a presentation on aminoglycosides

1. PRESENTED BY
SREYA. S
M. Pharmacy
DEPT OF PHARMACOLOGY

2. Introduction
Aminoglycosides are a group of bactericidal antibiotics,
Used to treat aerobic Gram –ve bacteria
 Aminoglycosides are called bactericidal antibiotics
because they kill bacteria directly. They accomplish this
by stopping bacteria from producing proteins needed for
their survival.
 Because aminoglycosides are normally used to treat
serious infections, they are typically administered into the
veins of the body (intravenously, or IV).
 However, some aminoglycosides can be taken orally, or as
ear or eye drops

3. History and Source
 Natural products or semisynthetic derivatives of
compounds produced by a variety of soil actinomycetes
 Streptomycin was first discovered in 1944 by waksman
 Isolated from a strain of Streptomyces griseus
 Gentamicin and netilmicin are derived from species of
the actinomycete Micromonospora

4. Systemic aminoglycosides Topical aminoglycosides
Streptomycin Neomycin
Gentamicin Framycetin
Kanamycin
Tobramycin
Amikacin
Sisomicin
Netilmicin
Paromomycin
CLASSIFICATION

5. Mechanism of Action
Aminoglycosides bind to 30s ribosomal units of
bacteria.An oxygen-dependent transport system is
necessary for aminoglycosides to reach their target site;
Pevents the formation of intiation complex,which is the
prerequisite for peptide synthesis
Lack of the formation of intiation complex causes the 30s
sub unit to MISREAD THE GENITIC CODE on mRNA
Incorrect aminoacids are thus incorporated into the
growing peptide chain,which are of no use for bacterial
growth
 LEADS TO BACTERIAL DEATH

6.  .

7. Aminoglycosides also act by Formed improper intiation
complex blocks the movement of ribosomes
Resulting in a mRNA chain attached with single
ribosomes (monosomes)
Thus amino glycoside also interfer in the assemble of poly
somes
Results in the accumulation of non functional ribosomes

8. PHARMACOKINETICS
 ABSORPTION:Aminoglycosides are highly polar , so
they have very poor oral bioavailability.
Therefore they are given parenterally or applied locally.
 DISTRIBUTION: These are poorly distributed and
poorly protein bound when given parenterally they failed
to reach intraoccular fluid or CSF.
 METABOLISM:As they do not penetrate more celluar
compartments they do not under go any significant
metabolism

9. EXCRETION:
Mainly by kidney through glomerular filtration.
Resulting in fairly high urinary concentration.
so they can be used in the treatment of URINARY
TRACT INFECTIONS .
 Their excetion is directly proportional to creatinine
clearence .
 Though normal half life varies from 1.5-3 hrs,it may
increased to 24-48 hrs in patients with renal insufficiency

10. Dosing regimens
 Gentamicin/tobramycin
sisomycin/netilmycin
 Streptomycin/kanamycin
amikacin
Single total daily dose regimen for patients with normal
renal function because of:
a. Aminoglycosides have concentration dependent killing
and a long post antibiotic effect
b. b. Plasma concentration remain subthresold for
ototoxicity and nephrotoxicity
3-5mg/kg/day
7.5-15mg/kg/day

11.  Single daily dose regimen is not used in:
 Patient with abnormal renal function and children
 Gentamicin is combined with β-lactam for bacterial
endocarditis
 Aminoglycosides exhibit CONCENTRATION
DEPENDENT KILLING i;e their increased
concentration kills an increased proportion of bacteria at
rapid rate
DOSE
OF RENALIN- =
SUFFICIENCY
NORMAL THERAPEUTIC
SERUM CREATININE VALUE
(mg/dl)

12. Post antibiotic effect
 Aminoglycosides exhibit concentration dependent killing.
They also possess significant Post-antibiotic effect.
Postantibiotic effect (PAE) is the term used to describe
suppression of bacterial growth that persists after brief
exposure of organisms to antimicrobials. PAE have
clinical impact on antimicrobial dosing regimens.
 Single daily dosing at least as effective as and no more
toxic than multiple dosing

13. Mechanism of resistance
Aquisition of cell membrane bound inactivating enzymes
that adenylate/acetylate or phosphorylate drug
Mainly by conjugation and transfer of plasmids
Nosocomial microbes have become rich in such
plasmids, some of which encode for multidrug resistance
Decreased efficiency of transporting mechanismof the
aminoglycosides into bacterial cytosol
Less common • Found in pseudomonas: 2nd phase
active transport defective
Deletion/alteration of receptor protein on 30 S ribosomal
unit by mutation: prevents attachment
Less common , Specific for particular drug , Seen in E.coli

14. Antibacterial spectrum
 Primarily against Gm –ve aerobic bacilli
– Proteus, pseudomonas – E.Coli,enterobacter –
Klebsiella – Shigella
 Only few Gm +ve cocci: – staph aureus, strepto viridans
 Not effective against Gm +ve bacilli, Gm-ve cocci and
anaerobes

16. Shared toxicities
 Ototoxicity
– Vestibular damage
– Cochlear damage
 Nephrotoxicity
 Neuromuscular blockade

17. Ototoxicity
 Ototoxicity results in irreversible, bilateral
highfrequency hearing loss and temporary
vestibular hypofunction Impairment of VIII
cranial nerve function , May be irreversible
Cochlear damage
Hearing loss and tinnitus – More with
neomycin , amikacin and kanamycin
Vestibular damage
Vertigo, ataxia, loss of balance
More with Streptomycin, gentamycin
• Tobramycin has both types of toxicity
• Netilimycin claimed to have low ototoxicity

18. Nephrotoxicity
 Tubular damage causes: Low g.f.r , Nitrogen retention Albuminuria ,
Casts
 High concentration is found in renal cortex and toxicity related to
total amount of drug received
Mechanism
Inhibit various phospholipases, sphingomyelinases, and ATPases, and
they alter the function of mitochondria and ribosomes
↓ PG synthesis and ↓ g.f.r
Incidence: 8-26%
Factor affecting nephrotoxicity
Total amount of drug administered
Duration of drug received
Advanced age, liver disease, diabetes mellitus, and septic shock↑
toxicity
Streptomycin and tobramycin are least nephrotoxic

20. Neuromuscular blockade
 Cause N-M junction blockade by
– Displacing Ca2+ from NM
junction
– By blocking post synaptic NM
receptors
– Inhibiting Ach release from
motor nerve
 Neomycin & streptomycin:
more propensity
 Tobramycin least likely to
produce it
 Myasthenic weakness increases
by these drugs

21. Contraindications
 Pregnancy: foetal ototoxicity
 With other ototoxic drugs: furosemide, minocycline
 With nephrotoxic drugs: vancomycin ,cisplatin
 Elderly patients
 Those with kidney disease
 Cautious use of muscle relaxants
 Do not mix with any other drug in same syringe

22. Gentamicin
 Cheapest and first line antibiotic
 3rd systemically antibiotic obtained from
micromonospora purpurea in 1964
Spectrum
Gram-ve bacilli like: E.coli, Klebsillea, Enterobacter,
H.Influenzae, proteus, serrratia, and pseudomonas
Many strain of brucella, campylobacter citrobacter,
Fransisella and yersinia are sensitive
Uses

23. USE
 Use restricted to serious Gm-ve bacillary infections
 Septicaemia, sepsis, fever in immunocompromised
patients – Used with penicillins
 Pelvic infections : with metronidazole
 SABE: with Penicillin G or ampicillin or vancomycin
 Coliform infection: with ampicillin or ceftriaxone
 Pseudomonal infections: with ticarcillin
 Meningitis by Gm-ve bacilli : III generation
cephalosporin alone or with gentamicin

24. Streptomycin
 Oldest aminoglycoside obtained from sreptomyces griseus
Spectrum
 H.Ducreyi, Brucella, Yersinia, Nocardia, Campylobacter
granulomatis, Francisella tularensis, M. Tuberculosis
Uses
Tuberculosis :Tuberculocidal
Acts only on extracellular bacilli
Use: in 2nd category T.B. for first two months
Dose:15 mg/kg i.m. thrice a week for 2 month
Subacute bacterial endocarditis
Plague: rapid cure within 7-12 days but tetracycline is drug of
choice
Tularemia: Streptomycin is drug

25. Streptomycin dependence:
 Certain mutant grown in presence of streptomycin
dependent on it
 Seen in tuberculosis
Toxicity
 Lowest nephrotoxicity
 Hypersensitivity reaction are rare: rashes, eosinophillia,
exfoliative dermatitis, and fever are reported
 Anaphylaxis is very rare

26. Kanamycin
 Obtained frorn S. kanamyceticus :in 1957
 Similar to streptomycin in all aspects
 Toxicity and narrow spectrum not used now
 Occasionally used in 2nd line drug in tuberculosis
Tobramycin
 Similar to gentamycin
 Used pseudomonas and proteus resistant to gentamycin
 Ototoxicty and nephrotoxicity is less
Sisomicin
 Identical to gentamicin
 More potent on pseudomonas and -hemolytic streptococci
 Used interchangeably with gentamicin

27. Amikacin
 Less toxic semisynthetic derivative of kanamycin
 Resistant to enzymes that inactivate gentamicin and
tobramcyin
 Widest spectrum of activity
Uses:
– Same as gentamicin
– Reserve drug for hospital acquired Gm-ve bacillary
infections
– Multidrug resistant TB along with other drugs Dose :
15mg/kg/day in 1-3 doses

28. Netilmicin
 Semisynthetic derivative of gentamycin
 Broader spectrum
 Relatively resistant to aminoglycoside inactivating
enzymes
 More active against klebsilla, Enterobacter and
styphylococcus
 Less active against pseudomonas
 Less ototoxic

29. Neomycin
 Wide spectrum
Use
Topically combine with polymixin and bacitacin) ,Infected
wound ,Ulcers , Burns , External ear infections
,Conjuctivitis
Orally
Preparation for bowel surgery:3 doses of 1g along with
metronidazole 0.5 g on day before surgery reduce
postoperative infection
Hepatic coma: By suppressing intestinal flora it decrease
NH3 production
Because of toxicity lactulose is used

30. Side effects
 Malabsorption syndrome with diarrhoea and
 stetorrhoea
 Hypersensitivity reactions, primarily skin rashes,
 occur in 6-8% of patients –with topical therapy
 Superinfection with candida
 Nephrotoxicity and ototoxicity
 Neuromuscular blockade with respiratory paralysis
Framycetin
Very similar to neomycin
Too toxic for systemic administration
Used topically on skin, eye ear

31. REFERENCES
• Tripathi K.D. Essentials Of Medical Pharmacology. 7th
ed. Jaypee Brothers Medical Publishers; 2014:[182-191]
• Rang H.P ,Dale M.M, Ritter J.M, Flower
R.J.Pharmacology. 6th ed.Elsevire: Churchill
livingstone;2008:[226-237
• http://www.medindia.net/articles/aminoglucosides.htm
• http://en.wikipedia.org/wiki/aminoglycosides

32. THANK YOU