AMINOGLYCOSIDES

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AMINOGLYCOSIDES

• The different members of this group share many
  properties in common.

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AMINOGLYCOSIDES

• Streptomycin
• Gentamicin
• Tobramycin
• Amikacin
• Netilmicin
• Kanamycin
• Neomycin

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AMINOGLYCOSIDES

• Amino sugars linked through glycosidic bonds.
• Polycations This is in part responsible for many
  of their shared pharmacokinetic properties

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ANTIBACTERIAL ACTIVITY

• Primarily active against aerobic gram negative
  bacteria.
• Active against many staphylococci and certain
  Mycobacteria.
• Anaerobic bacteria are not susceptible.

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SENSITIVITY AND RESISTANCE
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AMINOGLYCOSIDE TRANSPORT

• Transport across the cell membrane is by active
  transport.
• Antimicrobial activity is reduced in an anaerobic
  environment and at low pH.

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RESISTANCE

• Cross-resistance occurs to varying degrees with
  the different aminoglycosides.
• Amikaciin

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ABSORPTION AND DISTRIBUTION

• Oral bioavailability is low.
• Once daily dosing (postantibiotic effect).
• Distribution into most body tissues including the
  CNS is low.

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EXCRETION

• Rapidly and almost entirely excreted by
  glomerular filtration (proportional to creatinine
  clearance).
• Accumulation occurs with impaired renal function.

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PHARMACOKINETICS

• Monitor the serum concns of the drugs (T.I. is
  close to 1).

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THERAPEUTIC USES

• Severe , complicated infections.
• Often combined with ß-lactams.

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STREPTOMYCIN

• Bacterial endocarditis (combined with a
  penicillin or vancomycin).
• Tuberculosis.

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Gentamicin, Tobramycin, Netilmicin and Amikacin

• Similar in clinical indications and range of
  activity.
• Gentamicin is often preferred but resistance may
  limit its use.

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THERAPEUTIC USES

• Serious gram negative infections especially those
  due to Pseudomonas, Enterobacter, Klebsiella,
  Serratia etc.
• UTIs, bacteremia, meningitis, infected burns,
  pneumonia, osteomyelitis, ear infections etc.

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THERAPEUTIC USES

• Severe Pseudomonas infections are best treated
  with one of these 4 AGs plus an antipseudomonal
  penicillin or cephalosporin.
• Gentamicin combined with a penicillin is often
  used to treat bacterial endocarditis.

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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.

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DRUG INTERACTIONS

• Antipseudomonal penicillins inactivate
  aminoglycosides.
• Ethacrynic acid and other loop diuretics.
• Nephrotoxic agents.
• Neuromuscular blocking agents.

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SHARED PROPERTIES OF THE AMINOGLYCOSIDES
Inhibit protein synthesis by binding to the 30S ribosomal subunit
Pharmacokinetics-Poorly absorbed from the GI tract, Dont get into the CNS very well, Rapidly excreted by kidney
Toxicity-Ototoxicity, Nephrotoxicity, Neuromuscular blockade
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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 negative- infections
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Wheel of Bugs
Gram-negative
H. influenzae
Neissseria spp
E. Coli (coliforms)
Bacteroides spp
P. aeruginosa
Anaerobic
Clostridium spp
S. aureus
Streptococcus spp
Enterococcus spp
Gram-positive
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MECHANISM OF ACTION

• Bactericidal.
• They inhibit protein synthesis by binding
  irreversibly to the 30S ribosomal subunit.

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A
50S
Nascent polypeptide chain
Transferase site
aa
mRNA
template
P
AGs
30S
Mechanism of action of Aminoglycosides
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Mature protein
Blocks initiation
Growing polypeptide
50S
Premature termination
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Wrong amino acid is incorporated
30S
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mRNA translation
aminoglycoside
Effects of Aminoglycosides
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Aminoglycosides on Protein Synthesis
Mature Protein
Growing Polypeptide
50S
AUG
3
5
30S

mRNA translation
Amino Glycoside
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MECHANISM OF ACTION

• Exact mechanism of cell death is unknown.
• Postantibiotic effect.

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RESISTANCE

• Alterations in ribosomal proteins.
• Decreased permeability to the antibiotic.
• Induction of bacterial enzymes that inactivate
  these drugs.

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RESISTANCE

• Alterations in ribosomal proteins.
• Decreased permeability to the antibiotic.

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TOXICITY

• Ototoxicity (Vestibular and Auditory).
• Nephrotoxicity.
• Neuromuscular Blockade.

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OTOTOXICITY

• The most serious toxic effect (uncommon,
  irreversible and cumulative).
• Caused by all the aminoglycosides

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OTOTOXICITY

• Both auditory and vestibular dysfunction can
  occur.
• Results from destruction of sensory hair cells.

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OTOTOXICITY

• Several factors increase the risk.
• Careful monitoring is important.

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NEPHROTOXICITY

• Aminoglycosides accumulate in the renal cortex
  (mainly proximal tubules).
• Several factors may increase the risk.
• Reversible and usually mild.
• Reduced excretion can lead to ototoxicity.

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NEPHROTOXICITY

• Several factors may increase the risk.
• Reversible and usually mild.
• Reduced excretion can lead to ototoxicity.

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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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NEUROMUSCULAR BLOCKADE

• Results from decreased ACH release and decreased
  postsynaptic sensitivity.
• Treated with supportive measures and calcium (or
  neostigmine).