pharmacology of Aminoglucoside

1. Presented By
Dr. Manoj Kumar
Assistant Professor
Department of Pharmacology
Adesh Medical College & Hospital Ambala Can’t

2. Amino glycosides
 A group of bactericidal antibiotics
 Used to treat aerobic Gram –ve bacteria
 Hexose ring attached to amino sugars by glycosidic
linkages
 Natural or semi synthetic derivatives compounds
produced by the soil actinomycetes
 Streptomycin was first discovered in 1944
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3. Properties
1. Highly water-soluble, polar compounds.
2. Not absorbed orally they are given Parenteral.
3. Remain extracellular & poor penetration in CSF .
4. Excreted unchanged by the kidneys.
5. More active in alkaline pH.
6. All are bactericidal.
7. Inhibiting bacterial protein synthesis.
8. Mainly effective against gram –ve organisms.
9. They are ototoxicity and nephrotoxicity
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4. Classification
Systemic Topical
 Streptomycin
 Kanamycin
 Tobramycin
 Amikacin
 Gentamicin
 Sisomicin
 Netilmicin
 Neomycin
 Framycetin
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5. Mechanism of action
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6. 6

7. Resistance
 Alteration of 30S ribosomal unit
 Inactivation by enzymes
 Acetyltransferase,
phosphotransferase,
adenylyltransferase
 Decreased transport into
bacterial cell
 Mutation of porin channels
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8. Pharmacokinetics
 Highly polar basic drugs
 Water soluble
 Not absorbed from GIT
 Given IM, IV infusion, topical route
 Poor CNS penetration, eye
 Intrathecal or intraventricular injection
 More active in alkaline pH
 Injection not mixed with any other drug
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9. Absorption & transport
Passive diffusion via porin channels across cell wall
 Enhanced transport: by cell wall-active drugs such as penicillin or
vancomycin
Active transport across cell membrane into cytoplasm by an O2-
dependent process
 Inhibition of transport: by low extracellular pH, anaerobic
conditions by reducing gradient
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10. Pharmacokinetics
 Excretion through kidneys
 Directly proportional to creatinine clearance
Corrected dose =Normal dose x pt CrCl
CrCl
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11. Anti-bacterial spectrum
 Active against aerobic gram -ve organisms
 E.coli, Shigella, Proteus, Pseudomonas, Klebsiella
 Few gram +ve: S.aureus, S.viridans, S.fecalis
 Not effective against anaerobes, salmonella
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12. Aminoglycosides
 Synergistic action with βlactam antibiotics
 Weaken or inhibit bacterial cell wall synthesis
 AGs can penetrate through porin channels by diffusion
 Combination used in serious infections with gram-
negative bacteria
 Supra-additive killing
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13. Aminoglycosides
 Concentration dependent killing
 Post antibiotic effect
 Lasts for several hours
 Given as a single daily dose (even as short t1/2: 2-3 hrs)
 Advantages: less labour intensive, more feasible
 Exceptions: renal insufficiency, when given for synergism with
β-lactams for enterococcal endocarditis
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14. .
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15. Therapeutic uses
 Gram negative bacillary infection
 Septicemia, pelvic, abdominal sepsis
 Bacterial endocarditis
 Enterococcal, streptococcal,
staphylococcal infection of heart valves
 Tuberculosis
 Pneumonia
 Plague,
 Brucellosis
 Tularemia
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16. Therapeutic uses
 Topical: Neomycin, Framycetin
 Infections of conjunctiva, external ear
 To sterilize bowel of patients who receive
immunosuppressive therapy, before surgery
 Hepatic coma
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17. Adverse effects
Narrow margin of safety
 Nephrotoxicity
 Ototoxicity
 Neuromuscular blockade
 Hypersensitivity reactions
 Skin rash, fever, anaphylactic shock
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18. Adverse effects
 More likely to be encountered when
 Continued for >5 days
 Given at higher doses
 In elderly
 In renal insufficiency
 Other nephrotoxic drugs
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19. Nephrotoxicity
 S. creatinine levels >1.5mg/dl
 Responsible for 10-15% of all renal
failure cases
 Reversible
 Tubular damage
 Low GFR, albuminuria
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20. Nephrotoxicity
Inhibition of intracellular lysosomal phospholipase A2 in
renal brush border
Lysosomal distension, rupture, release of acid hydrolases,
free AGs in cytosol
Free AGs bind to organelles: displaces Ca2+ in
mitochondria  mitochondrial necrosis
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21. Nephrotoxicity
 Agents which decrease nephrotoxicity of AGs
 Verapamil
 Ca+2
 Polyaspartic acid
 Disadv: decrease antibacterial activity
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22. Ototoxicity
 Irreversible
 Impairment of 8th cranial nerve function
 Accumulate in endolymph, periplymph

Vestibular & Cochlear damage
 
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Vertigo, ataxia, loss
of balance
Hearing loss, tinnitus
Streptomycin, Gentamicin Neomycin, Kanamycin, Amikacin
Netilimicin is LEAST OTOTOXIC Aminoglycoside

23. Precautions
 Avoided in pregnancy
 Risk of fetal ototoxicity
 CI
 Patients with perforated ear drum
 Ototoxicity
 Caution
 Elderly
 Renal impairment
 Other ototoxic, nephrotoxic drugs
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24. Neuromuscular blockade
At very high doses
 Displace Ca+2 from NMJ
 Block post-synaptic NM receptors
 Inhibit release of ACh from motor nerve
Clinical aspect
 Aggravate weakness in patients of m.gravis
 Potentiate the action of SMRs
 More with Streptomycin, Neomycin
 Reversed by IV Calcium gluconate, IM Neostigmine
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25. .
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26. Streptomycin
 From S.griseus
 Sensitive to Nocardia, M.tb, Yersinia,
 Rapid IM absorption
 Uses
 TB (2nd line): 0.5-1 g IM/IV OD * 1-2 moths
 SABE: + Penicillin * 2 weeks
 Plague, tularemia, brucellosis (+ tetracycline)
 Current status: Gentamicin preferred
 Development of resistance
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27. GentamIcin
 Most commonly used
 More potent, cheap
 Broader spectrum
 Effective against Pseudomonas, E.coli, Klebsiella
 Ineffective against M.tb, S.pyogenes
 More ototoxic
 Dosage: 3-5 mg/kg/d, IM/IV
 Uses: respiratory infections in ICU, UTI, burns
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28. Amikacin
 A semi synthetic derivative of kanamycin
 Widest AMA spectrum
 15 mg/Kg/d IM/IV
 Uses
 TB: MDR-TB, Atypical mycobacteria
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29. Neomycin
 Highly ototoxic: Not given systemically
 Topical use (Ointments, creams, powder)
 Uses: hepatic coma, bowel preparation for elective
surgery
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30. Tobramycin
 Used in pseudomonal infections
 Can also be given through Inhalational Route
 Used in P. aeruginosa lower respiratory tract infections
complicating cystic fibrosis patients
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31. Spectinomycin
 Structurally related to AGs
 Active against many gram-positive & gram-negative
organisms
 Used as an alternative treatment for drug-resistant
gonorrhea or gonorrhea in penicillin-allergic patients
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32. Spectinomycin
 Rapidly absorbed after IM injection
 Adverse effects
 Pain at injection site
 Fever
 Nausea
 Nephrotoxicity
 Anemia rare
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33. Used
 Often combined with β-lactam
antibiotics
 Used in severe, complicated
infections
 Serious gram negative infections
especially to Pseudomonas,
Enterobacter, Klebsiella, Serratia
 UTIs
 Bacteremia
 Meningitis
 Infected burns
 Pneumonia
 Osteomyelitis
 Ear infections
 Single large dose more effective & less
toxic than multiple small doses
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