PHARMACOLOGY , CHEMOTHERAPY, AMINOGLYCOSIDES

1. AMINOGLYCOSIDE
ANTIBIOTICS

2. Systemic amino glycosides
Streptomycin
Gentamicin
Kanamycin
Tobramycin
Topical aminoglycosides
Neomycin Framycetin
Amikacin
Sisomicin
Netilmicin

3. MECHANISM OF ACTION
Common properties of aminoglycoside
antibiotics
1. All are used sulfate salts, which are
highly water soluble, solutions are
stable for months.
2. They ionize in solution; are not
absorbed orally;distribute only
extracellularly; do not penerate brain
of CSF.

4. MECHANISM OF ACTION
3. All are excreted unchanged in urine
by glomerular filtration.
4. All are bactericidal and more active
at alkaline pH.
5. They act by interferring with bacterial
protein synthesis.
6. All are active primarily against
aerobic gram-negative bacilli and do
not inhibit anaerobes.

5. MECHANISM OF ACTION
7. There is only partial cross resistance
among them.
8. They have relatively narrow margin
of safety.
9. All exhibit ototoxicity and
nephrotoxicity.

6. MECHANISM OF ACTION
Inhibitors of bacterial cell wall (β-
lactams, vancomycin) enhance entry
of aminoglycosides and exhibit
synergism.
Once inside the bacterial cell,
streptomycin binds to 30s-50s
interface

7. MECHANISM OF ACTION
The cidal action of these drugs
appears to be based on secondary
changes in the integrity of bacterial
cell membrane, because other
antibiotics which inhibit protein
synthesis (tetracyclines,
chloramphenicol, erythromycin) are
only static.

8. MECHANISM OF ACTION
After exposure to aminoglycosides,
sensitive bacteria become more
permeable; ions, amino acids and
even proteins leak out followed by cell
death. This probably results from
incorporation of the defective proteins
into the cell membrane.

9. MECHANISM OF ACTION
Aminoglycoside induced alteration of
cell membrane is augmentation of the
carrier-mediated entry of the
antibiotic. This reinforces the lethal
action.

10. MECHANISM OF ACTION
Also exert a long and concentration
dependent ‘postantibiotic effect’
despite their short t½(2-4 hr), single
injection of the total daily dose of
amino glycoside may be more
effective and possibly less toxic than
its convenctional division into 2-3
doses.

11. MECHANISM OF RESISTANCE
Acquisition of cell membrane bound
inactivating enzymes.
Decreasing the affinity of ribosomal
proteins.
Decreased efficiency of the
aminoglycoside transporting
mechanism.

12. SHARED TOXICITIES
Comparitive toxicity of aminoglycoside antibiotics (tentative)
Systemically used
aminoglycoside
Ototoxicity Nephrotoxicity
Vestibular Cochlear
1.Streptomycin + + + +
2. Gentamycin + + + + +
3. Kanamycin + + + + +
4. Tobramycin + + + +
5.Amikacin + + + + +
6. Sisomycin + + + + +
7. Netilmycin + + + +

13. 1. OTOTOXICITY
2. NEPHROTOXICITY
3. NEUROMUSCULAR BLAOCKADE

14. NEUROMUSCULAR BLOCKADE
Neomycin and streptomycin have
higherpropensity than kanamycin,
gentamycin or amikacin; tobramycin
is least likely to produce this effect.
The neuromuscular block can be
partially antagonized by i.v. injection
of a calcium salt. Neostigmine has
inconsistent reversing action.

15. PRECAUTION AND
INTERACTIONS
1. Avoid during pregnancy; risk of foetal
ototoxicity.
2. Avoid use of other ototoxic drugs, high
ceiling diuretics, minocycline.
3. Avoid use of other nephrotoxic drugs,
amphotericin b, vancomycin,
cyclosporine and cisplatin.
4. Do not mix aminoglycoside with any drug
in the same syringe/infusion bottle.

16. STREPTOMYCIN
Spectrum is relatively narrow; active
primarily against aerobic gram-
negative bacilli,H.ducreyi, Brucella,
Yersinia pestis, Francisella tularensis,
Nocardia, Calym.gramulomatis,
M.tuberculosis.Pseudomonas
unaffected.E.coli.,H.influenzae,Str.pn
eumoniae, Str.pyogenes, Staph
aureus have become largely resistant.

17. PHARMACOKINETICS
Highly ionized neither absorbed nor
destroyed in the g.i.t. distributed only
extracelluarly; Low concentrations are
attained in serious fluids like synovial,
pleural, peritoneal, concentrations I
CSF and aqueous humour are often
non therapeutic, even in the presence
of inflammation.

18. PHARMACOKINETICS
Streptomycin is not metabolized-
excreted unchanged in urine.
Glomerular filtration is the main
channel; tubular secretion and
reabsorption are negligible.t½ is 2-4
hours. Half life is prolonged and
accumulation occurs in patients with
renal insufficiency, in the elderly and
neonates who have low g.f.r.

19. ADVERSE EFFECTS
Vestibular disturbances. Auditory
disturbances are less common.
Lowest nephrotoxicity among amino
glycosides; probably because it is not
concentrated in the renal cortex.

20. USES
1. Tuberculosis.
2. Subacute bacterial endocarditis
(SABE)
3. Plague; tetracyclines have been
more commonly used.
4. Tularemia; streptomycin is the drug
of choice for this rare disease.

21. GENTAMICIN
Obtained from Micromonospora purpurea,
there are differences:
a. It is more potent.
b. It has a broader spectrum of action;
against Ps.aeruginosa and most strains
of proteus, E.coli, Klebsiella,
Enterobacter, Serratia.
c. It is ineffective against M.tuberculosis,
strep.pyogenes and Strep.pneumoniae.
d. It is relatively more nephrotoxic.

22. DOSE
(Creatinine clearance ≥100 ml/min)
3-5 mg/kg/day i.m.either as single
dose or divided in three 8 hourly
doses is recommended. Because of
concentration dependent bactericidal
postantibiotic effect. Once daily
dosing of aminoglycosides. It is more
convenient as well.

23. Guideline for doses adjustment of
gentamycin in renal insufficiency
CLcr (ml/min) % of daily dose
______________________________
70 70% daily
50 50% daily
30 30% daily
10-30 60% alternate day
<10 40% alternate day

24. USES
Gentamicin is the cheapest ,use
restricted to serious gram-negative
bacillary infections.
1. Gentamicin is very valuable for
preventing and treating respiratory
infections in critically ill patients; in
those with impaired host difference
(receiving anticancer drugs or high-
dose corticosteroids;AIDS;

25. USES
neutropenic), patients in resuscitation
wards, with tracheostomy or on
respirators; postoperative
pneumonias; patients with implants
and in intensive care units. It is often
combined with a penicillin/
cephalosporin or another antibiotic in
these conditions.

26. USES
2. Pseudomanas, Proteus or Klebsiella
infections; burn, urinary tract infection,
pneumonia, lung abscesses,
osteomyelitis, middle ear infection,
septicaemia are combined with
piperacillin or a third generation
cephalosporin for serious infections.

27. USES
3. Meningitis caused by gram-negative
bacilli, but benefits are uncertain.
4. SABE; gentamicin-PMMA
(polymethyil methacrylate) chains is
a drug delivery system for use in
osteomyelitis. It has improved cure
rates.

28. KANAMYCIN
Because of toxicity and narrow
spectrum of activity, it has been
largely replaced by other
aminoglycosides for treatment of
gram-negative bacillary infections.
Occasionally used as a second line
drug in resistant tuberculosis.

29. TOBRAMYCIN
The antibacterial and pharmacokinetic
properties, identical to gentamicin, but
it is 2-4 times more active against
Pseudomanas and proteus, including
those resistant to gentamicin.

30. TOBRAMYCIN
Not use ful for combining with
penicillin in the treatment of
enterococcal endocarditis. Serious
infections caused by Pseudomanas
and proteus are its major indications.
Ototoxicity and nephrotoxicity is
probably lower than gentamicin.

31. AMIKACIN
Semisynthetic derivative of
kanamycin. The outstanding feature
of amikacin is its resistance to
bacterial aminoglycoside inactivating
enzymes. It has the widest spectrum
of activity, including many organisms
resistant to other aminoglycosides.

32. AMIKACIN
Higher doses are needed for
Pseudomanas proteus and staph.
infections.
Used is the same as for gentamicin.
Reserve drug for hospital acquired
gram-negative bacillary infections
where gentamicin/ tobramycin
resistance is high.

33. AMIKACIN
It is effective in tuberculosis. More
hearing loss than vestibular
distrubance occurs in toxicity.

34. SISOMICIN
More potent on Psedomonas, a few
othjer gram-negative bacilli and β-
haemolytic streptococci can be
combined with penicilin for
SABE.Susceptible to aminoglycoside
inactivating enzymes can be used
interchangeably with gentamicin.

35. NETILMICIN
Broader spectrum of activity tyhan
gentamicin is relatively resistant to
aminoglycoside inactivating enzymes
effective against many gentamicin
resistant strains. More active against
Klebsiella.

36. NETILMICIN
Enterobactor and staphylococci less
active against Ps.aeruginosa.Less
ototoxic preferable in hospitals where
gentamicin resistance has spread.

37. NEOMYCIN
Active against most gram-negative
bacilli and some gram-positive cocci.
Pseudomonas and Strep.pyogenes
are not sensitive. Neomycin is highly
toxic to the internal ear (mainly
auditory) and to kidney. Not used
systemically.

38. USES
1. Topically (combination with
polymyxin, bacitracin,etc) for
infected wound ulcers, burn,
external ear infections,
conjunctivitis, but like other topical
antiinfective preparations, benefits
are limited.

39. USES
2. Orally for:
a) Preparation of bowel before surgery:
may reduce postoperative
infections.

40. USES
b) Hepatic coma: normally NH3 is
produced by colonic bacteria. This is
absorbed and converted to urea by
liver. In severe hepatic
failure,detoxication of NH3 does not
occur, blood NH3 levels rise and
produce encephalopathy.

41. USES
Neomicin, by suppressing intestinal
flora, diminishes NH3 production and
lowers its blood level; clinical
improvement is seen within 2-3 days.
Lactulose is preferred.

42. ADVERSE EFFECTS
It can decreases the absorption of
digoxin and many other drugs, as well
as bile acids. Neomycin is
contraindicated if renal function is
impaired.

43. FRAMYCETIN
Used topically on skin, eye, ear in the
same manner as neomycin.