part for pharmacokinetic properties shared by all
members of the group. For example, none is absorbed
adequately after oral administration, inadequate concentrations
are found in cerebrospinal fluid (CSF), and
all are excreted relatively rapidly by the normal kidney.
Although aminoglycosides are widely used and important
agents, serious toxicity limits their utility. All members
of the group share the same spectrum of toxicity,
most notably nephrotoxicity and ototoxicity, which can
involve the auditory and vestibular functions of the
eighth cranial nerve.
History and Source. Aminoglycosides are natural products or semisynthetic
derivatives of compounds produced by a variety of soil actinomycetes.
Streptomycin was first isolated from a strain of
Streptomyces griseus. Gentamicin and netilmicin are derived from
species of the actinomycete Micromonospora. The difference in
spelling (-micin) compared with the other aminoglycoside antibiotics
(-mycin) reflects this difference in origin. Tobramycin is one of several
components of an aminoglycoside complex (nebramycin) that is produced
by S. tenebrarius. It is most similar in antimicrobial activity and
toxicity to gentamicin. In contrast to the other aminoglycosides,
amikacin, a derivative of kanamycin, and netilmicin, a derivative of
sisomicin, are semisynthetic products. Other aminoglycoside antibiotics
have been developed (e.g., arbekacin, isepamicin, and sisomicin),
but they have not been introduced into clinical practice in the U.S.
because numerous potent, less toxic alternatives (e.g., broad-spectrum
β-lactam antibiotics and quinolones) are available.
Chemistry. The aminoglycosides consist of two or more
amino sugars joined in glycosidic linkage to a hexose
nucleus, which usually is in a central position (Figure
54–1). This hexose, or aminocyclitol, is either streptidine
(found in streptomycin) or 2-deoxystreptamine
(found in all other available aminoglycosides). These
compounds thus are aminoglycosidic aminocyclitols,
although the simpler term aminoglycoside is used commonly.
A related compound, spectinomycin, is an
aminocyclitol that does not contain amino sugars
(Chapter 55).
The aminoglycoside families are distinguished by the amino
sugars attached to the aminocyclitol. In the neomycin family, which
includes neomycin B and paromomycin, three amino sugars are
attached to the central 2-deoxystreptamine. The kanamycin and gentamicin
families have only two such amino sugars.
In the kanamycin family, which includes kanamycins A and B,
amikacin, and tobramycin, two amino sugars are linked to a centrally
located 2-deoxystreptamine moiety; one of these is a 3-aminohexose
(Figure 54–1).
Amikacin is a semisynthetic derivative prepared from
kanamycin A by acylation of the 1-amino group of the 2-deoxystreptamine
moiety with 2-hydroxy-4-aminobutyric acid.
The gentamicin family, which includes gentamicins C 1
, C 1a
, and
C 2
, sisomicin, and netilmicin (the 1-N-ethyl derivative of sisomicin),
contains a different 3-amino sugar (garosamine). Variations in methylation
of the other amino sugar result in the different components of
gentamicin (Figure 54–1). These modifications appear to have little
effect on biological activity.
Streptomycin differs from the other aminoglycoside antibiotics
in that it contains streptidine rather than 2-deoxystreptamine,
and the aminocyclitol is not in a central position, as shown here.