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Aminoglycosides

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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

 


©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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