History, Classification, Antibacterial spectrum, Mechanism of action, Bacterial resistance, Pharmacokinetics, Toxicities like ototoxicity and nephrotoxicity, Therapeutic uses of Amioglycoside.

1. Patel Omkumar P,
1st Semaster, Department of Pharmacology.

2. Contents
2
 History and Chemistry
 Classification
 Antibacterial spectrum
 Mechanism of action
 Bacterial resistance
 Pharmacokinetics
 Toxicities
 Precaution and interaction
 Therapeutic uses

3. History and Source
3
 Streptomycin was the first member discovered
in 1944 by Waksman.
 Streptomycin was first isolated from a strain of
Streptomyces griseus
 Aminoglycosides have polybasic amino groups
linked glycosidically to two or more
aminosugar.

4. Classification
4
Systemic Aminoglycoside
Streptomycin
Gentamicin
Kanamycin
Tobramycin
Amicacin
Sisomycin
Netlimycin

5. 5
Topical aminoglycoside
Neomycin
framycetin

6. Mechanism of action
6
 Bactericidal
 Bacterial killing is concentration-dependent
 A post-antibiotic effect

7. Antibacterial Spectrum of the
Aminoglycosides7
Netilmicin
Kanamyci
n
Tobramyc
in
Gentamici
n
Aerobic
gram-
negativ
e bacilli
Active
agains
t

8. 8
• Kanamycin and streptomycin has
limited spectrum
• Little activity against anaerobic
microorganisms or facultative bacteria
under anaerobic conditions

9. 9
 Action against most gram-positive bacteria is
limited
 In combination with a cell wall inhibitor
produces a synergistic bactericidal effect in
vitro against enterococci, streptococci, and
staphylococci

10. Mechanism of Action
10
 First Penetration in bacterial cell
 Bacterial cell wall through pores by passive
diffusion.
 Cytoplasmic membrane through active diffusion.
 Inhibition of protein synthesis
 Bind 30S ribosomal subunits and inhibit protein
synthesis

11. 11

12. Post antibiotic effect
12
 Aminoglycosides exhibit concentration
dependent killing.
 A post antibiotic effect ,that is, residual
bactericidal activity persisting after the serum
concentration has fallen below the MIC.

13. BACTERIAL RESISTANCE
13
Cell membrane bound inactivating enzyme
which inactivate aminoglycosides
Mutation decreasing the affinity of
Aminoglycoside to ribosomal proteins
Decreased transport mechanism

14. Pharmacokinetic
14
 Highly polar basic drugs: poor oral BA
 Administered parenterally or applied locally
 Poorly distributed and poorly protein bound,
distribute only extracellularly, do not penetrate
brain or CSF.

15. 15
 Nearly all IV dose is excreted unchanged in
urine
 Dose adjustment is needed in renal
insufficiency
 They have relatively narrow margin of safety
between therapeutic and toxic concentrations.

16. Ototoxicity
16
 Impairment of VIII cranial nerve function
(vestibulococlear nerve)
 Cochlear damage
 Hearing loss and tinnitus
 More with neomycin , amikacin and kanamycin
 Vestibular damage
 Vertigo, loss of balance
 More with Streptomycin, gentamycin
 Tobramycin has both types of toxicity
 Netilimycin claimed to have low ototoxicity

17. 17
• prograssive accumulation of these drugs
occur in the perilymph and endolymph of
the inner ear.
• Vestibular or cochlear part is affected
• Older patient and those with preexisting
are more effected
• May be irreversible

18. 18
• Result of accumulation and retention of
aminoglycoside in proximal tubular cells.
• Renal damage is totally reversible if
drug is discontinued.
Nephrotoxicity

19. 19
 Gentamicin, amikacin and tobramycin are
more toxic than streptomycin
 ↓ GFR, ↑ Serum creatinine
 ↓clearance of antibiotic → ↑ ototoxicity

20. 20
 Cause N-M junction blockade by
 By blocking post synaptic NM receptors
 Inhibiting Ach release from motor nerve
 Neomycin & streptomycin: more propensity
 Tobramycin least likely to produce it
 Myasthenic weakness ↑by these drugs
Neuromuscular blockade

21. 21
 Other Effects on the Nervous System.
• The administration of streptomycin may
produce dysfunction of the optic nerve,
including scotomas, presenting as
enlargement of the blind spot.

22. 22
 Anaphylaxis and rash are unusual
 Rare hypersensitivity reactions including skin
rashes, eosinophilia, fever, blood dyscrasias,
angioedema, dermatitis, stomatitis, and
anaphylactic shock have been reported.

23. Precaution and interaction
23
Avoid concurrent use of
other nephrotoxic and
ototoxic drug
Avoid during pregnancy
Avoid in patient with kidney
damage
Do not use muscle relaxant in
patient receiving aminoglycoside

24. Streptomycin
24
 It is the oldest aminoglycosides obtained from
streptomyces griseus.
 Limited usefulness as single agent
 Plague, tularemia and brucellosis
-In combination with tetracycline
 Reserve first line drug for tuberculosis used
only in combination

25. 25
 Adverse effect:
-Streptomycin has the lowest nephrotoxicity
among aminoglycosides, becouse it is not
concentrated in the renal cortex.
-rashes
-eosinophilia
-fever and exfoliative dermatitis
-anaphylaxis is very rare
- hypersensitivity reaction is rare.

26. Gentamicin
26
 Obtained from Micromonospora purpurea
 Most commonly used aminoglycoside
 More potent than Streptomycin
 Broader spectrum: pseudomonas, proteus, E.coli,
klebsiella, enterobacter, serratia
 Low cost,
 Acts synergistically with ampicillin, penicillin G,
Ticarcillin, ceftriaxone, Vancomycin

27. 27
 Ineffective against M.tuberculosis
 Relatively more nephrotoxic

28. Gentamicin (Uses)
28
 For preventing and treating respiratory
infections in critically ill patients.
 Pseudomonas,proteus,or klebsiella infection.
 Meningitis
 Subacute bacterial endocarditis
 Penicillin G/ampicillin/vancomycin with Gentamincin

29. Amikacin
29
 Less toxic semisynthetic derivative of
kanamycin
 Resistant to enzymes that inactivate
gentamicin and tobramcyin
 Widest spectrum of activity
 Uses:
 Same as gentamicin
 Multidrug resistant TB along with other drugs
 Dose : 15mg/kg/day in 1-3 doses

30. Tobramycin
30
 Identical to gentamicin
 Used in pseudomonas and proteus infections
 Ototoxicty and nephrotoxicity probably lower
than gentamicin.

31. Neomycin
31
 Wide spectrum active against Gm-ve bacilli and some
gm+ve cocci
 Pseudomonas and strep.pyogenes not sensitive
 Too toxic for parenteral use , limited to topical use
 Topically used in skin, eye and external ear infections
combined with bacitracin or polymyxin-B to widen
antibacterial spectrum

32. THERAPEUTIC USES
32

33. 33
Aminoglycosi
de
Main indication
Streptomycin Tuberculosis, bacterial endocarditis
Gentamicin Pneumonia, urinary tract
infection,middle ear infection,
meningitis
Kanamycin Tuberculosis
Tobramycin Infection caused by pseudomonas
and proteus
Amikacin Tuberculosis
Sisomycin Bacterial endocarditis