AMINOGLYCOSIDES

1. AMINOGLYCOSIDES • The different members of this group share many properties in common.

3. AMINOGLYCOSIDES • Streptomycin • Gentamicin • Tobramycin • Amikacin • Netilmicin • Kanamycin • Neomycin

4. AMINOGLYCOSIDES • Amino sugars linked through glycosidic bonds. • Polycations: This is in part responsible for many of their shared pharmacokinetic properties

5. ANTIBACTERIAL ACTIVITY • Primarily active against aerobic gram negative bacteria. • Active against many staphylococci and certain Mycobacteria. • Anaerobic bacteria are not susceptible.

6. SENSITIVITY AND RESISTANCE

7. AMINOGLYCOSIDE TRANSPORT • Transport across the cell membrane is by active transport. • Antimicrobial activity is reduced in an anaerobic environment and at low pH.

8. RESISTANCE • Cross-resistance occurs to varying degrees with the different aminoglycosides. • Amikaciin

9. ABSORPTION AND DISTRIBUTION • Oral bioavailability is low. • Once daily dosing (postantibiotic effect). • Distribution into most body tissues including the CNS is low.

10. EXCRETION • Rapidly and almost entirely excreted by glomerular filtration (proportional to creatinine clearance). • Accumulation occurs with impaired renal function.

13. THERAPEUTIC USES • Severe , complicated infections. • Often combined with β-lactams.

14. STREPTOMYCIN • Bacterial endocarditis (combined with a penicillin or vancomycin). • Tuberculosis.

15. Gentamicin, Tobramycin, Netilmicin and Amikacin • Similar in clinical indications and range of activity. • Gentamicin is often preferred but resistance may limit its use.

16. THERAPEUTIC USES • Serious gram negative infections especially those due to Pseudomonas, Enterobacter, Klebsiella, Serratia etc. • UTI’s, bacteremia, meningitis, infected burns, pneumonia, osteomyelitis, ear infections etc.

17. THERAPEUTIC USES • Severe Pseudomonas infections are best treated with one of these 4 AG’s plus an antipseudomonal penicillin or cephalosporin. • Gentamicin combined with a penicillin is often used to treat bacterial endocarditis.

18. THERAPEUTIC USES • Tobramycin is often used in pseudomonal infections. • Amikacin is used as the preferred agent in hospitals. • Netilmicin- may be useful in resistant infections.

19. DRUG INTERACTIONS • Antipseudomonal penicillins inactivate aminoglycosides. • Ethacrynic acid and other loop diuretics. • Nephrotoxic agents. • Neuromuscular blocking agents.

21. SHARED PROPERTIES OF THE AMINOGLYCOSIDES

22. THERAPEUTIC USES OF THE AMINOGLYCOSIDES

23. A Nascent polypeptide chain 50S Transferase site aa mRNA template P AG’s 30S Mechanism of action of Aminoglycosides

24. 5’ AUG 3’ AUG 5’ 3’ X AUG 3’ Mature protein Blocks initiation Growing polypeptide 50S Premature termination 5’ 3’ Wrong amino acid is incorporated 30S 5’ mRNA translation + aminoglycoside Effects of Aminoglycosides

25. Aminoglycosides on Protein Synthesis Blocks initiation 5’ 3’ Premature termination 3’ 5’ X 3’ 5’ Incorporation of wrong amino acid Mature Protein Growing Polypeptide 50S AUG 3’ 5’ 30S + mRNA translation Amino Glycoside

26. MECHANISM OF ACTION • Exact mechanism of cell death is unknown. • Postantibiotic effect.

27. RESISTANCE • Alterations in ribosomal proteins. • Decreased permeability to the antibiotic.

29. TOXICITY • Ototoxicity (Vestibular and Auditory). • Nephrotoxicity. • Neuromuscular Blockade.

31. OTOTOXICITY • The most serious toxic effect (uncommon, irreversible and cumulative). • Caused by all the aminoglycosides

33. OTOTOXICITY • Several factors increase the risk. • Careful monitoring is important.

36. NEPHROTOXICITY • Several factors may increase the risk. • Reversible and usually mild. • Reduced excretion can lead to ototoxicity.

37. NEUROMUSCULAR BLOCKADE • Rare but potentially serious. • Occurs at high concentrations of aminoglycosides or in patients with an underlying risk factor. • Acute neuromuscular blockade, respiratory paralysis and death can occur.

38. Amino Glycosides