MEDICINAL CHEMISTRY

1. AMINOGLYCOSIDES

2. CHEMISTRY OF
AMINOGLYCOSIDES
AMINOSUGAR 0 CENTRAL HEXOSE 0 AMINO SUGAR
 Glycosides are those plant products , where a
sugar moiety is joined to a non sugar moiety
with a ether linkage (-0-) .
If the sugar moiety is glucose,the glycoside is
called glucoside and if it is an AMINO SUGAR
then it is calledAMINO GLYCOSIDE.

7. MECHANISM OF ACTION
Aminoglycosides bind to 30s ribosomal units of bacteria
Pevents the formation of intiation complex,which is the prerequisite for
peptide synthesis
Lack of the formation of intiation complex causes the 30s sub unit to
MISREAD THE GENITIC CODE on mRNA
Incorrect aminoacids are thus incorporated into the growing peptide
chain,which are of no use for bacterial growth
LEADS TO BACTERIAL DEATH

9. CONTD………
Aminoglycosides also act by
Formed improper intiation complex blocks the movement of
ribosomes
Resulting in a mRNA chain attached with single ribosomes
(monosomes)
Thus amino glycoside also interfer in the assemble of poly
somes
Results in the accumulation of non functional ribosomes

10. PHARMACOKINETICS
 ABSORPTION: Aminoglycosides are highly polar ,
so they have very poor oral bioavailability.
• Therefore they are given parenterally or applied
locally.

11. CONTD…..
DISTRIBUTION: These are poorly distributed
and poorly protein bound when given
parenterally they failed to reach intraoccular
fluid or CSF.

12. CONTD…
• METABOLISM:As they do not penetrate more
celluar compartments they do not under go any
significant metabolism

13. CONTD……
 EXCRETION:
Mainly by kidney through glomerular filtration.
Resulting in fairly high urinary concentration.
so they can be used in the treatment of URINARY
TRACT INFECTIONS .
• Their excetion is directly proportional to creatinine
clearence .
• Though normal half life varies from 1.5-3 hrs,it may
increased to 24-48 hrs in patients with renal insufficiency

14. CONTD….
• The simplest formula uses the serum creatinine
levels to adjust the doses in renal insifficiency as
shown below
DOSE FOR ACASE NORMAL THERAPEUTIC
DOSE
OF RENAL IN-
SUFFICIENCY
SERUM CREATININE VALUE
(mg/dl)

15. POST ANTIBIOTIC EFFECT
• Aminoglycosides exhibit CONCENTRATION
DEPENDENT KILLING i;e their increased
concentration kills an increased proportion of
bacteria at rapid rate.
• They also possess significant POSTANTIBIOTIC
EFFECT,which means that they continue to
suppress the bacterial growth for several hours even
when their serum concentration falls below their
MIC.

17. CONTD….
• Cmax is 8-10 times greater then their MIC.
• If they are given divided doses it leads to toxicity.
• So aminoglycosides are given as a single daily doses
to reduce toxicity.
• It is necessary to measure peak and trough values
because they are active upto MIC level.

19. ANTI BACTERIAL RESISTANCE
o Synthesis of plasmid-mediated bacterial transferase
enzymes(acetyl transferases, phosphotransferases
and adenyl transferases) that can inactivate
aminoglycosides by acetylation, phosphorylation
and adenylation respectively.
o By devlopment of mutation or deletion of porin
channels.
o Alteration or deletion of the receptor proteins on 30s
ribosomal units.

20. ANTI BACTERIAL SPECTRUM
• Activity is primarily directed against Gram-negetive
aerobicbacilli(Ecoli,klebsiella,shigella, proteus
EXPECT SALMONELLA).
•Only a few Gram- positive cocci are inhibited
(Staphylococcus aureas,Streptococcus viridans and
faecalis).
• These are not effective against
BACILLI,GRAM-NEGETIVE
ANAEROBES.
GRAM-POSITIVE
COCCI and

24. 1. NEPHROTOXICITY:(reversible)
Inhibition of intracellular
phospholipase A2 in renal brush
lysosomal
border and
of free aminoglycoside into cytosol.
Then this free drug blocks the calcium
transport in mitochondria by displacing calcium
Leading to mitochondrial degeneration and
necrosis
Causes chronic renal failure
NEPHROTOXICITY

25. • OTOTOXICITY:(irreversible)
Aminoglycisides causes impairment of
cranial nerve function
8th
They accumulate in endolymph (vetibular),
perilymph (cochlear) and causes irreversible damage
Vestibular damage is characterised by vertigo,
ataxia and loss of balance,where as Cochlear
damage leads to hearing loss and tinnitus.

26. • NEUROMUSCULAR BLOCKADE:
It cause neuromuscular junction blocked
by blocking post synaptic Nm receptor and by
inhibiting
calcium mediated
release of
acetylcholine from
cholinergic neurons.

27. DRUG INTERACTIONS
• Aminoglycosides +local anaesthetics/skeletal
muscle relaxants
leads to paralysis
• Aminoglycosides should not be given with
ototoxic and nephrotoxic drugs like
tetracycline, furosemide, amphotericin B.