Aminoglycoside and it's uses , side effect

About aminoglycoside

1. Aminoglycosides

2. Aminoglycosides
•Allaminoglycosidesareproducedbysoil
actinomycetes.
•Obtainedfromthespeciesof
–Streptomyces(suffixmycin)
–andMicromonospora(suffixmicin)
•Semisyntheticderivativesalsoendupwithsuffix
micin.

3. Aminoglycosides
Streptomycin
Gentamicin
Tobramycin
Amikacin
Kanamycin
Neomycin
Paromomycin
Framycetin

4. Spectrum
•Narrowspectrum
–Aerobic gram negative bacilli
–Not effective against
•gram positive cocci & bacilli
•gram negative cocci
•andanaerobes

5. Mechanism of action

6. •Penetratethroughthebacterialcellwall
throughporinchannels
•entertheperiplasmicspace.
•Transported across the cytoplasmic
membrane
•Onceinsidethecell
•Thesedrugsbindto30Sribosomalunits
andpreventtheformationof“initiation
complex”–aprerequisiteforpeptide
synthesis.

7. •Accumulation of abnormalinitiation
complexes
•Misreadingof mRNA template
•Incorporation of incorrectaminoacids
into the growing peptide.
•Aberrantproteins

8. How ?????
Bactericidal

9. •Secondary changes in the bacterial cell
membrane
–resultant aberrant proteins may be insertedinto
the cell membrane
–Disruption of cytoplasmic membrane
–Altered permeability
–Sensitive bacteria become more permeable
–Ions, aminoacids, and even proteinsleak out
followed by bacterialcell death.

10. •Altered cell membrane
–Augmentationof carrier mediated entryof
the antibiotic
–Reinforcesthe lethalaction of
aminoglycoside.

11. Aminoglycosides
•Bactericidalantibiotics
•Rapidly bactericidal
•Bacterial killing -concentration
dependenthigher the concentration
greater the rate at which bacteria are
killed

12. •Penetratethroughthebacterialcellwall
throughporinchannelstoenterthe
periplasmicspace.
–So -lactam antibiotics which weaken/
inhibit bacterial cell wall synthesis
Facilitate passive diffusion of
aminoglycosides if given together
(synergistic action)
–-lactam antibiotics + Aminoglycosides

13. •Transported across the
cytoplasmic membrane
–Transport is blockedby
•anaerobicconditions
–Anaerobes not sensitive

14. •They also exert a long & concentration dependent
post antibiotic effectthat is, residual
bactericidal activity persisting after the serum
concentration has fallen below the minimum
inhibitory concentration
•duration of this effect is concentrationdependent.
•Characteristic feature

15. 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

16. •Given as a single daily dose results in a
higher peak tissue concentrationthan if the
total daily dose were divided and
administered at 8 or 12 hourly interval.

17. Pharmacokinetics

18. •Highly polardrugs
–very poor oralbioavailability
–hence given I.V. orI.M.
–Rapid absorption from i.m. sites.
•Poorly distributedand poorly protein
bound
–P/E -fail to reach intraocular fluid, or CSF,
–Highly polar drugs

19. •Gentamycin-cross BBBin meningeal
inflammation.
–Can be used in cerebral meningitis.
•Excreted through kidney, unchanged
•All are more active at alkaline pH than
acidic.

20. Antibacterial resistance

21. Threeprincipal 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 deletionor alterationof the receptor protein
on 30S (Target)ribosomal unit because of
mutations. Attachment of drug with 30S
ribosomal unit is thus prevented.

22. Toxicity

23. OtotoxicityNephrotoxicity
Neuromuscular
blockade

24. Ototoxicity
•Accumulate in the endolymphand
perilymphof inner ear
•Vestibular/cochlear sensory cells & hairs
undergo concentration dependent destructive
changes.
•leading to vestibularand cochleardamage
which is irreversible.

25. •Dose& durationof treatment related
adverse effect
•Drugs concentrated in labrinthine fluid,
slowly removed as plasma levels fall.
•Ototoxicity greater when plasma levels
are persistently high.

26. •Old patients more susceptible.
•Vestibulartoxicity is more with
Streptomycin & Gentamycin
•Cochleartoxicity is more with
neomycin & amikacin.

27. Nephrotoxicity
•Attainhigherconcentrationintherenalcortex
•Manifests as tubular damageresulting in
–loss of urinary concentrating power
–low g.f.r.
–nitrogen retention
–albuminuria & casts.

28. •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 nephrotoxicityis
–reduced clearance of antibiotic
–higher blood levels
–enhanced Ototoxicity.

29. •neomycin, gentamicin, amikacinand
tobramycinare more nephrotoxic than
streptomycin.
•10-15%ofallrenalfailurecases.

30. Neuromuscular blockade
•Unusual toxic reaction
•Inhibit pre-junctional release of
acetylcholine from cholinergic neurons.
•Reduce postsynaptic senstivity to the
transmitter

31. •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

32. Precautions & Interactions

33. •Pregnancy–risk of foetal ototoxicity
•Patients past middleage; compromised renal
functions.
•Patients with kidneydamage
•Avoid concurrent use of
Ototoxic drugsminocycline & high ceiling diuretics
Nephrotoxic drugsamphotericin B, vancomycin,
cyclosporin & cisplatin
Muscle relaxants.
•Do not mix it with any drug in the same syringe/infusion bottle.

34. Therapeutic uses

35. Gentamycin
•Economical& firstlineaminoglycoside
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.

36. •SABE: Gentain combination with
penicillinsynergistic, 4-6 weeks
treatment.
•Meningitiscaused by g-ve bacilli.
–III gen. cephalosporins preferred.

37. 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.

38. AMIKACIN
•Resistance to aminoglycoside
inactivating enzymes special role in
seriousnosocomialG-vebacillary
infectionsin hospitals where
gentamycinand tobramycinresistant
microorganisms are prevalent.

39. Netilmicin
•As it is not metabolised by
aminoglycoside inactivating enzymes so
active against bacteria resistantto
gentamycin

40. Kanamycin
•Use declined
•Most toxic

41. NEOMYCIN
•Wide spectrum aminoglycoside
•Gramnegativebacilli& some grampositivecocci
•Highly toxicto internal ear & kidney, not used
systemically.
•Poorly absorbed from GIT
•Oral & topical administration does not cause
systemic toxicity.

42. •Topical uses
–Infected wounds ulcers, burn,
external ear infections, conjunctivitis
etc.
–Combination with polymixin,
bacitracin
•Oral uses
–Preparation of bowel before surgery
–Hepatic coma.

43. Hepatic coma:
•NH
3produced by colonic bacteria, detoxified
by liver, urea.
•Hepatic failure detoxification does not occur
blood NH
3level rises & produces
encephalopathy.
•Neomycinsuppresses intestinal flora,
diminishes NH
3production & lowers its blood
level. Clinical improvement in 2-3 days.
•Lactulosepreferred.

44. Framycetin
•Same as neomycin
•Too toxic for systemic administration
•Used topicallyon skin, eye, ear in the same
manner as neomycin
Soframycin
1% skin cream,
0.5% eye drops or ointments

45. Thank you