Aminoglycosides
Content
Aminoglycosides
• Mechanism
of action
• Pharmacokinetics
• Adverse
effects
• Clinical
uses
Objectives
At the end of this session, students will be able to:
• List
various aminoglycosides
• Describe
the mechanism of action of aminoglycosides
• Outline
the pharmacokinetics of aminoglycosides
• Explain
the clinical uses of aminoglycosides
Aminoglycosides
• Two
amino sugar aminocyclitol (non-sugar) by a glycosidic bond
• In
streptomycin, aminocyclitol is placed lateral to the aminosugar (Streptose) in
turn joined by another amino sugar (N-methyl-L-glucosamine)
• Two
amino sugars jointly called streptobiosamine
• Obtained
from genus Streptomyces
Structure of aminoglycoside
Aminoglycosides Classification
• Streptomycin
• Gentamicin
• Sisomicin
• Netilmicin
• Kanamycin
• Tobramycin
• Amikacin
• Neomycin
• Paromomycin
• Soframycin
• Spectinomycin
Aminoglycosides – Mechanism of action
• Bactericidal,
Concentration dependent killing
• Post
antibiotic effect – dose dependent
• Drug
diffuses through outer coat of gram negative bacteria
• Aqueous
porin channels
• Reached
periplasmic space
• May
also bind to 50s ribosomal subunit
• Prevents
the formation of initiation complex
• Freezing
of protein synthesis
• Misreading
of genetic code on mRNA
• Incorporation
of incorrect aminoacids
• Loss
of cell membrane integrity
Mechanism of resistance
• Inactivation
of drug
– Plasmid
mediated acetyl transferase
– Plasmid
mediated adenyl transferase
– Plasmid
mediated phosphotransferase
• Restriction
in the entry of drug though deletion or mutation of channels
• Alteration
in the binding site
Pharmacokinetics
• Polar
cation – No absorption when given orally
• Given
parenteral (IM) or topical
• On
IM administration – good
bioavailability, peak plasma – 30-90 mins
• Accumulates
on pleural cavity and in synovial fluid
• Metabolism – insignificant
• In
pregnancy – accumulates in foetal plasma – hearing loss
• Excretion
– Kidney
Antimicrobial spectrum
Narrow spectrum – effective against gram positive bacteria
• Shigella
• Proteus
• Enterobacter
• Pseudomonas
aeruginosa
• Klebsiella
• Serratia
Adverse effects
Renal
toxicity – reversible
• Accumulation
in kidney
• Degranulation
of lysosome
• Release
of acid hydrolase
• Digestion
of cell organelles
• Digested
organelles are sloughed off
• Excreted
in urine
Ototoxicity
• Accumulates
in perilymph and endolymph
• Damage
to VIII cranial nerve
• Vestibular
toxicity – by streptomycin and gentamycin
– Ataxia
– Loss
of body balance
• Cochlear
toxicity – Neomycin and amykacin
– Hearing
difficulties
– Tinnitus
Neuro-muscular
blockade – during
• Deplacement
of calcium from neuromuscular junction
• Inhibition
of ach release
• Calcium
gluconate as i.v injection
• AchE
inhibitors
Clinical uses
• Streptomycin
– TB, plague, tularemia, Bacterial endocarditis
• Many
aminoglycosides are combined with penicillin and cephalosporins
• UTI,
hospital acquired pneumonia, osteomylitis, meningitis, peritonitis, burns and
otitis
Summary
• Aminoglycosides
consists of two amino sugar joined by aminocyclitol (non-sugar) by a glycosidic
bond
• They
act by inhibiting protein synthesis by binding to 30s and sometime 50s
ribosomal subunits
• Inhibited
by divalent cations
• Resistance
develops early
• Used
in TB, tularemia, bacterial endocarditis, UTI
• Associated
adverse effects like ototoxicity, renal toxicity and neuro muscular blockade