AMINOGLYCLOSIDES

Amino + Glycoside
• Polybasic amino groups linked glycosidically to
two or more aminosugar.
 Aminoglycosides
Are a class of antibiotics used mainly in the treatment of
aerobic gram-negative bacilli infections, although they
are also effective against other bacteria including
Staphylococci and Mycobacterium tuberculosis. They are
often used in combination with other antibiotics.
General character of aminoglycosides
• Formulations are Sulfate or hydrochloric salts.
• Formulations are water soluble and stable.
• Highly polar basic drugs.
• Ionize during dissolution.
• Distribution inside the cells is minimal.
• Penetration through BBB is minimal.
• Bactericidal in nature.
• More active in alkaline pH
• Concentration dependent
• Mainly gram negative
• Therapeutic index is narrow.
Classification
-Systemic -Topical
• Streptomycin • Neomycin
• Gentamicin • Framycetin
• Kanamycin
• Amikacin
• Sisomicin
• Tobramycin
• Netilimicin
 Side effects
• Ototoxic
• Nephrotoxic
• Neuromuscular blockage
• Etc. ( Teratogenicity)
 Ototoxic
• results in irreversible, bilateral high frequency hearing
loss and temporary vestibular hypofunction.
• Released from there when plasma concentration
decreases.
• Damage of sensory and hair cells.
 Cochlear
• Starts from base spreads to apex
• High frequency affected first
• Recovery is very poor.
• Deafness may be permanent, more in elderly.
• Present with tinnitus followed by hearing loss
 Vestibular

• Presents with Vertigo, Ataxia, Nystagmus

 Nephrotoxicity

• More damage of cortical nephrons.

• Related to total exposure.
• More in elderly
• More in pre-existing renal disease
• Tubular damage
 Neuromuscular Blockade

• More with Neomycin and Streptomycin

• Reduce Acetylcholine release from Motor endings.
• Interfere with mobilization of synaptic vesicles.
• Decreased sensitivity of muscle end plates to
acetylcholine.
 General properties of Aminoglycosides
• Highly water soluble, so not absorbed orally.
• More active at alkaline pH.
• Excreted unchanged in urine.
• Bactericidal, inhibit protein synthesis.
• Active against gram negative bacteria.
Properties
• They ionize in solution
- Not absorb orally
- Distribute only extracellularly
 Mechanism of Action

• Aminoglycoside inhibit protein synthesis by binding with

high affinity to the A-site on the 16s ribosomal RNA of the
30S ribosome.
• Passive diffusion via porin channels across outer membrane.
• Irreversible inhibition of protein synthesis.
• “Post antibiotic effect”
 MOA
• Initial entry of Aminoglycosides through bacterial cell wall to
periplasmic space.
• Advantage of adding beta lactams
-Beta lactams antibiotics weaken the bacterial cell wall
-Facilitate passive diffusion of Aminoglycoside. (synergism)
• Penetration is dependent on maintenance of polarized
membrane
• Oxygen dependent active process.
• Prevent polysome formation.
• Inhibit formation of initiation complex
• Inhbit protein synthesis
 Post antibiotic effect
• Antibacterial activity persists beyond the time during
which measurable concentration is present.
• Slow recovery after reversible nonlethal damage to cell
structures.
• Time taken for enzyme synthesis for cell growth.
 Pharmacokinetics
• Poor oral absorption from intact GIT mucosa
• After intramuscular injection, peak concentration in 30-60min.
• Highly polar, mainly extra cellular
• Cleared by kidneys.
• Normal half life in serum: 2-3hours
• Can cross the placenta
 Distribution
• Because of their polar nature, the aminoglycosides do
not penetrate into most cells, the central nervous
system, or the eye.
• Plasma protein binding: neglible
• Concentration of aminoglycosides in secretions and
tissues are low.
 Elimination

• Excreted almost entirely by glomerular filtration.

• Large fraction of a parenterally administered dose is
excreted unchanged during first 24hours.
 Streptomycin
• Was first discovered in 194 by Waksman
• Oldest aminoglycoside obtained from Streptomyces
griseus.
• Natural products or semisynthetic derivatives of
compounds produced by variety of soil actinomycetes.
• Narrow spectrum (Gram negative + M. tuberculosis)
• Streptomycin is the first drug to show antitubercular acitivity
• Acts against extracellular bacilli.
• Also active against Atypical Mycobacterium
 Uses:

• Tuberculosis
• Subacute bacterial endocarditis
• Plague
• Tularemia
 Gentamicin
• Derived from species of the Actinomycete
micromonospora.
• Cheapest and first line antibiotic.
• 3rd systemically antibiotic obtained from
micromonospora purpurea in 1964.
• Most commonly used Aminoglycosides
• Broader spectrum (but not effective in TB)
• Synergism with Beta lactams.
 Gentamicin-PMMA
(Polymethyl methacrylate)

• A new drug delivery system for Osteomyelitis.

• Small acrylic beads impregnated with gentamicin.
• Threaded over surgical wire and implanted in bone
cavity.
 Kanamycin
• Obtained from S. kanamyceticus in 1957.
• Similar to streptomycin in all aspects.
• Toxicity and narrow spectrum not used now.
• Occasionally used in 2nd line drug in tuberculosis.
 Tobramycin
• Similar to gentamicin
• Intramuscular or intravenous injection
• Superior activity against pseudomonal infection,
proteus along with beta lactams.
• Ineffective to gentamicin.
• Used pseudomonas and proteus resistant to
gentamycin
• Ototoxicity and nephrotoxicity is less.
 Amikacin
• Semisynthetic derivative of Kanamycin, less
toxic.
• Resistant to enzyme inactivation.
• Multi drug resistant T.B
• Has widest spectrum of activity
• Next to Gentamicin regarding use.
• Reserve drug as alternate to Gentamicin
• More hearing loss
 Neomycin
• Wide spectrum
• Topically for injected wound, buns, ulcers,
external ear infection, conjunctivitis.
• Highly cochlear toxic, and nephrotoxic
• Most common use is topical, ointment, eye, and
eardrops.
• Neomycin with polymyxin-B solution is used as
irrigant in urinary bladder to prevent bacteriuria
associated ith use of indwelling catheter.
 Uses:
• Oral:
- Hepatic coma suppresses coliforms
- Gut surgery
• Topically combine with polymixin and bacitracin.
• Oral neomycin has damaging effect on intestinal villi
Malabosorption syndrome.
• Damages colonic flora-deficiency of Vitamin K
superinfection.
• Not used systemically (Except for preparation of bowel for
surgery and in Hepatic coma or Hepatic Encephalopathy)
 Hepatic coma (Hepatic Encephaopathy)

• Colonic bacteria produce NH3.

• NH3 can cross BBB.
• NH3 is toxic to nervous systems
• NH3 is converted to Urea by Liver
• In hepatic failure conversion of NH3 to Urea does not occur.
• Increased level of NH3 produces encephalopathy.
• Neomycin suppresses colonic flora.
• NH3 production in colon is reduced.
• Other drug used for this purpose is Lactulose.
 Framycetin (Soframycin)
• Extracted from Steptomyces lavendulae
• Similar to Neomycin
• Used mainly topically
(ointment, cream, eye drops)
 Netilmicin
• Semisynthetic derivative of gentamycin
• Broader spectrum
• Reatively resistant to aminoglycoside inactivating enzymes
• More active against klebsiella, enterobacter and
staphylococcus
• Less active against pseudomonas
• Resistant to most inactivating enzymes.
• Less ototoxic
 Sisomicin
• From Micromonospora inyoensis.
• Similar to Gentamicin but more potent on
pseudomonas, beta haemolytic streptomycin.
• Subacute bacterial endocarditis
• Susceptible to inactivating enzymes.
 Paramomycin
• Chemically related to Neomycin
• Activity against protozoan parasites.
• To treat intestinal amoebiasis
• Cryptosporidiosis in immunocompromised
 Spectinomycin
• Obtained from Streptomyces
• Not true aminoglycoside chemically
• Single dose 40mg/kg intramuscular used for gonorrhoea
alternative to penicillin.
• Nephrotoxicity and ototoxicity very rare.
• Chlamydial treatment along with doxycycline