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

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  1. 1. Patel Omkumar P, 1st Semaster, Department of Pharmacology.
  2. 2. Contents 2  History and Chemistry  Classification  Antibacterial spectrum  Mechanism of action  Bacterial resistance  Pharmacokinetics  Toxicities  Precaution and interaction  Therapeutic uses
  3. 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. 4. Classification 4 Systemic Aminoglycoside Streptomycin Gentamicin Kanamycin Tobramycin Amicacin Sisomycin Netlimycin
  5. 5. 5 Topical aminoglycoside Neomycin framycetin
  6. 6. Mechanism of action 6  Bactericidal  Bacterial killing is concentration-dependent  A post-antibiotic effect
  7. 7. Antibacterial Spectrum of the Aminoglycosides7 Netilmicin Kanamyci n Tobramyc in Gentamici n Aerobic gram- negativ e bacilli Active agains t
  8. 8. 8 • Kanamycin and streptomycin has limited spectrum • Little activity against anaerobic microorganisms or facultative bacteria under anaerobic conditions
  9. 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. 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. 11
  12. 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. 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. 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. 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. 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. 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. 18 • Result of accumulation and retention of aminoglycoside in proximal tubular cells. • Renal damage is totally reversible if drug is discontinued. Nephrotoxicity
  19. 19. 19  Gentamicin, amikacin and tobramycin are more toxic than streptomycin  ↓ GFR, ↑ Serum creatinine  ↓clearance of antibiotic → ↑ ototoxicity
  20. 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. 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. 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. 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. 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. 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. 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. 27  Ineffective against M.tuberculosis  Relatively more nephrotoxic
  28. 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. 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. 30. Tobramycin 30  Identical to gentamicin  Used in pseudomonas and proteus infections  Ototoxicty and nephrotoxicity probably lower than gentamicin.
  31. 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
  33. 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