LIAQUAT COLLEGE OF MEDICINE & DENTISTRY
DEPARTMENT OF PHARMACOLOGY
PROF. DR. ASYA REHMAN
AMINOGLYCOSIDESAMINOGLYCOSIDES
aminoglycosides are a group of bactericidal antibiotics
0obtained from STREPTOMYCES.
the aminoglycosides include :
- STREPTOMYCIN
- NEOMYCIN
-KANAMYCIN
- AMIKACIN
-GENTAMYCIN
- TOBRAMYCIN
- SISOMICIN
- NETILMYCIN $ others
Aminoglcosides are mostly used against, gram negative
enteric bacteria especially in BACTEREMIA AND SEPSIS
In combination with vancomycin or penicillin for
endocarditis and for the treatment of T.B.
Streptomcin is the best & oldest of the aminoglycosides
Gentamicin,tobramycin and amikacin are the most widely
used.
Neomycin kanamycin are now limited totopical use or oral
use
General properties of the aminoglycosides
1. Physical and chemical properties
Have a hexose ring to which various amino
sugars are attached by glycoside linkages.
Water soluble,stable in solution.
More active in alkaline ph.
Exhibit synergism with beta lactams or
vancomycin in vitro
Eradicate inf.more rapidly than would be by
use of single drug therapy.
Although at high conc.may complex with beta
lactam drugs and should not be mixed
together for administration
2. Mechanism of action:
M.O.A of streptomycin is closely studied but all act
similarly.
Aminoglycosidesa re irreversible inhibitors of PROTEIN
SYNTHESIS( precise mechanism of bactericidal activity not
known)
First effect is passive diffusion through porin channels across the
entire membrane
Drug then actively transported into the cell.
Low extracellular ph and anerobic conditions inhibit transport
Transport may be enhanced by cell wall active drugs such as
Penicillin or Vancomycin
After entrance ,the drug binds to specific 30S- subunit ribosomal
proteins.(S12 in case of Streptomycin
Protein synthesis is inhibited by ABINOGLYCOSIDES in
at least three different ways
1 . Interfere with the initiation complex of peptide formation
.
2. Induce misreading of mRNA ,which causes incorporation of
incorrect amino acids into the peptide, resulting in nonfunctional or
toxic proteins.
3. They cause break up of polysomes into nonfunctional monosomes
These activities occur more or less simultaneously and the over all
effect is irreversible and lethal for the cell
Mechanism of resistance:
Three mechanisms have been identified.
1. the microorganisms produce transferase enzyme that
inactivates the aminoglycoside by
adenylation,acetylation or phosphorylation.
2. Impaired entry of Aminoglycoside in the cell.
May be Genotype or phenotype
3. The receptor protein on 30 S ribosomal subunit may be
deleted or altered as a result of mutation.
PK and once Daily Dosing
Aminoglycosides are absorbed very poorly.from intact GIT,but absorbed if
ulcarations are present, the entire dose is excreted out in feces after
adm.
Aft.I/M inj. Well absorbed and peak conc.reached in 30 - 90 min
Aminoglycosides are highly polar compound and therefore do not enter
cells readily.
Usually adm. I/V
In pts. With normal renal func .adm.in 2-3 equal divided doses.
Aminoglycosides have conc. Dependent killing i.e increasing conc. Will
kill an increasing proportion of bacteria and at rapid rate.
Significant post antibiotic effect.
For these properties,a given total amnt. Of Aminoglycoside would have
better efficacy when adm. As as ingle dose rather then in multiple doses.
Numerous clinical studies have demonstrated that a single dose is as
effective and no more or less toxic than multiple doses with few
exceptions.such as
-in pregnancy and pediatrics
-in streptococcal,staphylococcal and enterococal endocarditis
ADVANTAGES OF ONCE DAILY DOSING
POTENTIAL PRACTICAL ADVANTAGES ARE:
- determination of serum conc. is unnecessary unless
aminoglycosides are given for more then 3 days.
- Less nursing time is required.
- Once daily dosing lends itself to outpatient therapy
- Although dose monitoring and adjusting still required to minimize
toxicity particularly in renal insufficiency.
- If pitfalls are avoided,like rapidly changing renal func as in septic
shock,once daily dosing is safe and effective.
- The goal is to adm. The drug so that conc.of 1µg/ml is present b/w
18 – 24 hrs after dosing,providing sufficient time for the drug
washout, before the next is given.
- Aminoglycosides are largely excluded from CNS and eye.although in
infection and neonal meningitis levels may be high.
- Even after parenteral adm.the conc.of Aminoglycosides are not high
in most of the tissues except renal cortex.
Adverse effects
All aminoglycosides are OTOTOXIC and NEPHROTOXIC
when therapy is cont .for more then 5 days.at higher doses or in renal
insufficiency.
Concurrent use with loop diuretics e.g furosemide or other
nephrptoxic antimicrobial agents e.g vancomycin or amphotericin.they
can potentiate nephrotoxicity and should be avoided.
OTOTOXICITY can manifest itself in the form of :
- auditory damage,resulting in tinnitus
- high frequency hearing loss initially
Or as Vestibular damage resulting in :
- ataxia
- vertigo
loss of balance
NEOMYCIN
KANAMYCIN MOST OTOTOXIC
AMIKACIN
STREPTOMYCIN
GENTAMICIN most vestibulotoxic
NEOMYCIN
GENTAMICIN most nepherotoxic
TOBRAMYCIN
In very high doses aminoglycosides produces
curare like effect with neuromuscular blockade
that results in respiratory paralysis.
Paralysis usually reversed by calcium gluconate
or Neostigmine
Toxicity is unlikely to occur unless a certain
thresh hold concentration is reached, but once
achieved , time above this thresh hold becomes
critical.
The precise thresh hold is not defined but a
conc. Above 2µg/ml is predictive of toxicity.
CLINICAL USES
MOST COMMONLY USED AGAINST
- gram– ve enteric bacteria (when resistant and
suspicion of sepsis)
- Almost always used in combination with a β lactam
anti bacteria in order to extend coverage to include :
- Potential gram positive pathogens and to take
advantage of synergism between these 2 classes of
drugs.
This combination (Penicillin + Aminoglycosides) to
achieve bactericidal activity in treatment of
enterococcal endocarditis & to shorten the duration of
therapy in Viridans streptococcal and staphylococcal
Endocardtis.choosing depends on inf.&susceptibility of
bacteria isolated.
