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Aminoglycosides
Mode of action
- bind to the A-site of the 30S subunit of bacterial ribosomes (mammalian
cells do not have a 30S subunit). This is an energy dependent process.
Binding disturbs elongation of the peptide chain.
- aminoglycosides also impair translational accuracy resulting in misreading
of the mRNA sequence and/or premature termination of protein synthesis
- poorly lipid soluble and therefore unable to pass through bacterial cell
membranes to reach target site.
- pass across outer membrane of gram -ve bacteria by a non-energy dependent
mechanism that involves the drug induced disruption of bridges between
lipopolysaccharide molecules
- transport across cytoplasmic (inner) membrane is dependent on the
transmembrane electrical potential and therefore is dependent on
energy-requiring mechanisms which maintain the transmembrane potential.
- anaerobic environments and low external pH result in a reduction in the
transmembrane potential and hence in the effectiveness of aminoglycosides
- the aberrant proteins produced as a result of misreading may be inserted
into the cell membrane, altering permeability and enhancing aminoglycoside
entry into bacterial cells
Resistance
- predominant mechanism is production of enzymes that inactivate functions
responsible for drug activity. Bacteria that produce several types of
enzymes are becoming more common. These bacteria exhibit resistance to a
multiple aminoglycosides
- membrane impermeability to aminoglycosides results in resistance to all
aminoglycosides
Pharmacodynamics
- concentration-dependent
killing
- post-antibiotic effect. Probably due to irreversible binding to ribosomes
- synergistic activity with antibiotics that act on cell wall synthesis as
these facilitate entry of aminoglycosides into bacteria
- antagonized by chloramphenicol and tetracyclines. Probably by inhibition
of energy-dependent uptake and interference with movement of ribosome along
mRNA
Adverse effects
- ototoxicity and neurotoxicity concentration dependent (high trough levels
much more helpful in predicting VIII damage and nephropathy than peak levels).
Aminoglycoside excretion closely related to GFR
- neuromuscular blockade is a minor pharmacological effect. Contra-indicated
in patients with myasthenia gravis
- occasionally antagonism of factor V may result in bleeding
- cross placenta and may cause VIII damage in the fetus and thus should not be
used in pregnancy
Further reading
Van Bambeke F. Mechanisms of action. In Armstrong D, Cohen J.
Infectious diseases. Mosby, London, 1999, pp7/1.1-7/1.14
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