this research done by students of pharmacy college for pharmacology and toxicology department , and among 30 research in different topic our research has NO.1 in content , design , presentation
2. OUTLINE
1. Introduction
2. Mechanism nephrotoxicity
3. Risk factor
4. Symptom of toxcity
5. Biomarker assessment
6. Test used to measuring drug level
7. Strategies to prevent toxcity
8. Studies and clinical trailer
3. INTRODUCTION…
Amino glycoside 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.
4. CONT.…
Amino glycosides are thought to work by inhibiting
protein synthesis inside bacteria. Kill rates of bacteria
are increased when higher concentrations of amino-
glycoside are present; however, the margin between a
safe and a toxic dose is narrow and monitoring is often
needed, although once daily dosing increases the safety
window.
5. CONT…
Impairment of kidney function and hearing loss are the
most common side effects of amino-glycoside. Amino
glycosides tend to be used when other less toxin
antibiotics are contraindicated or ineffective
6.
7. MECHANISM OF NEPHROTOXICITY …
Gentamicin is the most potent nephrotoxic aminoglycoside
upon which most studies on aminoglycoside nephrotoxicity
are based.
Gentamicin was the first aminoglycoside synthesised. It is a
powerful antibiotic and is the aminoglycoside with the
broadest spectrum
8. CONT…
Pathogenesis Aminoglycoside-associated is primarily due
to accumulation of high drug concentrations within
proximal tubular epithelial cells, and subsequent generation
of reactive oxygen species that produce mitochondrial
injury, which leads to cellular apoptosis and necrosis. This
results in cell sloughing from proximal tubular basement
membranes into the tubular lumen, which can result in
tubular obstruction back leakage of the glomerular filtrate
across the damaged tubular epithelium
9. CONT…
Toxicity is related to cationic charge of the drugs in which
facilitates their binding to negatively charged renal tubular
epithelial membrane phospholipids in the proximal tubules,
followed by intracellular transport and concentration The
number of cationic groups the drug molecule appear to
correlate with the degree of nephrotoxicity, which is
consistent with the observation of higher rates of toxicity
with neomycin versus gentamicin followed by tobramycin,
then amikacin.1
10.
11. RISK FACTOR FOR NEPHROTOXICITY …
1. . Dose and duration of drug treatment
2. . Recent aminoglycoside therapy
3. . Preexisting renal insufficiency
4. . Preexisting hepatic disease
5. . Elderly age
6. . Concomitant nephrotoxic drug administration
7. .diabetes
8. Potassium depletion 9. Magnesium depletion
13. BIOMARKER ASSESSMENT FOR RENAL
TOXCITY INDUCED BY A GLYCOSID
1-Kidny injury
molecules _1
2-neutrophil
gelatinase-
associated
lipocalin
Researchers found that during
amino glycosides treatment,
Kim-1
inc. by 2
fold
NGAL
inc. by 4
fold
whereas
creatine
value inc.
only 1
times
Creatine test not usually used since its
related to advance step of Kidny disease
14. LD 50% of gentamicinsulfate
Oral >5000mg/kg
IV 96mg/kg
IM 384mg/kg
Injection (vial )
Tab
Cream
Sol. For skin apply
Neomycin >gentamicin > tobramycin >amikacin.
15. >2
ug/mL
<10
ug/mL
<2
ug/mL
4 – 8
ug/mL
GENTAMICIN LEVEL, SERUM/PLASMA
drawn 30-
60 minutes
after
infusion
trough
level
drawn just
before the
next dose
Particle Enhanced
Turbidimetric Inhibition
Immunoassay (Petinia)
16. GENDER DIFFERENCES IN AMINOGLYCOSIDE
INDUCED NEPHROTOXICITY: ,
94 pt.
45 GT 49 AK
33% 37% 6.7% 31%
17. AMINO-GLYCOSIDES USE IN PATIENTS
OVER 75 YEARS OLD AND CHILDREN
.amino glycoside dosing used in elderly patients probably
need therapeutic drug monitoring and dose adjustment. . To
minimise nephrotoxicity, short treatments are necessary and
avoiding others nephrotoxic drugs (Ex: cisplatin) could be
relevant.
Conversely paediatric studies have shown lower rates and
extended interval dosing may have reduced toxicity further.
18. PHARMACOKINETIC RELATED TO DOSE
ADMINISTRATION TIME
Pharmacokinetic parameters and the incidences of
nephrotoxicity were compared between the morning,
afternoon and evening groups. Results 310 general ward
and 411 intensive care unit patients were included. No
significant differences were found in patient characteristics
between the morning, afternoon and night groups. The time
period of administration did not affect aminoglycoside
pharmacokinetics or the incidence of nephrotoxicity.
19. AMUNO GLYCOSIDE WITH
RENAL IMPAIRMENT PT.
Extended
dose
interval >24
h seems to
be effective
But only 1% pt. Studied reported with irreversible nephrotoxicity
20. STRATEGIES TO PREVENT
NEPHROTOXICITY
Recent studies have indicated that newer agents, such as
third-generation cephalosporins and aztreonam, often may
be as therapeutic and cost-effective as the amino glycosides
without the nephrotoxicity associated with the latter agents.
21. CONT…
efforts to reduce aminoglycoside toxicity have been
focused on decreasing cellular uptake. The most notable of
these to have clinically demonstrated success was the use
of consolidated dosing of amino glycosides. The uptake of
amino glycosides by renal tubular cells is a saturable
process. By giving the total daily amount of drug as a bolus
as is done with once daily (or consolidated) dosing
regimens, uptake is minimised and less toxicity occurs.
.
22. CONT…
Effects of saturable uptake on kidney cortical accumulation
in single daily versus three times daily dosing. In three
times daily dosing (shown in red), all of the area under the
curve (AUC; red shaded area) contributes to the uptake of
the aminoglycoside into the kidney cortex. However, above
a certain threshold (indicated by the arrow), the receptor-
mediated uptake of the aminoglycoside is saturated and
serum concentrations above this level do not contribute to
the uptake of aminoglycoside into the renal cortex
23. CONT…
.As this threshold is exceeded in single daily dosing
(shown in green), a proportion of the single daily dose
AUC does not contribute to renal uptake. Thus, the area
below this threshold contributes to renal uptake (the green
area in single daily dosing). As the green area is smaller
than the red area, the renal uptake in single daily dosing is
thought to be lower than with the three times daily dosing
regimen.As the green area is smaller than the red area, the
renal uptake in single daily dosing is thought to be lower
than with the three times daily dosing regimen.
