an complete pharmacological description of aminoglycosides with drugs

1. Done by: Neetu ojha
Pharm.D III yr

2. Definition, Structure
• These are group of natural and semisynthetic antibiotics having polybasic
amino groups linked glycosidically to two or more animosugar

3. CLASSIFICATION
Systemic Topical
Streptomycin Neomycin
Gentamicin Framycetin
Kanamycin
Amikacin
Sisomicin
Tobramycin
Netilimicin

5. History, Source
• Streptomicin was the first member discovered in 1944 by Waksman
and his collegues and active against tuberculi bacilli.
• Neomycin was the next to be isolated in 1949 but it coud not be used
systemically.
• Others have been discovered later and all aminoglycosides are
produced by soil actinomecetes
• Source: Most of them are prepared from natural fermentation from
various species of streptomyces
• The exception are gentamicin which is fermented from
Micromonospora purpurea and amikacin which is first antibiotic
obtained by chemical modification of kanamycin

6. Properties
1. All are sulfate salts which are highly soluble in water and solutions
are stable for months
2. They ionize in solution, not absorbed orally, distribute only
extracellularly and do not penetrate in brain and CSF
3. All are excreted unchanged in urine
4. All are bactericidal and more active at alkaline pH
5. Act by interfering bacterial protein synthesis
6. Active against aerobic gm –ve bacteria, but spectrum differs
7. Partial cross resistance, organisms resistant to one amino glycoside
may still respond to another
8. Narrow margin of safety
9. All exhibit ototoxity and nephrotoxicity.

7. Post antibiotic effect
Aminoglycosides exhibit concentration dependent
killingincreased conc. Can kill more bacteria at rapid
rate
They also possess significant Post-antibiotic effect
continue to suppress bacterial growth several hours
after fall in MIC(Minimum Inhibitary Concentration)
Single daily dosing at least as effective as and no more
toxic than multiple dosing renal cortical uptake is a
capacity dependent saturable processenhanced
bactericidal activity

8. Antibacterial spectrum
• Aerobic G-ve bacteria ( Citrobacter, Enterobacter, E. coli, proteus, shigella,
proteus, Pseudomonas, Enterococci and Staph aureus )
• Streptomycin and kanamicin are active against mycobacterium
tuberculosis while amikacin, gentamicin and tobramycin are active against
S. faecalis and P. aeruginosa.
• They are not effective against G+ve bacilli, G-ve cocci and anaerobes
• Aminoglycosides are not effective against anaerobes because the
penetration of aminoglycoside across porin channel depend upon
polarized membrane and oxygen dependent active process, since lack
of oxygen make them ineffective against anaerobes
• Sometimes even facultative anaerobes are resistant in oxygen supply
deficient

9. Mechanism of Action
• The aminoglycosides are bactericidal antibiotics and all having
same general pattern of action. It is described in two ways
1. Transport of amino glycoside through the bacterial cell wall and
cytoplasmic membrane depending upon polarity and oxygen
dependent active process
2. Binding to ribosome resulting in inhibition of protein synthesis
• The aminoglycosides act on bacterial 30Sribosomes and distort the
messenger ribonucleic acid translation of genetic code, so prevent
the formation of normal complex required to initiate protein
synthesis.
• Different aminoglycosides cause misreading at different levels
depending on their selective affinity for specific ribosomal
proteins.
• They also combines anionic membrane groups and damage the
bacterial cell membranes (proteins, aminoacids leak out) and also
block energy production of Kreb’s cycle.

11. RESISTANCE
May be plasmid mediated inactivation by microbial enzymes or
Failure of drug penetration mutation of porin channel , so
decrease in aminoglycoside transport mechanism (decrease in
premeability of pores in outer coat if bacteria)
Synthesis of metabolizing enzymes
Acetyl transferaseacetylation
Phosphotransferase phosphorylation
Adenyltransferase adenylation
Mutation may alter ribosomal binding site for the
aminoglycosidesprevent binding to 30S
• Cross resistance is observed.

12. Pharmacokinetics
 ABSORPTION: highly ionised, not absorbed or destroyed by G.I.T , I.M- rapid,
plasma peak concentration-30-60 mins.
 DISTRIBUTION: Extracellularly -20-30%, High concentration in endolymph
and renal cortex , do not cross b.b.b. , may cross placenta , they get
distributed in serous fluids like synovial, pleural , peritoneal etc
 EXCRETION: Excreted unchanged in urine . Main channel of excretion is
glomerular filtration , plasma T half : 2-4 hrs
 After chronic dosing : 2-3 weeks drug persists in urine
 In elderly people and neonates , the drug dosing should be low as they low
glomerular filtration rate
 Renal clearance of aminoglycosides parallels creatinine . So an creatinine
clearance of 70ml/ min indicates no reduction of daily dose of
aminoglycosides.

13. Shared toxicities
1. Ototoxicity:
 Vestibular and cochlear part affected with aminoglycosides. These drugs
get concentrated in labyrinthine fluid. Ototoxicity is greater when plasma
concentration of drug is high.
 Vestibular/cochlear sensory cells get destructive changes, aminoglycoside
ear drops are contraindicated .
 Cochlear damage:
 Hearing defect, deafness, tinnitus appears, on stopping drug tinnitus
disappers.
 Vestibular damage:
 Headache, nausea, vomiting, dizziness, nystagmus, ataxia, vertigo.
2. Nephrotoxicity:
 Tubular damage resulting in loss of urinary concentrating power, low GFR,
nitrogen retention, albuminuria and casts.

14. Continued…
• Aminoglycosides attain high concentration in renal cortex and toxicity is
related to total amount of drug receiving drug by patient.
• It is more in elderly and in those with preexisting kidney disease. However,
the kidney damage is reversible if drug is discontinued.
• It has been suggested that aminoglycosides interfere with production of
prostaglandins in kidney and so there is reduced GFR.
3. Neuromuscular blockade:
• All aminoglycosides reduce Ach release from motor nerve ending, they
have curare like action and cause neuromuscular blockade that can cause
paralysis and fatal respiratory arrest.
• They may cause apnea on iv injection,the blockade if severe can be
effectively treated by neostigmine.

15. Precautions and interactions
• Avoid during pregnancy, risk of foetal ototoxicity.
• Avoid concurent use of other ototoxic drugs e.g. high ceiling diuretics,
minocycline
• Avoid concurrent use of other nephrotoxic drugs. E.g. amphotericine B,
vancomycin, cephalothin, cyclosporin etc
• Cautious use in patients past middle age and in those with kidney damage
• Cautious use in muscle relaxants.
• Do not mix aminoglycosides with any drug in same syringe or infusion bottle.

16. STREPTOMYCIN
• It is older antibiotics and obtained by Streptomyces griseus, used in past but now
used for treatment of TB.
• The antibacterium spectrum is relatively narrow.
• Sensitive to H.ducrey, Brucella, Yersinia pestis, F.tularensis, Nocardia, M.
tuberculosis, E. coli, Klebsiella, enterococci, Shigella
• Resistance
• Many organisms develop rapid resistance. E. coli, S.aureus. S.pneumoniae are
resistant
• Resistance occurs by: 1. 1st
step mutation
• 2. Acquisition of plasmid which codes for inactivation of
enzymes
• Streptomycin dependence
• Certain mutants become dependent on streptomycin as they promote mutant
growth bi induced misreading of genetic code which becomes normal feature for
organisms . Occurs mainly in Tb
• Cross resistance:
• Partial or unidirectional cross resistance occur.

17. Pharmacokinetics
Neither absorbed nor destroyed
in git.
Absorption from injection site
in muscle is rapid.
Distributed extracellularly,
volume of distribution 0.3 L/kg
Attains low concentration in
synovial, pleural fluid.
It is not metabolized. Excreted
unchanged in urine
Plasma half life is 2-4 hrs
Adverse effects
Vestibular disturbances,
auditory disturbances
Nephrotoxicity
Hypersensitivity are rare-rashes,
eosinophilia, dermatitis
Pain at injection site
Paresthesias and scotoma are
occasional
Preparation:
Ambistryn 0.75, 1 g dry powder
per vial.

18. CONTRAINDICATION: pregnancy causes foetal ototoxicity
DOSE: Tb – 1g or 0.75 g i.m OD or thrice weekly for 30-60
days
Acute infection: 1g i.m OD or BD for 7-10 days
USES: 1.TB
2. SABE: given with pencillin/ampicillin/vancomycin for 4-6
weeks
3. Plague: rapid cure within 7-12 days
4. Tularemia: Streptomycin cures it in 7-10 days

19. GENTAMICIN
• It was obtained from Micromonospora purpurea in1964 and has become most
common antibiotic in acute infections
• The properties include
• Plasma half life 2-4 hours after i.m. injections same as streptomycin
• But it has following differences from streptomycin
• It is more potent
• It has boarder spectrum of action and effective against P. aeruginosa and most
strains of Proteus, E.coli, Klebsiella, enterobactor, Serratia
• It is not effective against M.tuberculosis, Str.pyogenes, stre. Pneumoniae, and
some Stre. Aureus
• It is more nephrotoxic.

20. uses
Use restricted to serious Gm-ve bacillary infections
Septicaemia, sepsis, fever in immunocompromised patients
used with penicillins /cephalosporins
Pelvic infections : with metronidazole
SABE: with Penicillin G or ampicillin or vancomycin, where
gentamicin dose is 1mg/kg for 8 hrs i.m
Coliform infection: with ampicillin or ceftriaxone
Pseudomonal infections: with ticarcillin
Meningitis by Gm-ve bacilli : III generation cephalosporin alone
or with gentamicin
Topical-infected burns, wounds, skin lessions (with purulent
exudates

21. KANAMYCIN
Obtained from S.Kanamycetius , similar to streptomycin
and even against M.tuberculosis but lack activity on
pseudomonas
More toxic to cochlea and kidney , hearing loss id
irreversible . Because of toxicity and narrow spectrum it is
replaced by other drugs.
DOSE : 0.5 g i.m BD

22. TOBRAMYCIN
Identical to gentamicin and obtained from S. tenebrarius
Used in pseudomonas and proteus infections
Ototoxicty and nephrotoxicity probably lower
DOSE: 3-5mg/kg I.M in 1-3 doses
Less toxic semisynthetic derivative of kanamycin but more hearing loss
occurs
Resistant to enzymes that inactivate gentamicin and tobramcyin
Widest spectrum of activity
Uses: Same as gentamicin
Reserve drug for hospital acquired Gm-ve bacillary infections
Multidrug resistant TB resistant to streptomycin, along with other
drugs
Dose : 15mg/kg/day in 1-3 doses

23. SISOMICIN
• Identical to gentamicin and also equal in toxicities and susceptible to
aminoglycosides inactivating enzymes.
• More potent on pseudomonas and β-hemolytic streptococci and obtained
from Micromonospora inyoensis.
NETILMICIN
Resistant to many enzyme that inactivate gentamicin and tobramycin 
additional ethyl group protects from enzymatic degradation
Lowest toxicity among aminoglycosides
Semisynthetic derivative of sisomicin
More active against klebsiella, enterobacter & staphylococci
Less active against pseudomonas aeruginosa
Doses and pharmacokinetics similar to gentamicin
Uses-Septicemia, Lower respiratory tract infection
Urinary tract infection, peritonitis and endometritis

24. Framycetin
Obtained from S. lavendulae . Similar to neomycin
.Toxic for systemic administration , used topically on
eye,skin and ear.
Paromomycin
Properties similar to neomycin
Effective against visceral leishmainiasis by parentral route
Uses –
Intestinal infections
Treatment of hepatic encephalopathy
Treatment of amoebiasis

25. Neomycin
wide spectrum active against Gm-ve bacilli and some gm+ve
cocci and obtained from S.fradiae
Pseudomonas and strep.pyogenes are not sensitive
Too toxic for parenteral use , limited to topical use
DOSE: 0.25-1g QID oral, 0.3-0.5% topical.
USES:Topically used in skin, eye and external ear infections
combined with bacitracin or polymyxin-B to widen
antibacterial spectrum and to prevent emergence of
resistant strains
Orally
Preparation of bowel before surgery 1 gm TDS
Hepatic coma: Supresses ammonia forming coliforms
prevents encephalopathy (Lactulose more preferred)
Bladder irrigation along with polymyxin B

26. ADR: Low sensitizing potential, rashes , oral
neomycin damage intestinal villi. Prolonged
treatment causes malabsorption syndrome , diarrhoea
Decreasing the absorption of digoxin , bile acids ,
suppresses gut flora causing superinfection by
candida
It is excreted unchanged in kidney causing kidney
damage and ototoxicity
In serous cavity it causes apnoea due to muscle
paralysing action .