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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
- 11. © Ramaiah University of Applied Sciences 11 Faculty of Pharmacy Mechanism of Action
- 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
- 13. © Ramaiah University of Applied Sciences 13 Faculty of Pharmacy Mechanism of Resistance
- 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
- 16. © Ramaiah University of Applied Sciences 16 Faculty of Pharmacy
- 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