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Similar to Mpl201 t 11 aminoglycosides
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Mpl201 t 11 aminoglycosides
- 1. © Ramaiah University of Applied Sciences
1
Faculty of Pharmacy
Aminoglycoside Antibiotics
At the end of this lecture, the student will be able to:
• Describe the mechanism of action of aminoglycosides
• Outline the structure and pharmacokinetics of
aminoglycosides
• Explain the clinical uses of aminoglycosides
- 2. © Ramaiah University of Applied Sciences
2
Faculty of Pharmacy
Contents
Aminoglycosides
• Mechanism of action
• Pharmacokinetics
• Adverse effects
• Clinical uses
- 3. © Ramaiah University of Applied Sciences
3
Faculty of Pharmacy
Aminoglycosides
• Two amino sugars joined to a aminocyclitol (non sugar) by a
glycosidic (-O-) bond
• In majority of AGs aminocyclitol moiety is 2-deoxystreptamine
aminosugar-O-2-deoxystreptamine-O-aminosugar
• In streptomycin, aminocyclitol is placed lateral to the
aminosugar (Streptose) in turn joined by another amino sugar
(N-methyl-L-glucosamine)
• Two amino sugars jointly called streptobiosamine
• Obtained from genus Streptomyces
- 4. © Ramaiah University of Applied Sciences
4
Faculty of Pharmacy
Structure of Aminoglycoside
• Highly polar compounds
• Available as soluble
sulfate/hydrochloride salts
• None absorbed from the GIT
• Administered iv, im
• No accumulation in CNS
• Excreted through kidneys
• More active in alkaline pH
• Hence a urinary alkaliniser
increases effectiveness in
treatment of UTIs
- 5. © Ramaiah University of Applied Sciences
5
Faculty of Pharmacy
Aminoglycosides
• Streptomycin
• Gentamicin
• Sisomicin
• Netilmicin
• Kanamycin
• Tobramycin
• Amikacin
• Neomycin
• Paromomycin
• Soframycin
• Spectinomycin
-mycin- obtained from Streptomyces
-micin- obtained from Micromonosporas
-Semisynthetic derivatives- micin
- 6. © Ramaiah University of Applied Sciences
6
Faculty of Pharmacy
Aminoglycosides – Mechanism of action
- 7. © Ramaiah University of Applied Sciences
7
Faculty of Pharmacy
Aminoglycosides – Mechanism of action
• Bactericidal, Concentration dependent killing
• Post antibiotic effect – residual bactericidal activity after the
concentration of drug below MIC
• Post antibiotic effect - dose dependent
• Drug diffuses through outer coat of gram negative bacteria
• Aqueous porin channels
• Reached periplasmic space
- 8. © Ramaiah University of Applied Sciences
8
Faculty of Pharmacy
Mechanism of Action
• Transport through cytoplasmic membrane - oxygen
dependent active process
• Energy dependent phase-1
• Inhibited by divalent cations like calcium, Magnesium
• Also by hyper osmolality, acidic pH and anaerobic respiration
• Once inside – binds to 30s ribosomal subunit
- 9. © Ramaiah University of Applied Sciences
9
Faculty of Pharmacy
Mechanism of Action
• May also bind to 50s ribosomal subunit
• Prevents the formation of initiation complex
• Freezing of protein synthesis
• Formation of polysomes is prevented
• Disaggregation of polysomes occur
• Monosomes with only one ribosomes attached to each strand
is formed
- 10. © Ramaiah University of Applied Sciences
10
Faculty of Pharmacy
Mechanism of Action
• Misreading of genetic code on mRNA
• Incorporation of incorrect aminoacids
• Loss of cell membrane integrity
• Inceased permeability
• Leakage of vital nutrients
• Augmentation of carrier mediated entry of antibiotics
• Energy dependent phase II
- 12. © Ramaiah University of Applied Sciences
12
Faculty of Pharmacy
Mechanism of Resistance
• Inactivation of drug
– Plasmid mediated acetyl transferase
– Plasmid mediated adenyl transferase
– Plasmid mediated phosphotransferase
• Restriction in the entry of drug through deletion or mutation
of channels
• Alteration in the binding site
- 14. © Ramaiah University of Applied Sciences
14
Faculty of Pharmacy
Pharmacokinetics
• Polar cation - No absorption when given orally
• Given parenteral (IM) or topical
• On IM administration - good bioavailability, peak plasma – 30-
90 mins
• Accumulates on pleural cavity and in synovial fluid
• Metabolism - insignificant
• In pregnancy – accumulates in foetal plasma – hearing loss
• Excretion – Kidney
- 15. © Ramaiah University of Applied Sciences
15
Faculty of Pharmacy
Antimicrobial Spectrum
Narrow spectrum – effective against gram negative bacteria
• Shigella
• Proteus
• Enterobacter
• Pseudomonas aeruginosa
• Klebsiella
• Serratia
- 17. © Ramaiah University of Applied Sciences
17
Faculty of Pharmacy
Adverse Effects
Renal toxicity – reversible
• Accumulation in kidney
• Degranulation of lysosome
• Release of acid hydrolase
• Digestion of cell organelles
• Digested organelles are sloughed off
• Excreted in urine
- 18. © Ramaiah University of Applied Sciences
18
Faculty of Pharmacy
Adverse Effects
Ototoxicity
• Accumulates in perilymph and endolymph
• Damage to VIII cranial nerve
• Vestibular toxicity – by streptomycin and gentamycin
– Ataxia
– Loss of body balance
• Cochlear toxicity – Neomycin and amykacin
– Hearing difficulties
– Tinnitus
- 19. © Ramaiah University of Applied Sciences
19
Faculty of Pharmacy
Adverse Effects
Neuro-muscular blockade – during
• Deplacement of calcium from neuromuscular junction
• Inhibition of ach release
• Calcium gluconate as i.v injection
• AchE inhibitors
- 20. © Ramaiah University of Applied Sciences
20
Faculty of Pharmacy
Clinical Uses
• Streptomycin – TB, plague, tularemia, Bacterial endocarditis
• Many aminoglycosides are combined with penicillin and
cephalosporins
• UTI, hospital acquired pneumonia, osteomylitis, meningitis,
peritonitis, burns and otitis
- 21. © Ramaiah University of Applied Sciences
21
Faculty of Pharmacy
Summary
• Aminoglycosides consists of two amino sugar joined by
aminocyclitol (non sugar) by a glycosidic bond
• They act by inhibiting protein synthesis by binding to 30s and
sometime 50s ribosomal subunits
• Polar cation - No absorption when given orally, Given
parenteral (IM) or topical, On IM administration - good
bioavailability, peak plasma – 30-90 mins
• Accumulates on pleural cavity and in synovial fluid
• Streptomycin – TB, plague, tularemia, Bacterial endocarditis
• Many aminoglycosides are combined with penicillin and
cephalosporins
• UTI, hospital acquired pneumonia, osteomylitis, meningitis,
peritonitis, burns and otitis
