Guided By Dr. Chandraih godugu Niper Hyderabad
Prasented BY Jatoth vishnu RT/2016/604Niper Hyderabad
MECHANISM OF AMINOGLYCOSIDES IN NEPHRO AND OTO
TOXICITY
CONTENTS
Introduction
History
Definition of aminoglycosides
Mechanism of toxicity
Mechanism of nephrotoxicity
Mechanism of ototoxicity
Conclusion
References
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INTRODUCTION
• Aminoglycosides are among the oldest antibiotics available to treat serious infections caused by primarily, Gram-negative bacteria
• The most commonly utilized parenteral agents in this class
– Gentamicin
– Tobramycin
– Amikacin
– Sisomicin
– Tobramycin
– Netilimicin
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Topical Neomycin Framycetin
•Aminoglycosides are concentration-dependent bactericidal agents
•That undergo active transport into the cell where they inhibit
protein synthesis on the 30S subunit of the bacterial ribosome
•As the use of aminoglycosides became more widespread, the
toxic effects of these agents, most notably ototoxicity and
nephrotoxicity
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HISTORY
• Aminoglycosides, which were developed in the 1940s
• Some of the oldest antibiotics used to treat serious infections caused
by gram-negative and some gram-positive bacteria
• The earliest aminoglycosides originated from
– Streptomyces spp
– Micromonospora spp
• Since that time there have been several aminoglycosides developed
with gentamicin, tobramycin, and amikacin being the 3 most commonly
used parenteral agents.
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DEFINITION
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Amino glycosides are a group of bacterial antibiotics which act by inhibiting the bacterial
protein synthesis
MECHANISM OF ACTION
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• Initially they penetrate bacterial
cell wall, to reach periplasmic
space through poring channels
(passive diffusion)
• Further transport across
cytoplasmic membrane takes
place by active transport by
proton pump; an oxygen-
dependent process
MECHANISM OF ACTION
• Bind 30S ribosomal subunits and interfere the initiation complex
• Induce misreading of genetic code on mRNA
• Breakup of polysomes into monosomes
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AMINOGLYCOSIDE-INDUCED NEPHROTOXICITY
• It is estimated that up to 25% of all patients who receive
aminoglycoside therapy develop nephrotoxicity
• Aminoglycosides appear to exert their nephrotoxic effects via 3
general mechanisms
– renal tubular toxicity
– reduced glomerular filtration
– reduction in renal blood flow
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RENAL TUBULAR TOXICITY• Renal tubular toxicity is the primary mechanism by which
aminoglycosides cause nephrotoxicity
• In the proximal tubule of the nephron, these agents undergo endocytosis and concentrate in
Lysosomes Golgi body, and Endoplasmic reticulum
• Once a threshold is reached, the aminoglycosides empty into the cytosol and act on the mitochondria to induce
– apoptosis
– necrosis
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RENAL TUBULAR TOXICITY
• Furthermore, they inhibit a number of transporters in the proximal tubule
• Which affects tubular reabsorption and compromises cell viability• Early signs that damage is occurring are increases in urinary
excretion of– calcium,– magnesium,– proteins, – And other organic anions
• Sometimes it resulting in hypocalcemia, hypomagnesemia, and proteinuria
• As the damage continues, increased excretion of potassium and sodium can be seen along with increases in serum creatinine05/02/23 Aminoglycosides 11
REDUCED GLOMERULAR FILTRATION• In the glomerulus, aminoglycosides induce mesangial contraction
• Which leads to decreased glomerular filtration rate (GFR)
• Aminoglycosides cause increases in intracellular calcium levels leading
to this mesangial contraction
• These include induction of platelet-activating factor secretion
• Activation of the renin–angiotensin–aldosterone system, production of
vasoconstrictors such as endothelin-1 and thromboxane A2
• and increases in reactive oxygen species and oxidative stress
• By increasing intracellular calcium levels through these mechanisms, the
smooth muscle mesangial cells contract, leading to decreased GFR.
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REDUCTION IN RENAL BLOOD FLOW
• Reduction in renal blood flow secondary to increased vascular resistance in the
renal vascular bed
• This takes place initially after damage to the proximal tubule has occurred, as a
means to prevent loss of fluid and electrolytes
• Then as endothelin 1 and thromboxane A2 have been released
• A reduction in renal blood flow occurs, which ultimately reduces GFR
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AMINOGLYCOSIDE-INDUCED OTOTOXICITYOtotoxicity:-
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Ototoxicity is quite simply, ear poisoning (oto = ear) which results from exposure to drugs of chemicals that damage the inner ear or the vestibule- cochlear nerve (the nerve sending balance and hearing information from the inner ear to the brain)
History
• Ototoxicity refers to medication-caused auditory and/or vestibular
system dysfunction those results in hearing loss or disequilibrium
• Aminoglycoside antibiotics are the first ototoxic agents to highlight
the problem of drug-induced hearing and vestibular loss
• It has long been known that the major irreversible toxicity of
aminoglycosides is ototoxicity
• This finding first came to light shortly after the discovery of
streptomycin
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CONT….• Aminoglycosides have variable types
– Cochleotoxicity
– Vestibulotoxicity
• primarily vestibulotoxic
– Streptomycin
– Gentamicin
• primarily cochleotoxic
– Amikacin
– Neomycin
– Dihydro streptomycin
– Kanamycin
• Cochlear damage can produce permanent hearing loss, and damage to the vestibular apparatus results in dizziness, ataxia, and/or nystagmus
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Mechanism• Significant progress has been made in understanding
aminoglycoside ototoxicity
• Which seems to be mediated by the disruption of mitochondrial
protein synthesis
• The over activation of glutamatergic receptors (N-methyl-D-
aspartate), and the formation of free radicals
• After systemic administration, AGs are detected in the cochlea within
minutes.
• Fluorescently labeled gentamicin was detected in the stria vascularis
10 minutes after injection in mouse
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CONT…• In the stria vascularis, the fluorescently tagged gentamicin increased
over time mainly in marginal cells, but also in intermediate and basal
cells as well as fibrocytes, plateauing after 3 hours
• These observations suggest that gentamicin enters the inner ear fluids
from the strial capillaries through the strial marginal cells
• In the organ of Corti, fluorescence from labeled gentamicin starts
increasing 1 hour after systemic injection
• Hair cells demonstrate fluorescent gentamicin intracellularly after 3
hours
• In rat cochlear tissues, gentamicin concentrations were measured by
a radioimmunoassay and peaked 3 hours after systemic application05/02/23 Aminoglycosides 18
CONT……• Inside the hair cell, AGs cause damage, either directly or indirectly,
• by first inducing disarray of stereocilia and ultimately ending with
apoptotic cell death
• The presence of AGs within hair cells leads to increased formation of
reactive oxygen species (ROS) or free radicals
• A common mechanism for the formation of ROS is the Fenton
reaction:
Fe2+ +H2O2 Fe⟶ 3+ + OH− + •OH
• When gentamicin combines with iron salts, the gentamicin-iron
complex enhances iron-catalyzed oxidations and, thereby, directly
promotes the formation of ROS
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CONT…• Gentamicin causes condensation of the nuclei of outer hair cells
followed by the loss of mitochondrial membrane potential and
apoptosis
• Reactive oxygen species, known to play a role in gentamicin-induced
ototoxicity
• It is promote the opening of the mitochondrial permeability pore
• c-Jun N-terminal kinase (JNK) pathway also plays a role in gentamicin-
induced cochlear and vestibular hair cell death in vivo
• Another study demonstrated that gentamicin causes a dose-dependent
increase in intracellular calcium in hair cells of chick tissue cultures of
sensory epithelium05/02/23 Aminoglycosides 20
• Ototoxicity in cochlear and vestibular hair cells has been the
inhibition of mitochondrial protein synthesis
• Many aminoglycosides cause excitotoxicity in hair cells as a result of
their agonist action at the polyamine site on the N- methyl-D-
aspartate (NMDA) receptor
• Aminoglycoside antibiotics enhance the function of NMDA receptors
by interaction with a polyamine modulatory site
• Because they can mimic the positive modulatory actions of
endogenous polyamines
• Accordingly, high doses of aminoglycosides may increase calcium
entry through the NMDA receptor-associated channel
• It promote degeneration of hair cells and cochlear nerve fibers
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CONCLUSION
• The use of aminoglycosides has dropped dramatically since the1970s with the development of newer, safer antibiotics.
• However, since that time bacterial resistance has been increasing,• And aminoglycosides are being considered, once again, as options
to treat multidrug resistant pathogens.• While concern of nephrotoxicity still exists, this adverse effect
can be limited by utilizing these agents in the right population.
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Reference• Selimoglu E, Kalkandelen S, Erdogan F. Comparative vestibulotoxicity
of different aminoglycosides in the Guinea pigs. Yonsei Med J 2003;
44: 517-22.
• Sandhya, P., S. Mohandass, and P. Varalakshmi. 1995. Role of DL
alphalipoic acid in gentamicin induced nephrotoxicity. Mol. Cell.
Biochem. 145:11–17.
• Kurt A, Wargo et al. aminoglycosides induced nephrotoxicity. journal of
pharmacy practice 2014, vol 27(6):573-577.
• Paul M, Tulkens aminoglycosides: nephrotoxicity. 1999:1003-1012.
• Erol selimoglu. Aminoglycosides induced ototoxicity. Current
pharmaceutical design 2007:13, 119-126.
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