Transcript Aminoglycosides

AMINOGLYCOSIDES

The different members of this group
share many properties in common.
AMINOGLYCOSIDES
Streptomycin
 Gentamicin
 Tobramycin
 Amikacin
 Netilmicin
 Kanamycin
 Neomycin

AMINOGLYCOSIDES


Amino sugars linked
through glycosidic
bonds.
Polycations: This is
in part responsible
for many of their
shared
pharmacokinetic
properties
ANTIBACTERIAL
ACTIVITY

Primarily active against aerobic gram negative
bacteria.

Active against many staphylococci and certain
Mycobacteria.

Anaerobic bacteria are not susceptible.
SENSITIVITY AND
RESISTANCE
AMINOGLYCOSIDE
TRANSPORT

Transport across the cell membrane is by
active transport.

Antimicrobial activity is reduced in an
anaerobic environment and at low pH.
RESISTANCE

Cross-resistance occurs to varying degrees with
the different aminoglycosides.

Amikaciin
ABSORPTION AND
DISTRIBUTION

Oral bioavailability is low.

Once daily dosing (postantibiotic effect).

Distribution into most body tissues
including the CNS is low.
EXCRETION

Rapidly and almost entirely excreted by
glomerular filtration (proportional to
creatinine clearance).

Accumulation occurs with impaired renal
function.
THERAPEUTIC USES

Severe , complicated infections.

Often combined with β-lactams.
STREPTOMYCIN

Bacterial endocarditis (combined with a
penicillin or vancomycin).

Tuberculosis.
Gentamicin, Tobramycin,
Netilmicin and Amikacin

Similar in clinical indications and range
of activity.

Gentamicin is often preferred but
resistance may limit its use.
THERAPEUTIC USES

Serious gram negative infections
especially those due to Pseudomonas,
Enterobacter, Klebsiella, Serratia etc.

UTI’s, bacteremia, meningitis, infected
burns, pneumonia, osteomyelitis, ear
infections etc.
THERAPEUTIC USES

Severe Pseudomonas infections are best
treated with one of these 4 AG’s plus an
antipseudomonal penicillin or
cephalosporin.

Gentamicin combined with a penicillin is
often used to treat bacterial endocarditis.
THERAPEUTIC USES

Tobramycin is often used in pseudomonal
infections.

Amikacin is used as the preferred agent
in hospitals.

Netilmicin- may be useful in resistant
infections.
DRUG INTERACTIONS

Antipseudomonal penicillins inactivate
aminoglycosides.

Ethacrynic acid and other loop diuretics.

Nephrotoxic agents.

Neuromuscular blocking agents.
SHARED PROPERTIES OF THE AMINOGLYCOSIDES
Inhibit protein synthesis by binding to
the 30S ribosomal subunit
Pharmacokinetics-Poorly absorbed
from the GI tract, Don’t get into the
CNS very well, Rapidly excreted by
kidney
Toxicity-Ototoxicity, Nephrotoxicity,
Neuromuscular blockade
THERAPEUTIC USES OF THE AMINOGLYCOSIDES
Streptomycin
T.B., Endocarditis
Gentamicin
Endocarditis, gram negative
infections, Pseudomonas
Tobramycin
Gram negative infections,
Pseudomonas
Amikacin
Reserve drug for gram negativeinfections
Nascent polypeptide
chain
50S
A
Transferase
site
aa
mRNA
template
P
30S
Mechanism of action of Aminoglycosides
AG’s
Mature protein
Blocks initiation
Growing polypeptide
5’
50S
3’
30S
AUG
Wrong amino acid is
incorporated
5’
mRNA translation
3’
Premature termination
5’
5’
AUG
3’
X
AUG
+ aminoglycoside
Effects of Aminoglycosides
3’
Aminoglycosides on Protein Synthesis
Mature Protein
Growing Polypeptide
5’
AUG
Blocks initiation
5’
3’
Premature termination
3’
50S
3’
5’
X
30S
+
mRNA translation
Amino
Glycoside
5’
3’
Incorporation of wrong amino acid
MECHANISM OF ACTION

Exact mechanism of cell death is
unknown.

Postantibiotic effect.
RESISTANCE

Alterations in ribosomal proteins.

Decreased permeability to the antibiotic.
TOXICITY

Ototoxicity (Vestibular and Auditory).

Nephrotoxicity.

Neuromuscular Blockade.
OTOTOXICITY
 The
most serious toxic effect
(uncommon, irreversible and
cumulative).
 Caused
by all the aminoglycosides
OTOTOXICITY

Several factors increase the risk.

Careful monitoring is important.
NEPHROTOXICITY



Several factors may increase the risk.
Reversible and usually mild.
Reduced excretion can lead to ototoxicity.
NEUROMUSCULAR
BLOCKADE

Rare but potentially serious.

Occurs at high concentrations of
aminoglycosides or in patients with an
underlying risk factor.

Acute neuromuscular blockade,
respiratory paralysis and death can
occur.
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