AMINOGLYCOSIDES.ppt

ANTIMICROBIAL AGENTS
THE AMINOGLYCOSIDES
Charles Odongo Okot
Dept. of Pharmacology and Therapeutics, FOM

THE AMINOGLYCOSIDES
 All contain amino sugars linked to an aminocyclitol
ring by glycosidic bonds
 They are polycations, this is responsible 4 their
shared pharmacokinetic properties (seen in
absorption, distribution, excretion)
 Used primarily to treat infections caused by aerobic
gram-negative bacteria
 Resistance has developed over the years by
mutations and plasmid acquisition

HISTORY AND SOURCE
 Their development was a result of a well- planned
scientific search for antibiotics- stimulated by the
discovery of penicillin
 Waksman and co-workers examined a number of soil
actinomycetes (1939-1943)
 Made the first public announcement of the discovery of a
new antibiotic streptomycin in 1944
 In 1949, they isolated neomycin from a soil organism
Streptomyces fradiae

CHEMISTRY
 They consist of two or more amino sugars joined by
glycosidic linkage to a hexose nucleus (this is the
aminocyclitol ring)
 This aminocyclitol is either streptidine (in streptomycin) or
deoxystreptamine(others)
 They are aminoglycosidic aminocyclitols although the
simpler term aminoglycosides is commonly used to
describe them
 Spectinomycin is an aminocyclitol which does not contain
amino sugars

PHARMACODYNAMICS
 They diffuse through aqueous channels formed by
porins in the outer membrane of G-ve bacteria (into
the periplasmic space)
 Subsequent transport across the inner
(cytoplasmic) membrane is dependent on electron
transport (a negative interior)
 This is the energy-dependent transport phase, it is
rate limiting & can be blocked by divalent cations,
hyperosmolarity, a low pH and anaerobic
environments

 The last two conditions impair ability of the bacteria to
maintain a membrane potential
 Thus, antimicrobial activity is reduced in the anaerobic
environment of an abscess, hyperosmolar acidic urine
etc
 Upon entry into the cell, aminoglycosides bind irreversibly
to 30s ribosomal subunits: blocking initiation of protein
synthesis, causing misreading and premature termination
of mRNA translation
 This leads to production of incomplete or fake proteins,
with loss of their function

 Aminoglycosides are rapidly bactericidal
 Bacterial killing is concentration dependent
 The higher the concentration, the greater the killing rate
and proportion killed
 Also has a post-antibiotic effect (residual bactericidal
activity persisting after the serum levels have fallen below
MIC)
 This effect is concentration dependent
 These properties account for the efficacy of once-daily
dosing of aminoglycosides
 Once daily dosing is now known to be effective and safer
than the older regimen

ANTIBACTERIAL SPECTRUM
 Activity of gentamicin, tobramycin, amikacin, and
netilmicin is primarily against aerobic gram-negative
bacilli
 Kanamycin and streptomycin have a more limited
spectrum and should not be used to treat Serratia or
P.aeruginosa infections
 Aminoglycosides have no activity against anaerobes (or
facultatives in anaerobiasis)
 Little activity on G +ve bacteria, resistance in Strep.
pneumoniae & Strep. pyogenes

 Aminoglycosides act synergistically with cell wall agents
(Penicillins/Vancomycin)
 In fact streptomycin or gentamicin in combination with a
penicillin are active on enterococci and streptococcus at
clinically achievable concentrations
 Gentamicin and tobramycin show similar activity on G-ve
bacilli although tobramycin tends to be more active
against Proteus and Pseudomonas

 Gentamicin and tobramycin are active on most
staphylococcal species in-vitro. They should however
never be used alone in clinical staphylococcal infections
as resistance develops rapidly
 Amikacin and netilmicin both synthetic derivatives have
broad-spectrum activity
 They show remarkable resistance to aminoglycoside
inactivating enzymes and are useful in treating
nosocomial infections caused by such resistant
organisms

PHARMACOKINETICS
1. Absorption: poorly absorbed across GIT (less than 1% of
administered dose), they are eliminated quantitatively in
the feces
 GIT diseases like ulcers and inflammatory bowel
diseases increase their absorption
 Absorption is possible on large wounds, skin burns or
serosal surfaces, long term topical use may intoxicate
renal patients
 They are absorbed rapidly from I.M sites of injection with
peaks in 30-90 minutes

2.Distribution: they are largely excluded from most cells,
from CNS, eye or lung tissue
 Not protein bound, apparent volume of distribution
approximates that of ECF
 Concentrations in secretions & tissues are low, high
conc. only found in renal cortex, perilymph and
endolymph of inner ear, this contributes to nephrotoxicity
& ototoxicity characteristic of this group of drugs
 Diffusion into pleural and synovial fluids is slow but
concentrations approximate those in plasma with
repeated administration

 Inflammation increases penetration into peritoneal and
pericardial cavities
 25% of plasma levels may reach CSF in meningitis, yet
this is sub-therapeutic
 Intrathecal administration achieves good levels in CSF
but rarely employed since better alternatives (cef/3) can
be used
 They can accumulate in fetal plasma and amniotic fluid,
may cause hearing loss in exposed neonates

3. Elimination: they are excreted almost entirely by
glomerular filtration with high concentrations achieved in
urine
 Most drug is excreted unchanged during the first 12
hours, almost all by 24 hours
 They have similar t1/2 varying btn 2-3 hrs
 Accumulation of drug is seen in anephric patients and
those with critical illness, in such cases, therapeutic drug
monitoring is recommended to ensure optimum activity
and avoid toxicity

 Trough (just before) & peak (30 min. after) plasma
levels are determined
 Accumulated drug may be removed by peritoneal or
hemodialysis
 Aminoglycosides can be inactivated by various
penicillins in-vitro and in patients with end-stage
renal failure

ADVERSE EFFECTS
 All aminoglycosides have potential to produce
reversible and irreversible vestibular, cochlear and
renal toxicity
 These toxicities are likely when plasma
concentrations are persistently high as they
accumulate in these tissues
 The half lives are 5-6 times longer in these tissues
than in plasma

 Ototoxicity is largely irreversible resulting from
progressive destruction of vestibular and cochlear
sensory cells
 Older patients are more prone to deafness since sensory
hair cells decrease with age
 Drugs like ethacrynic acid and furosemide potentiate the
ototoxic effects of AMGs
 Streptomycin, gentamicin affect vestibular function
preferentially while kanamycin, amikacin and neomycin
affect auditory.
 Tobramycin affects both equally
 Netilmicin is less toxic than other drugs

CLINICAL SYMPTOMS
 Cochlear toxicity: high pitch tinnitus often the first
symptom, auditory impairment follows if drug not
discontinued. High pitch sound is lost first so patient
may not be aware (outside conversational range)
 Vestibular toxicity: headache may precede onset of
labyrinthine dysfunction, this is followed by an acute
stage with nausea, vomiting and loss of balance.
Vertigo and difficulty in sitting and standing follow

NEPHROTOXICITY
 Up to 26% of patients who receive an aminoglycoside for
more than several days may develop mild renal
impairment that is almost always reversible
 Toxicity is a result of accumulation and retention of drug
in proximal tubular cells
 Continued use may lead to distal tubular cell damage and
reduced glomerular filtration, this increases plasma levels
leading to more toxicity

 Signs of renal damage include:
1. Rise in plasma creatinine
2. Hypokalemia
3. Hypocalcemia
4. Hypophosphatemia
5. Acute tubular necrosis (seen last, rarely)
 Impairment in renal function is always reversible since
renal tubular cells have the capacity to regenerate

 Several variables seem to influence nephrotoxicity and
these include:
1. A correlation with total amount of drug administered
2. A longer course of therapy
3. Continuous infusion appears more toxic than
intermittent dosing
4. Constant plasma levels of drug above critical levels
(this is manifest by elevated trough serum
concentrations)

TRADITIONAL THERAPY DESIGN
 Aminoglycosides have traditionally been given in divided
doses (2 or 3 times/day)
 This was aimed at maintaining plasma levels above MIC
during Tx the course
 This has now been found to increase the risk of toxicity
as “above critical” plasma levels are reached 2 or 3
times/day
 The risk is even greater when treatment is designed for a
longer duration, in excess of four days!

NEW INFORMATION
 Several clinical trials published in the ‘90s have shown
that once daily dosing is no less efficacious than multiple
dosing yet it is obviously less toxic as only one peak
concentration is reached per day (not 2/3)
 This new treatment design is safer and cheaper in long
term use
 Aminoglycosides show a concentration dependent rather
than time dependent killing effect seen in penicillins

 Neomycin is the most while streptomycin the least
nephrotoxic, this correlates directly with their abilities to
concentrate in the kidneys
 Drugs like amphotericin B, cyclosporine, vancomycin and
cisplatin may potentiate aminoglycoside induced
nephrotoxicity
 Furosemide enhances nephrotoxicity in animal studies if
concurrent fluid depletion is not corrected
 Advanced age, liver disease and septic shock have been
suggested as risk factors

 The most important fear of nephrotoxicity is reduced
excretion of drug which in turn will lead to ototoxicity
 Monitoring plasma drug levels during long term or high
dose therapy is there4 useful
 High dose therapy may not increase toxicity by itself, the
frequency and duration of such high dose do.
 Aminoglycosides alter mitochondrial and ribosomal
function, inhibit phospholipases, ATPases to various
extents, they seem to impair generation of membrane
derived autacoids and intracellular 2nd messengers

NEUROMUSCULAR BLOCKADE
 Acute neuromuscular blockade and apnea have been
attributed to aminoglycosides
 In this regard, neomycin is most potent while gentamicin
and tobramycin least
 This effect is potentiated by anaesthesia or the use of a
neuromuscular blocker
 Patients with Myasthenia gravis are particularly
susceptible to this effect
 AMGs inhibit prejunctional release of ACH while reducing
postsynaptic sensitivity too!

 Ca2+ overcome this effect and I.V calcium is used to
reverse or prevent this effect
 Cholinesterase inhibitors like edrophonium neostigmine
have also been used
 Peripheral neuritis, perioral parasthesias, optic nerve
dysfunction are associated with streptomycin
 AMGs have little allergenic potential and are not linked
with pseudomembranous colitis since they do not affect
anaerobes

AMINOGLYCOSIDES.ppt

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