Aminoglycosides

Aminoglycosides

Content

Aminoglycosides

•       Mechanism of action

•       Pharmacokinetics

•       Adverse effects

•       Clinical uses

Objectives

At the end of this session, students will be able to:

•       List various aminoglycosides

•       Describe the mechanism of action of aminoglycosides

•       Outline the pharmacokinetics of aminoglycosides

•       Explain the clinical uses of aminoglycosides

Aminoglycosides

•       Two amino sugar aminocyclitol (non-sugar) by a glycosidic bond

•       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

Structure of aminoglycoside

Aminoglycosides Classification

•       Streptomycin

•       Gentamicin

•       Sisomicin

•       Netilmicin

•       Kanamycin

•       Tobramycin

•       Amikacin

•       Neomycin

•       Paromomycin

•       Soframycin

•       Spectinomycin

Aminoglycosides – Mechanism of action

•       Bactericidal, Concentration dependent killing

•       Post antibiotic effect  - dose dependent

•       Drug diffuses through outer coat of gram negative bacteria

•       Aqueous porin channels

•       Reached periplasmic space

•       May also bind to 50s ribosomal subunit

•       Prevents the formation of initiation complex

•       Freezing of protein synthesis

•       Misreading of genetic code on mRNA

•       Incorporation of incorrect aminoacids

•       Loss of cell membrane integrity

Mechanism of resistance

•       Inactivation of drug

–      Plasmid mediated acetyl transferase

–      Plasmid mediated adenyl transferase

–      Plasmid mediated phosphotransferase

•       Restriction in the entry of drug though deletion or mutation of channels

•       Alteration in the binding site

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

Antimicrobial spectrum

Narrow spectrum – effective against gram positive bacteria

•       Shigella

•       Proteus

•       Enterobacter

•       Pseudomonas aeruginosa

•       Klebsiella

•       Serratia

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

        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

        Neuro-muscular blockade – during

•       Deplacement of calcium from neuromuscular junction

•       Inhibition of ach release

•       Calcium gluconate as i.v injection

•       AchE inhibitors

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

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

•       Inhibited by divalent cations

•       Resistance develops early

•       Used in TB, tularemia, bacterial endocarditis, UTI

•       Associated adverse effects like ototoxicity, renal toxicity and neuro muscular blockade