AMINOGLYCOSIDES

Dr. Sukanta Sen

 Bacteriocidal antibiotic.
 Name end up with a suffix “mycin” are
obtained from genus streptomyces
Streptomycin streptomyces

 Others whose name end up with suffix

“micin” are obtained from micromonospora.
Gentamicin micromonospora
Chemistry:
 Glycosides derived from microorganisms
Structure:
Two aminosugars joined to a aminocyclitol
(a nonsugar) by a glycosidic (-o-) bond.
 In majority of aminoglycosides ,the aminocyclitol
moiety is 2-deoxystreptamine which is centrally
placed in between two aminosugars.

(AMINOSUGAR)- O-(2-deoxystreptadine)-O-(AMINOSUGAR)
 Basic Characteristics
 These are highly polar basic drugs (hydrophilic)
 Less than 1% of a dose is absorbed after either oral or rectal
administration
 Administered either by I.M or I.V
 Because of their polar nature, they do not penetrate into most
cells, the CNS, or the eye. None provides adequate
concentration in CSF
 All are excreted through kidney, entirely by glomerular
filtration

 All are active at alkaline pH than acidic. Hence use of urinary

alkaliser increases their effectiveness in the t/t of UTIs.
 Half-lives 2-3 h in patients with normal renal function.

 Because the elimination of aminoglycosides depends almost

entirely on the kidney, a linear relationship exists between the
concentration of creatinine in plasma and the t1/2 of all
aminoglycosides in patients with moderately compromised renal
function.

 Because the incidence of nephrotoxicity and ototoxicity is likely

related to the overall drug exposure to aminoglycosides, it is
critical to reduce the maintenance dosage of these drugs in
patients with impaired renal function
 Drugs:
 Streptomycin,

 gentamicin,

 sisomicin,

 netilmicin,

 Kanamycin,

 tobramycin,

 amikacin,

 neomycin,

 paromomycin ,

 soframycin & spectinomycin

 Spectinomycin is not a true aminoglycosides because
aminocyclitol is not connected to any aminosugar.
MOA: penetrate through bacterial cell wall through porin
channels

periplasmic space

Further transport across cytoplasmic membrane by energy &

O2 dependent active transport

Then drugs bind to 30S ribosomal units of bacteria

Prevent the formation of “initiation complex’ (which is
prerequisite for peptide synthesis)

Misreading of m-RNA

Incorrect aminoacids are thus incorporated into the growing

peptide chain

Miscoded peptide chain elongation

Inhibit bacterial protein synthesis

Q. That is why ,β-lactam antibiotics which weaken or inhibit
the bacterial cell wall synthesis,facilitate the passive diffusion
of aminoglycosides if given together (synergistic action).

Q. O2 dependent transport can not take place under anerobic

conditions, aminoglycosides are inactive against anaerobic
bacteria.
 Post-antibotic effect:
 Aminoglycosides continue to suppress the bacterial growth even
when their serum concentration falls below their MIC (minimum
inhibitory conc.).

 Reason is due to disruption in 30S ribosomal function

 Resumption of bacterial ribosomal functions requires time for

the synthesis of new ribosomes.

 The post-antibiotic effect last for several hours that’s why these
drugs can be given in a single daily dose despite their short half
life.
 Antibacterial resistance:
 Three principal mechanism:
(1) synthesis of plasmid mediated bacterial transferases
enzymes that can inactivate aminoglycosides.these
enzymes are
 acetyltransferase acetylation
 Phosphotransferase phosphorylation
 Adenyltransferase adenylation
(2) Mutation of porin channels or masking O2 +energy
dependent transport system
(3) Alteration of receptor protein on 30S ribosomal unit
because of mutations.
 Pharmacokinetics
 ●highly polar, polycationic drugs which are less
membrane permeable---so poor oral BA.
● Excretion through kidneys,is directly proportional
to creatinine clearance of the patient.
● dose adjustment to be done in renal failure.
Dose for a case of renal failure
normal therapeutic dose
=
serum creatinine value (mg/dl)
 Antibacterial spectrum:
 Gram-ve aerobic bacilli (E.colli, Klebsiella,
shigella,Proteus).
 Only a few gram+ve cocci.
 Not effective against gram+ve bacilli, gram-ve
cocci and anaerobes.

STREPTOMYCIN:
Used in t/t of plague,tularemia, brucellosis,sub acute
endocardiatis,as first line reserve drug in t/t of
TB.
Dose- 1gm/day,I.M.
Gentamicin:
 Most commonly used aminoglycosides.
 Act synergistically with ampicillin, benzathine penicillin,
ticarcillin, cetriaxone & vancomycin.
 Uses- for pelvic infections- with metronidazole,
 For SABE –with benzathine penicillin.
 For enterococcal endocardiatis –with vancomycin.
Sisomicin:
Chemically & pharmacologically same as gentamicin.
Netilmicin:
Semisynthetic derivative of sisomicin.
Relative resistant to inactivating enzymes
Tobramycin:
 Usefulness in gentamicin resistant cases.
Kanamycin:
 Higher ototoxicity & nephrotoxicity than others.
 2nd line drug for resistant TB.
Amicacin:
Semisynthetic derivative of kanamycin.
2nd most commonly used aminoglycoside.
Effective in MDR-TB.
Neomycin & Framycetin:

 Are too toxic for parenteral use.

 Used as urinary bladder irrigant a/w the use of indwelling

catheter-neomycin plus polymyxin-B.

 Orally as preoperative intestinal antiseptic before surgery

with Erythromycin.

 Neomycin is useful in hepatic coma, as it suppresses

ammonia producing colliform bacteria. Blood ammonia
levels therefore get decreased & encephalopathy is thus
prevented.
Paromomycin:

Used to t/t intestinal ameobiasis, cryptosporiodiosis

(chronic watery diarrheoa with abdominal cramps) in
immunocompromised patients.

Spectinomycin:

•Alternative t/t in gonorrhoea in pts who are allergic to

penicillin.

• nephrotoxicity & ototoxicity are VERY RARE.

  ADVERSE EFFECTS:
Nephrotoxicity:

 Caused by an inhibition of an intracellular lysosomal

phospholipase-A2 in the renal brush border.

 This leads to lysomal distention, rupture, and release of acid

hydrolases & free aminoglycosides into the cytosol.

 This free drug binds to other cellulae organelles, e.g., in

mitochondria it displaces Ca+ leading to mitochondrial
degeneration & necrosis.
 The necrotic cellular debris then sloughs off & is passed in
the urine.

 Concurrent use of Loop diuretics (furosemide &

ethacrynic acid) or other nephrotoxic agents such as
vancomycin, amphotericin-B, polymyxin-B,
vancomycin, angiotensin-converting enzyme inhibitors,
cisplatin & cyclosporine potentiate the nephrotoxicity.
OTOTOXICITY:
 Dose-limiting adverse effect
 Irreversible, bilateral high-frequency hearing loss and
temporary vestibular hypofunction
 Degeneration of hair cells and neurons in the cochlea correlates
with the loss of hearing.
 Impairment of 8th cranial nerve function.
 Accumulate in endolymph & perilymph of the innear ear
leading to vestibular & cochlear damage.
 A high-pitched tinnitus often is the first symptom of toxicity.
 If the drug is not discontinued, auditory impairment may
develop after a few days. The tinnitus may persist for several
days to 2 weeks after therapy is stopped.
Vestibular toxicity is more with streptomycin & while cochlear
damage is more with neomycin, kanamycin & amikacin.

Q. The aminoglycosides induced ototoxicity is worsened by co-

administration of vancomycin, furosemide, ethacrynic acid.

NEUROMUSCULAR BLOCKADE:

They can cause neuromuscular junction blockade, by blocking

postsynaptic NM receptor & by inhibiting Ca+ mediated
release of Acetylcholine from cholinergic neurons.
  NEUROMUSCULAR BLOCKADE

Q. Acute neuromuscular blockade and apnea have been attributed

to the aminoglycosides; patients with myasthenia gravis are
particularly susceptible.

 Neuromuscular blockade generally has occurred after

intrapleural or intraperitoneal instillation of large doses of an
aminoglycoside; however, the reaction can follow intravenous,
intramuscular, and even oral administration of these agents.

 Neuromuscular blockade may be reversed by intravenous

administration of a Ca+ salt.
OTHER UNTOWARD EFFECTS:

 Rare hypersensitivity reactions—including

 skin rashes,

 eosinophilia,

 fever,

 blood dyscrasias,

 angioedema,

 exfoliative dermatitis,

 stomatitis, and a

 naphylactic shock
 Therapeutic Uses
1. Urinary Tract Infections - not indicated for the treatment of
uncomplicated

2. Pneumonia- ineffective for the treatment of pneumonia due to

anaerobes or S. pneumoniae

 An amino-glycoside in combination with a β-lactam antibiotic is

recommended as standard therapy for hospital-acquired
pneumonia in which a multiple drug- resistant gram-negative
aerobe is a likely causative agent.

3. Meningitis
4. Peritonitis Associated with Peritoneal Dialysis

5. Bacterial Endocarditis

6. Sepsis

7. Topical Applications

8. Streptomycin treatment of tuberculosis, and

9. Paromomycin is used orally for intestinal amebiasis and in

the management of hepatic coma.
All of the following factor the risk of
Aminoglycosides renal toxicity, except
(AIPGME 02)
1. Elderly person
2. Hypokalemia
3. Simultaneous use of penicillin
4. Aminoglycosides administration in recent past
 A patient has Hepatic Encephalopathy.The
drug used for gut sterilizationin this patient
is (AIPGME 2000)
1) Neomycin
2) Netilmicin
3) Bleomycin
4) None of the above
Gentamicin, the aminoglycoside antibiotic produces
nerve deafness by causing (J&K05)
1) Demyelination of 8th cranial nerve fibres

2) Thickening of ear drum

3) Destruction of auditory ossicles

4) Obstruction of mechano sensitive channels in the

stereocillia of hair cells