AMINOGLYCOSIDES

The different members of this group share many properties in common.

AMINOGLYCOSIDES
Streptomycin Gentamicin Tobramycin Amikacin Netilmicin Kanamycin Neomycin

AMINOGLYCOSIDES

Amino sugars linked through glycosidic bonds. Polycations: This is in part responsible for many of their shared pharmacokinetic properties

ANTIBACTERIAL ACTIVITY

Primarily active against aerobic gram negative bacteria.

Active against many staphylococci and certain Mycobacteria.

Anaerobic bacteria are not susceptible.

SENSITIVITY AND RESISTANCE

AMINOGLYCOSIDE TRANSPORT

Transport across the cell membrane is by active transport. Antimicrobial activity is reduced in an anaerobic environment and at low pH.

RESISTANCE

Cross-resistance occurs to varying degrees with the different aminoglycosides.

Amikaciin

ABSORPTION AND DISTRIBUTION

Oral bioavailability is low. Once daily dosing (postantibiotic effect). Distribution into most body tissues including the CNS is low.

EXCRETION

Rapidly and almost entirely excreted by glomerular filtration (proportional to creatinine clearance).

Accumulation occurs with impaired renal function.

THERAPEUTIC USES

Severe , complicated infections. Often combined with -lactams.

STREPTOMYCIN

Bacterial endocarditis (combined with a penicillin or vancomycin).

Tuberculosis.

Gentamicin, Tobramycin, Netilmicin and Amikacin

Similar in clinical indications and range of activity. Gentamicin is often preferred but resistance may limit its use.

THERAPEUTIC USES

Serious gram negative infections especially those due to Pseudomonas, Enterobacter, Klebsiella, Serratia etc.

UTIs, bacteremia, meningitis, infected burns, pneumonia, osteomyelitis, ear infections etc.

THERAPEUTIC USES

Severe Pseudomonas infections are best treated with one of these 4 AGs plus an antipseudomonal penicillin or cephalosporin. Gentamicin combined with a penicillin is often used to treat bacterial endocarditis.

THERAPEUTIC USES

Tobramycin is often used in pseudomonal infections. Amikacin is used as the preferred agent in hospitals. Netilmicin- may be useful in resistant infections.

DRUG INTERACTIONS

Antipseudomonal penicillins inactivate aminoglycosides. Ethacrynic acid and other loop diuretics. Nephrotoxic agents. Neuromuscular blocking agents.

SHARED PROPERTIES OF THE AMINOGLYCOSIDES

Inhibit protein synthesis by binding to the 30S ribosomal subunit

Pharmacokinetics-Poorly absorbed from the GI tract, Dont get into the CNS very well, Rapidly excreted by kidney Toxicity-Ototoxicity, Nephrotoxicity, Neuromuscular blockade

THERAPEUTIC USES OF THE AMINOGLYCOSIDES

Streptomycin Gentamicin Tobramycin Amikacin

T.B., Endocarditis Endocarditis, gram negative infections, Pseudomonas Gram negative infections, Pseudomonas Reserve drug for gram negativeinfections

Nascent polypeptide chain

50S

aa mRNA

Transferase site

template

30S

AGs

Mechanism of action of Aminoglycosides

Mature protein
Blocks initiation 5
50S
AUG

Growing polypeptide Premature termination

5 5 3
30S

AUG

Wrong amino acid is incorporated 5

AUG

X
3

mRNA translation

+ aminoglycoside

Effects of Aminoglycosides

Aminoglycosides on Protein Synthesis

Mature Protein Growing Polypeptide Blocks initiation 5 Premature termination 3

AUG

50S

30S +

X
5 3

mRNA translation

Amino Glycoside

Incorporation of wrong amino acid

MECHANISM OF ACTION

Exact mechanism of cell death is unknown. Postantibiotic effect.

RESISTANCE

Alterations in ribosomal proteins. Decreased permeability to the antibiotic.

TOXICITY

Ototoxicity (Vestibular and Auditory). Nephrotoxicity.

Neuromuscular Blockade.

OTOTOXICITY
The

most serious toxic effect (uncommon, irreversible and cumulative). by all the aminoglycosides

Caused

OTOTOXICITY

Several factors increase the risk.

Careful monitoring is important.

NEPHROTOXICITY

Several factors may increase the risk. Reversible and usually mild. Reduced excretion can lead to ototoxicity.

NEUROMUSCULAR BLOCKADE

Rare but potentially serious. Occurs at high concentrations of aminoglycosides or in patients with an underlying risk factor. Acute neuromuscular blockade, respiratory paralysis and death can occur.

ve s ic e l ch o l n ie a ce ty l tr an s f er a se
AC h

AC h

AC h A ce ty C l oA + C h AC h

/0 TD H 7 9

AC h

hg i h a ff n i i ty up t a ke

Amino Glycosides

AC h AC h

AC h

Ac +C h

r e ce p t or

AC h e s t er a se

td h