AMINOGLYCOSIDES

G Vijay Narasimha KumarAsst. Professor,

Dept.of. PharmacologySri Padmavathi School of Pharmacy

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 called AMINO GLYCOSIDE.

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

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

PHARMACOKINETICS

ABSORPTION: Aminoglycosides are highly polar , so they have very poor oral bioavailability.

• Therefore they are given parenterally or applied locally.

CONTD…..

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

CONTD…

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

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

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- SERUM CREATININE VALUE SUFFICIENCY (mg/dl)

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 POST ANTIBIOTIC EFFECT,which means that they continue to suppress the bacterial growth for several hours even when their serum concentration falls below their MIC.

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.

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.

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 GRAM-POSITIVE BACILLI,GRAM-NEGETIVE COCCI and ANAEROBES.

1.NEPHROTOXICITY:(reversible) Inhibition of intracellular lysosomal

phospholipase A2 in renal brush border and release of free aminoglycoside into cytosol.

Then this free drug blocks the calcium mediated transport in mitochondria by displacing calcium

Leading to mitochondrial degeneration and necrosis

Causes chronic renal failure

NEPHROTOXICITY

• OTOTOXICITY:(irreversible) Aminoglycisides causes impairment of 8th

cranial nerve function

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.

• NEUROMUSCULAR BLOCKADE: It cause neuromuscular junction blocked

by blocking post synaptic Nm receptor and by inhibiting calcium mediated release of acetylcholine from cholinergic neurons.

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.