Download Aminoglycosides

Aminoglycosides
Aminoglycosides
• All aminoglycosides
actinomycetes.
are
produced
by
soil
• Obtained from the species of
– Streptomyces (suffix mycin)
– and Micromonospora (suffix micin)
• Semisynthetic derivatives also end up with suffix
micin.
Aminoglycosides
Streptomycin
Gentamicin
Tobramycin
Amikacin
Kanamycin
Neomycin
Paromomycin
Framycetin
Spectrum
• Narrow spectrum
–Aerobic gram negative bacilli
–Not effective against
• gram positive cocci & bacilli
• gram negative cocci
• and anaerobes
Mechanism of action
• Penetrate through the bacterial cell wall
through porin channels
• enter the periplasmic space.
• Transported across the cytoplasmic
membrane
• Once inside the cell
• These drugs bind to 30S ribosomal units
and prevent the formation of “initiation
complex” – a prerequisite for peptide
synthesis.
• Accumulation of abnormal initiation
complexes
• Misreading of mRNA template
• Incorporation of incorrect aminoacids
into the growing peptide.
• Aberrant proteins
How ?????
Bactericidal
• Secondary changes in the bacterial cell
membrane
– resultant aberrant proteins may be inserted into
the cell membrane
– Disruption of cytoplasmic membrane
– Altered permeability
– Sensitive bacteria become more permeable
– Ions, aminoacids, and even proteins leak out
followed by bacterial cell death.
• Altered cell membrane
–Augmentation of carrier mediated entry of
the antibiotic
–Reinforces the lethal action of
aminoglycoside.
Aminoglycosides
• Bactericidal antibiotics
• Rapidly bactericidal
• Bacterial killing - concentration
dependent higher the concentration
greater the rate at which bacteria are
killed
• Penetrate through the bacterial cell wall
through porin channels to enter the
periplasmic space.
–So -lactam antibiotics which weaken/
inhibit bacterial cell wall synthesis
Facilitate passive diffusion of
aminoglycosides if given together
(synergistic action)
–-lactam antibiotics + Aminoglycosides
• Transported across the
cytoplasmic membrane
–Transport is blocked by
• anaerobic conditions
–Anaerobes not sensitive
• They also exert a long & concentration dependent
post antibiotic effect that is, residual
bactericidal activity persisting after the serum
concentration has fallen below the minimum
inhibitory concentration
• duration of this effect is concentration dependent.
• Characteristic feature
Post antibiotic effect
• Account for efficacy of once daily dosing
regimens of aminoglycosides. Short half
life(2-4 hrs)(2-3 divided doses).
• Single daily dose as effective as multiple
dosing.
• No more toxic & even less toxic, Less renal
accumulation, less toxic
• Given as a single daily dose results in a
higher peak tissue concentration than if the
total daily dose were divided and
administered at 8 or 12 hourly interval.
Pharmacokinetics
• Highly polar drugs
–very poor oral bioavailability
–hence given I.V. or I.M.
–Rapid absorption from i.m. sites.
• Poorly distributed and poorly protein
bound
–P/E - fail to reach intraocular fluid, or CSF,
–Highly polar drugs
• Gentamycin - cross BBB in meningeal
inflammation.
– Can be used in cerebral meningitis.
• Excreted through kidney, unchanged
• All are more active at alkaline pH than
acidic.
Antibacterial resistance
Three principal mechanisms for the development of
resistance:
• Synthesis of plasmid mediated bacterial
transferase enzymes that can inactivate
aminoglycosides.
• Mutation/deletion of porin channels resulting in
decreased transport of aminoglycoside into the
bacterial cytosol.
• By deletion or alteration of the receptor protein
on 30S (Target) ribosomal unit because of
mutations. Attachment of drug with 30S
ribosomal unit is thus prevented.
Toxicity
Ototoxicity
Nephrotoxicity
Neuromuscular
blockade
Ototoxicity
• Accumulate in the endolymph and
perilymph of inner ear
• Vestibular/cochlear sensory cells & hairs
undergo concentration dependent destructive
changes.
• leading to vestibular and cochlear damage
which is irreversible.
• Dose & duration of treatment related
adverse effect
• Drugs concentrated in labrinthine fluid,
slowly removed as plasma levels fall.
• Ototoxicity greater when plasma levels
are persistently high.
• Old patients more susceptible.
• Vestibular toxicity is more with
Streptomycin & Gentamycin
• Cochlear toxicity is more with
neomycin & amikacin.
Nephrotoxicity
• Attain higher concentration in the renal cortex
• Manifests as tubular damage resulting in
–loss of urinary concentrating power
–low g.f.r.
–nitrogen retention
–albuminuria & casts.
• More in elderly & patient with pre-existing
renal disease.
• Totally reversible (PCT cells regenertae
)provided drug is promptly discontinued.
• An important implication of aminoglycoside
induced nephrotoxicity is
– reduced clearance of antibiotic
– higher blood levels
–enhanced Ototoxicity.
• neomycin, gentamicin, amikacin and
tobramycin are more nephrotoxic than
streptomycin.
• 10-15% of all renal failure cases.
Neuromuscular blockade
• Unusual toxic reaction
• Inhibit pre-junctional release of
acetylcholine from cholinergic neurons.
• Reduce postsynaptic senstivity to the
transmitter
• Intrapleural/intraperitoneal
instillation of large doses of AG
Reaction can follow after i.v, im, oral
• Association with anaesthesia
• Co-administration of other NM
blocking agents
• Patients with Myasthenia gravis
particularly susceptible to NMB by AG
Precautions & Interactions
• Pregnancy – risk of foetal ototoxicity
• Patients past middle age; compromised renal
functions.
• Patients with kidney damage
• Avoid concurrent use of
Ototoxic drugs minocycline & high ceiling diuretics
Nephrotoxic drugs amphotericin B, vancomycin,
cyclosporin & cisplatin
Muscle relaxants.
•
Do not mix it with any drug in the same syringe/infusion bottle.
Therapeutic uses
Gentamycin
• Economical & first line aminoglycoside
antibiotic
• Low therapeutic index: use is restricted to
serious gram negative bacillary
infections.
–Psuedomonas , Proteus , Kleibsiella
infections :burns, UTI, pneumonia, lung
abcesses, osteomyelitis are important areas
of use of gentamycin.
• SABE: Genta in combination with
penicillin synergistic, 4-6 weeks
treatment.
• Meningitis caused by g-ve bacilli.
–III gen. cephalosporins preferred.
Streptomycin
• Bacterial Endocarditis:
– Enterococcal
– in combination with penicillin, synergistic, 4-6 weeks
treatment
– Gentamicin preferred; lesser toxicity
• Tuberculosis: multi drug regime
• Plague: effective agent for all forms of plague.
• Tularaemia: DOC for this rare disease.
AMIKACIN
• Resistance to aminoglycoside
inactivating enzymes special role in
serious nosocomial G-ve bacillary
infections in hospitals where
gentamycin and tobramycin resistant
microorganisms are prevalent.
Netilmicin
• As it is not metabolised by
aminoglycoside inactivating enzymes so
active against bacteria resistant to
gentamycin
Kanamycin
• Use declined
• Most toxic
NEOMYCIN
• Wide spectrum aminoglycoside
• Gram negative bacilli & some gram positive cocci
• Highly toxic to internal ear & kidney, not used
systemically.
• Poorly absorbed from GIT
• Oral & topical administration does not cause
systemic toxicity.
• Topical uses
–Infected wounds ulcers, burn,
external ear infections, conjunctivitis
etc.
–Combination with polymixin,
bacitracin
• Oral uses
–Preparation of bowel before surgery
–Hepatic coma.
Hepatic coma:
• NH3 produced by colonic bacteria, detoxified
by liver, urea.
• Hepatic failure detoxification does not occur
blood NH3 level rises & produces
encephalopathy.
• Neomycin suppresses intestinal flora,
diminishes NH3 production & lowers its blood
level. Clinical improvement in 2-3 days.
• Lactulose preferred.
Framycetin
• Same as neomycin
• Too toxic for systemic administration
• Used topically on skin, eye, ear in the same
manner as neomycin
Soframycin
1% skin cream,
0.5% eye drops or ointments
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