Aminoglycosides are antibacterial drugs used in the treatment of – predominantly – gram-negative infections. They are also inactive against anaerobic bacteria. Aminoglycosides work by inhibiting protein synthesis, specifically by binding irreversibly to the 30S ribosomal subunit. Examples of aminoglycosides include gentamicin, amikacin, netilmicin, and streptomycin. They are poorly absorbed from the gut and are therefore administered parenterally. Adverse effects are dose-related and include ototoxicity, renal damage and neuromuscular blockade. The pharmacology of aminoglycosides is such that they exacerbate weakness in those with myasthenia gravis. First, though, let's take a closer look at the pharmacology of aminoglycosides - how and why they work.
What are aminoglycosides?
Aminoglycosides are a class of drugs used, for the most part, in the treatment of aerobic gram-negative infections - anaerobes are simply unable to take up the drug. They are bactericidal in effect. The name of any given aminoglycoside is dependent on which organism it’s derived from.
Aminoglycosides with the suffix –mycin derive from the Streptomyces genus, whereas aminoglycosides with the suffix –micin – derive from the Micromonospora genus. Aminoglycosides are poorly absorbed from the gut, so they are administered to patients via the intravenous or intramuscular route.
Pharmacology of Aminoglycosides
Aminoglycosides are primarily effective against aerobic gram-negative bacteria, but are limited in effect with anaerobic gram-negatives and most gram-positives. They work by inhibiting protein synthesis, specifically by binding irreversibly to the 30S portion of the ribosome. This, in turn, inhibits translation from mRNA. It also increases the frequency by which misreading’s occur with the genetic code. For these reasons, aminoglycosides are bactericidal, and not bacteriostatic, in effect.
Despite this mechanism, resistance is still a problem – something which occurs by several means. Resistance is, among other ways, transferred by plasmids. This is caused by the production of enzymes which chemically modify the aminoglycoside drug in the bacterial periplasmic space. These chemical modifications include acetylation, phosphorylation, or through the addition of an adenylyl group. Resistance may also occur if the aminoglycoside cannot penetrate the cell wall.
In this case, aminoglycosides may be administered alongside penicillins – the latter of which disrupts cell wall synthesis. Some aminoglycosides – such as netilmicin – are less susceptible to these enzymatic changes, and is therefore a suitable alternative in patients who prove to have gentamicin-resistant strains. Resistant bacteria may also present with modified ribosomal subunits, thereby reducing drug binding and overall antibacterial effectiveness. This is particularly true in the case of streptomycin.
Aminoglycosides must be given via intravenous or intramuscular routes, not least because of their diabolical absorption from the gut. They all have relatively short half-lives, oscillating around the 1-4 hour mark. Aminoglycosides do not cross the blood-brain barrier, but they do cross the placenta. They are rapidly eliminated by the kidney. Tobramycin is available in IV, IM and inhalational routes – the latter of which is used to treat cystic fibrosis patients infected with Pseudomonas aeruginosa.
Adverse effects are dose-dependent – most of which are reversible. Ototoxicity and renal damage are two of the most prominent such effects. Ototoxicity may progress to such an extent where auditory loss becomes irreversible. Balance, too, is affected in this way. Mutations in the mitochondrial 12S ribosomal RNA gene predispose patients to these effects. Netilmicin causes less ototoxicity than other aminoglycosides. Retention of aminoglycosides in the proximal tubule of the kidney leads to renal damage. This damage is typically reversible.
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