mechanism of amino glycosides in nephro and oto toxicity

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

05/02/23 Aminoglycosides 2

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


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


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.


DEFINITION


Amino glycosides are a group of bacterial antibiotics which act by inhibiting the bacterial

protein synthesis

MECHANISM OF ACTION


• 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


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


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


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.


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


AMINOGLYCOSIDE-INDUCED OTOTOXICITYOtotoxicity:-


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


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


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


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


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


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.


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.


mechanism of amino glycosides in nephro and oto toxicity

Health & Medicine