This document provides information on aminoglycoside antibiotics, including their mechanism of action, sites of action, classification, and examples like gentamicin and streptomycin. Aminoglycosides bind to bacterial ribosomes and inhibit protein synthesis, exerting a bactericidal effect. They are effective against many gram-negative bacteria but can cause adverse effects like ototoxicity and nephrotoxicity due to accumulation in tissues like the inner ear and kidneys. Precautions must be taken with dosing and combinations with other drugs to avoid toxicity issues.

1. AMINOGLYCOSIDE
ANTIBIOTICS
Presented by
Rajeshri V.Chindhalore
MPharm first year
Pharmacology Department
Smt.KishoritaiBhoyar College Of Pharmacy, Kamptee,
Nagpur

2. Index
• Introduction
• History and Source
• General Properties
• Classification
• Mechanism of action
• Mechanism of Resistance
• Pharmacokinetics
• Dosing Regimens
• Adverse Effects
• Different antibiotics
• Uses

3. Mechanism Of Bacterial Protein Synthesis
• Number of antibiotics exert their antimicrobial effect by targeting bacterial ribosomes and inhibiting
bacterial protein synthesis.
• Bacterial ribosomes differ structurally from Mammaliancytoplasmic ribosomes and are composed of 30S
and 50S subunit(Mammalianribosomes have 40S and 60S subunit).
Steps involved in bacterial protein synthesis
• Messenger RNA(mRNA)attaches to the 30S ribosome.
• Initiation complex of mRNA start protein synthesis and Polysome formation.
• Nacent peptide chain is attached to the peptidyl(P) site of the 50S ribosome.
• Next amino acid(a) is transported to the Acceptor(A) site of the ribosome by its specific tRNA which is
complementary to the base sequence of the next mRNA codon(C).
• Nascent peptide chain is transferred to the newly attached amino acid by peptide bond formation.
• Elongated peptide chain shifted back from ‘A’ to the ‘P’ site
• Ribosome moves along the mRNA to expose the next codon for amino acid attachment.
• Process terminated by he termination complex and the protein is released.

4. Fig.Different steps involved in the bacterial protein synthesis and the
site of action of antibiotics

5. Site of action of Antibiotics
1. Aminoglycocides:-Aminoglycosides bind to several sites at 30S and 50S subunit-
freeze initiation of protein synthesis,interfere with Polysome formation and cause
misreading of mRNA code.
2. Tetracycline:-Tetracycline bind to 30S ribosome and inhibit Aminoacyl tRNA
attachmentto the 'A’ site.
3. Chloramphenicol:-Chloramphenicol binds to 50S ribosome-interferes with peptide
bind formation and transfer of peptide chain from 'P’ site.
4. Macrolide & Lincosamide:-Macrolide and Lincosamide bindsto 50S ribosome and
interfere with translocation of the elongated peptide chain back from 'A’ site to 'P’
site and the ribosome does not move along the mRNA to expose the next
codon.Peptide Synthesis may be prematurely terminated.
5. Oxazolidinone:-Oxazolidione bind to 23S fraction of the 50S ribosome-interfere
with formation of ternary N-formylmethionine tRNA and prevent tRNA formation.

6. Antibiotics
Inhibit bacterial protein synthesis
Oxazolodinone
antibiotic
Aminoglycocides
antibiotic
Tetracycline
antibiotic
Chloramphenicol
antibiotic
Macrolide and
Lincosamide
antibiotic
Bind to 23S
fraction of 50S
ribosome
InInterfere with
tRNA formation
Inhibitprotein
synthesis
(Bacteriostatic)
Bind to 30S and
50S ribosome
Misreading mRNA
code
Inhibitprotein
synthesis
(Bactericidal)
Bind to 30S
ribosome
Inhibit attachment
of Aminoacyl tRNA
to Acceptor site on
mRNA
Inhibitprotein
synthesis
(Bacteriostatic)
Bind to 50S ribosome
Inhibit transfer of
peptide chain on
acceptor site
Inhibitprotein
synthesis
(Bacteriostatic)
Bind to 50S
ribosome
Interfere with
translocation
Inhibitprotein
synthesis
(Bacteriostatic)

7. Introduction
• Natural and semisynthetic antibiotics having polybasic amino groups
linked glycosidically to two or more aminosugar(streptidine,2-deoxy
streptamine,garosamine).
Structure
Aminoglycocides Antibiotics

8. • Aminoglycosides are used for the treatment of serious infections due
to Gram negative bacilli.
• It produce Bactericidal action by inhibiting bacterial Protein synthesis.
• It is most effective against Gram negative bacteria.

9. History and Source
• Aminoglycocides are produced by Soil
Actinomycetes.
• Streptomycin was the first member discovered in
1944 by Waksman and his colleagues.
• Isolated from a strain of Streptomyces griseus.

10. Common Properties of Aminoglycosides antibiotics
1. All are used as sulfate salts,which are highly water soluble, solution
are stable for month.
2. Not absorbed orally.Do not penetrate brain or CSF.
3. All are excreted unchanged in urine by glomerular filtration.
4. All are Bactericidal and more active at alkaline pH.
5. They act by interfering with bacterial protein synthesis.
6. They have relatively Narrow margin of safety.
7. All exhibit ototoxicity and nephrotoxicity.
8. All are active against Aerobic Gram Negative Bacilli and do not
inhibit anaerobes.

11. Classification
• Systemic Aminoglycocides
Eg.Streptomycin Amikacin
Gentamycin Sisomicin
Kanamycin Netilmicin
Tobramycin Paromomycin
• Topical aminoglycocides
Eg.Neomycin
Framycetin

12. Mechanism Of Action
• Aminoglycocides antibiotics shows Bactericidal action in two steps:-
a)Transport of the aminoglycocides through the bacterial cell wall and
cytoplasmic membrane.
b) Binding to ribosomes resulting in inhibition of protein synthesis.

13. a) Transport of aminoglycocides through the bacterial cell
wall and cytoplasmic membrane
• Transport of aminoglycocides into the
bacterial cell wall through Porin
channel.
• Penetration is dependent upon
maintenance of a polarized membrane
and on Oxygen dependent active
processes.
• Penetration also favoured by high pH.

14. b)Inhibition of protein synthesis
• Bind to 30S and 50S ribosomes on bacterial mRNA strand
• Freeze initiation of protein synthesis
• Prevent Polysome formation and promote disaggregation to
monosomes
• Distoration of mRNA codon recognition
• Misreading of the code
• Inhibit Protein synthesis

15. Dig. Mechanism action of Aminoglycocides
Aminoglycocides
Bind 30S and 50S ribosomes
Freeze initiation, prevent Polysome formation,Misreading
mRNA code
Inhibit bacterial Proteins Synthesis

16. • Cidal action depend on secondary changes in the integrity of bacterial
cell membrane.
• After exposure to Aminoglycocides, sensitive bacteria become more
permeable
• Ions,amino acid and even proteins leak out
• Cell death

17. Fig.Mechanism action of Aminoglycocides antibiotics

18. Mechanism of Resistance
• Aminoglycocides is acquired the Resistance by one of the following
mechanism:-
A) Acquisition of cell membrane bound inactivating enzyme which
Phosphorylate/adenylate/acetylate the drug.
• Enzyme are acquired mainly by conjugation and transfer of plasmid.
• Nosocomial microbes have become rich in plasmid.

19. B)Mutation
• Mutation at the binding site decreasing the affinity of ribosomal
proteins that normally bind the aminoglycocides.
C) Disturbance in transport mechanism
• Decreased efficiency of the aminoglycocides transporting mechanism.

20. Pharmacokinetics
Absorption
• Highly ionized
• Neigher absorbed nor destroyed in the g.i.t
• Polycationic structure of aminoglycocides prevent adequate
absorption after oral administration (Except Neomycin),must be given
parenterally (IV,IM).
• Single daily dose regimen for patients with normal renal function.

21. Distribution
• Distributed only extracellularly.
• Peak plasma level are attained in 30-60 minutes.
• Higher concentration are present in endolymph and renal cortex,
which are responsible for ototoxicity and nephrotoxicity.
• Concentration are adequate in CSF,even in the presence of inflamed
meninges.
• For Central nervous system infection the intrathecal or
intraventricular route may be utilized.
• All aminoglycocides cross placenta and can be found in foetal blood
or amniotic fluid.

22. Elimination
• More than 90% of parenteral aminoglycocides are excreted
unchanged in the urine.
• Accumulation occurs in patients with renal dysfunction, thus dose
adjustment are required.
• The plasma t1/2 ranges between 2-4 hours but small amount of drug
persists longer in tissues.

23. • The short half life of Aminoglycocides the daily doses are
conventionally divided into 3 equal parts and injected i.m. every 8
hours.

24. Adverse effects
1)Ototoxicity
• Irreversible,high frequency of hearing loss and
temporary vestibular hypofunction.
• Include vestibular and cochlear damage.
• Drug concentrated in labyrinthine fluid and slowly
removed from it when the plasma concentration
falls.
• Ototoxicity higher when plasma concentration of
drug is persistently high.
• For Gentamycin:-2ug/ml.
• Aminoglycoside ear drop can cause ototoxicity
when instilled in patients with perforated
eardrum.

25. Cochlear damage
• Start from the base and spreads to the apex.
• Symptoms:-Progressive hearing loss
-Deafness
-Tinnitus
• On stopping the drug, tinnitus disappears in 4-10 days,but frequency
loss persists.

26. Vestibular damage
• Symptoms:-Headache
Nausea
Vommiting
Dizziness
Nystagmus
Vertigo
Ataxia
2) Nephrotoxicity
• Tubular damage cause:-Low g.f.r
-Nitrogen retention
-Albuminuria
-Casts
• High concentration in the renal cortex and toxicity us related to the total amount
of the drug received by the patients.

27. • Interfere with Prostaglandin synthesis in the kidney.Reduce PGs
synthesis,reduce g.f.r.
• Strptomycin and Tobramycin are less nephrotoxic.
3) Neuromuscular blockade
• Reduce Ach release from the motor nerve endings.
• Decrease the sensitivity of the muscle end plate to Ach.
• This Antagonized by i.v.injection of Ca salt.
4) Hypersensitivity
• Rashes, eosinophilia,fever and exfoliative dermatitis

28. Precaution and Interactions
1. Avoid aminoglycocides during Pregnancy:risk of foetal ototoxicity.
2. Avoid concurrent use of other nephrotoxic drugs
eg.NSAIDs,Amphoterecin B, Vancomycin, Cyclosporine,Cisplatin.
3. Cautious use in patients more than 60 years age and in those with
kidney damage.
4. Cautious use of muscle relaxants in patients receiving an
aminoglycocides.
5. Do not mix aminoglycocides with any drug in the same syringe/infusion
bottle.

29. Gentamycin
• Obtained from Micromonospora purpurea.
• High potent and broad spectrum activity.
• Use for acute infection.
• Effective against Aerobic gram negative bacilli including
E.coli,Klebsiella pneumonia,Enterobacter,H.influenzae.
• Ineffective against Mycobacterium tuberculosis and other
mycobacteria.
Use:-
1. Use to prevent and treat Respiratory tract infection combine with
other antibiotics.
2. Pseudomonas,Proteus or Klebsiella infection:Burn, urinary tract
infection, pneumonia,lung, abscesses, osteomyelitis, middle ear
infection, septicemia,etc with other antibiotics.

30. 3. In meningitis:-Meningitis cause by gram negative Bacilli.
4. Subacute bacterial endocarditis (SABE).
• Dose:-3-5 mg/kg/days(Single dose or divided in 3 doses)IM Or in IV
line over 30-60 minutes.
• Route of administration:- By parenteral route,topical(eye/ear
drop,skin cream).
• Brand name:-GARAMYCIN,GENTASPORIN

31. Streptomycin
• Oldest aminoglycocides
• Obtained from Streptomyces griseus
• Less potent, narrow spectram activity
• Active against Aerobic Gram negative bacilli
Includes,H.ducreyi,Brucella,Yersinia pestis,Nocardia, Mycobacterium
tuberculosis.
• Uses:-1)in Mycobacterium tuberculosis
2) Subacute bacterial endocarditis (SABE)
3) Plague:-Effects rapid cure in 7-12 days
4)Tularemia:-DOC
5)Other infection:-UTI, Septicemia, peritonitis.

32. • Adverse effect:- Vestibular disturbances
-Lowest Nephrotoxicity
-Pain at injection site
• Containdication:-In pregnancy
-Topical use
• Dose:-Acute infection:1g i.m. OD Or BD for 7-10 days
Tuberculosis:-1g or 0.75g I.m.OD or thrice weekly for 30-60 days
• Route of administration:-Parenteral
• Brand name:-AMBISTRYN Injection

33. Tobramycin
• Obtained fromS.tenebrarius
• 2-4 times more active against Pseudomonas and Proteis
• Alternative to Gentamycin
• Ototoxicity and nephrotoxicity is probably less than Gentamycin.
• Dose:-3-5mg/kg/day in 1-3 doses.
• Route of administration:- Parenteral and Eye drop
• Brand name:-TOBACIN 20,60,80mg in 2ml inj ; 0.3% eye drop
TOBRANEG 20,40,80mg per 2ml inj

34. Neomycin
• Obtained from S.fradiae
• Wide spectrum aminoglycoside against most gram negative bacilli and some gram
positive cocci
• Highly toxic to the internal ear and to kidney
• Not used systemically
• Absorption from the g.i.t. is minimal
• Oral and topical administration does not ordinarily cause syestemictoxicity
• Uses:-
1) Topical
For wound,ulcer,burn, external ear infection, conjunctivitis.
2) Oral
a) Preperation of bowel before surgery:3 doses of 1g along with Metronidazole 0.5g
on day before surgery) may reduce postoperative infection.
b) Hepatic coma

35. • Adverse effects:-Hypersensitivity
-Kidney damage and ototoxicity
• Dose:-0.25-1gQID oral,0.3-0.5% topical
• Brand:-NEOMYCIN SULPHATE:350,500mg tab,0.3% skin oint,
0.5% skin cream,eye oint
-NEBASULF: Neomycin sulphate 5.0mg+Bacitracin 250 U
-NEOSPORIN: Neomycin 3400 iu+Polymyxin B 5000 U
+Bacitracin 400 iu/g oint and powder for
surface application