Sandeep Mewada Pharmacology & Medicinal chemistry

1. Aminoglycoside
• Aminoglycoside is a medicinal and bacteriologic
category of traditional Gram-negative
antibacterial therapeutic agents that inhibit
protein synthesis and contain as a portion of the
molecule an amino-modified glycoside (sugar).
• Aminoglycoside antibiotics display bactericidal
activity against Gram-negative aerobes and
some anaerobic bacilli where resistance has not
yet arisen but generally not against Gram-
positive and anaerobic Gram-negative bacteria.

3. •Streptomycin is the first-in-
class aminoglycoside
antibiotic.
•It is derived from
Streptomyces griseus and is
the earliest modern agent
used against tuberculosis.

4. 2-deoxystrept-amine, 2D
representation, oxygens, nitrogens
(with attached hydrogens) in red, blue.

5. Other examples of
aminoglycosides include
• the deoxystreptamine-containing agents
•kanamycin,
•tobramycin,
• gentamicin,
• and neomycin

6. Nomenclature
• Aminoglycosides that are
derived from bacteria of the
Streptomyces genus are
named with the suffix -mycin,
whereas those that are
derived from Micromonospora
are named with the suffix -
micin

7. Mechanisms of action
• Aminoglycosides display concentration-
dependent bactericidal activity against "most
gram-negative aerobic and facultative anaerobic
bacilli" but not against gram-negative anaerobes
and most gram-positive bacteria.
• These activities are attributed to a primary mode
of action as protein synthesis inhibitors, though
additional mechanisms are implicated.
• The inhibition of protein synthesis is mediated
through aminoglycosides' energy-dependent,
sometimes irreversible binding, to the cytosolic,
membrane-associated bacterial ribosome .

8. Pharmacokinetics and
pharmacodynamics
• There is a significant variability in the relationship
between the dose administered and the resultant
plasma level in blood.
• Therapeutic drug monitoring (TDM) is necessary to
obtain the correct dose. These agents exhibit a post-
antibiotic effect in which there is no or very little drug
level detectable in blood, but there still seems to be
inhibition of bacterial re-growth.
• This is due to strong, irreversible binding to the
ribosome, and remains intracellular long after plasma
levels drop, and allows a prolonged dosage interval.
• Depending on their concentration, they act as
bacteriostatic or bactericidal agents.

9. Indications
• Aminoglycosides are useful
primarily in infections involving
aerobic, Gram-negative bacteria,
such as
• Pseudomonas,
• Acinetobacter,
• and Enterobacter.

10. • Mycobacteria, including the bacteria that
cause tuberculosis, are susceptible to
aminoglycosides.
• Streptomycin was the first effective drug in the
treatment of tuberculosis.
• aminoglycosides are mostly ineffective against
anaerobic bacteria, fungi, and viruses.
• Infections caused by Gram-positive bacteria
can also be treated with aminoglycosides, but
other types of antibiotics are more potent and
less damaging to the host.

11. Nonsense suppression
•The interference with mRNA
proofreading has been
exploited to treat genetic
diseases that result from
premature stop codons

12. Routes of administration
• They are not absorbed from the gut, they are
administered intravenously and
intramuscularly.
• Some are used in topical preparations for
wounds.
• Oral administration can be used for gut
decontamination (e.g., in hepatic
encephalopathy).
• Tobramycin may be administered in a
nebulized form.

13. Clinical use
• The recent emergence of infections due to Gram-
negative bacterial strains with advanced patterns of
antimicrobial resistance has prompted physicians to
reevaluate the use of these antibacterial agents.
• Aminoglycosides are in pregnancy category D,that is,
there is positive evidence of human fetal risk based
on adverse reaction data from investigational or
marketing experience or studies in humans, but
potential benefits may warrant use of the drug in
pregnant women despite potential risks.

14. •Aminoglycoside can
cause inner ear toxicity
which can result in
sensorineural hearing
loss.
Adverse effects

15. Contraindication for specific diseases
• Aminoglycosides can exacerbate weakness in
patients with myasthenia gravis, and use is
therefore avoided in these patients.
• Aminoglycosides are contraindicated in patients
with mitochondrial diseases as they may result
in impaired mtDNA translation, which can lead
to irreversible hearing loss, tinnitus, cardiac
toxicity, and renal toxicity.
• However, hearing loss and tinnitus have also
been observed in some patients without
mitochondrial diseases.