Pharmacology PPT

1. Aminoglycosides
Dr. Chintan M Doshi

2. Introduction
• These drugs are used primarily to treat
infections caused by aerobic gram-negative
bacteria
• Aminoglycosides are bactericidal inhibitors of
protein synthesis

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. Contd.
• Difference in spelling (-micin) compared with
the other aminoglycoside antibiotics (-mycin)
reflects this difference in origin

5. Chemistry
• The term aminoglycoside stems from their
structure:
• Two aminosugars joined by aminocitol by
glycosidic bond:
Aminosugar-o- -o-Aminosugar
2-deoxystreptamine

6. Contd.
• In streptomycin aminocyclitol is streptidine:
• - -o- -o-
Streptobiosamine
Streptidine Streptose
aminosugar
N-methyl-L-Glucosamine
aminosugar

7. Contd.
• Spectinomycin is not aminoglycoside because
aminocyclitol is not connected to any
aminosugar

8. Properties
1) All are used as sulfate salts ,which are high
water soluble; solution are stable for months
2) They ionize in solution
-not absorb orally
-distribute only extracellularly
-don’t penetrate CSF or brain

9. 3) Excreted unchanged in urine
4) Bactericidal and more active at alkaline pH
5) Act by interfering with protein synthesis
6) Active against gram-ve aerobic bacilli and do
not inhibit anaerobes
7) There is only partial cross resistance among
them
8) Low margin of safety
9) Exhibit ototoxicity and nephrotoxicity

10. Mechanism of action
1. Transport of aminoglycoside through cell wall
and cytoplasmic membrane
2. Binding to ribosomes resulting in inhibition
of protein synthesis

11. Transport of drug
• Diffuse across the outer coat of bacteria
through porin channel
• Penetration is oxygen dependent active
process
• Inactivated under anaerobic condition
• Also favoured by high pH

12. Inhibition of protein synthesis
Bind to 30s, 50s ribosome as well as 30s-
50s interface
Freeze initiation, prevent polysome
formation and misreading of mRNA code
Inhibit protein synthesis

14. • Cidal action due to secondary change in cell
membrane
• Energy dependent phase II process
• After exposure sensitive bacteria become
more permeable
• Ions, amino acid and protein leak out
Cell death

15. • Cidal effect is concentration dependent:
• Rate of bacterial cell killing directly related to
ratio of peak antibiotic concentration to MIC
• Also exert post antibiotic effect

16. Mechanism of resistance
a. Aciquisition 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
Aciquisition of cell membrane bound inactivating
enzymes that adenylate/acetylate or phosphorylate
drug

17. b)
 Less common
 Specific for particular drug
 Seen in E.coli
Mutation decrease affinity of ribosomal proteins that
normally bound to aminoglycoside

18. Contd
• C)
• Less common
• Found in pseudomonas: 2nd phase active
transport defective
Decrease efficiency of aminoglycoside transport
mechanism

19. Phramakokinetics
Absorption
 Highly polar cations
 very poorly absorbed from the GI tract
 Absorption of gentamicin from the GI tract may
be increased by GI disease (e.g., ulcers or
inflammatory bowel disease)

20. Contd.
• All the aminoglycosides are absorbed rapidly
from intramuscular sites of injection

21. Distribution
 Because of their polar nature, the aminoglycosides
do not penetrate into most cells, the CNS, or the
eye
 Plasma protein binding: neglible
 Vd:25% of lean body weight –equal to ECF
 Concentrations of aminoglycosides in secretions
and tissues are low

22. Elimination
 Excreted almost entirely by glomerular filtration
 Large fraction of a parenterally administered
dose is excreted unchanged during first 24 hours
 t1/2: 2-4 hrs
 Aminoglycosides can be inactivated by various
penicillins in vitro and thus should not be
admixed in solution

23. Dosing regimens
CREATININE CLEARANCE
(mL/min)
% OF MAXIMUM DAILY
DOSE
FREQUENCY OF DOSING
100 100
75 75 Every 24 hours
50 50
25 25
20 80
10 60 Every 48 hours
<10 40

24. Contd.
• Gentamicin/tobramycin
/sisomycin/netilmycin
 Streptomycin/kanamycin/
amikacin
7.5-15mg/kg/day
3-5mg/kg/day

25. Contd.
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. Plasma concentration remain subthresold for
ototoxicity and nephrotoxicity

27. Single daily dose regimen is not used in:
a. Patient with abnormal renal function and
children
b. Gentamicin is combined with β-lactam for
bacterial endocarditis

28. Untoward Effects
Ototoxicity
 Ototoxicity results in 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
 Ototoxicity higher when plasma concentration of drug
is persistently high
 For gentamycin: 2μg/ml

29. Contd.
 Interfere with the active transport system
essential for the maintenance of the ionic
balance of the endolymph
 Ear drops also can ototoxicity when given in
patient with perforated eardrum

30. Cochlear toxicity
• Start from base to apex
Symptoms:
• Tinnitus –high pitched
• Progressive hearing loss
• Duration: On stopping of drug, tinnitus
disappears but frequency loss persist

31. Vestibular toxicity
• Headache
• Nausea, vomiting
• Dizziness
• Nystagmus
• Vertigo
• Ataxia

32. 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

33. 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

34. Contd.
• Advanced age, liver disease, diabetes mellitus,
and septic shock↑ toxicity
• Streptomycin and tobramycin are least
nephrotoxic

35. Neuromuscular blockade
• ↓ release of Ach from motor nerve endings
• Antagonizes Ca+2 and ↓ sensitivity of muscle
end plates to Ach
• Neomycin and streptomycin have higher
incidence
• Apnoea and fatalities when streptomycin was
put into peritoneal/ or plural cavity

36. Precautions and interactions
a. Avoid during pregnancy: risk of foetal
ototoxicity
b. Avoid concuurent use of nephrotoxic drug:
 NSAIDS
 Vancomycin
 Cisplatin
 Amphotericin B
 Cyclosporine

37. Contd.
c) Cautious use of other ototoxic drug:
 Vancomycin
 Minocycline
 Furosemide
d)Cautious use in renal damage and old age
e)Cautious use of muscle relaxant
f)Don’t mix aminoglycoside with any drug in same syringe

38. Classification
Systemic aminoglycosides

39. Contd.
Topical aminoglycosides
• Neomycin
• Framycetin

40. 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

41. Contd.
Uses
Preventing and treating respiratory infection
in:
 Critically ill patient
 Impaired host defence: AIDS, neutropenia,
Corticosteroids
 Patient on resuscitation wards
 Post operative pneumonia
 With implants
 ICU patients
 Combined with penicillin/cephalosporin

42. • Not used in community acquired pneumonia as it
is caused by gram positive cocci and anaerobes
Psuedomonas, proteus, or Klebsiella
 Burns
 UTI
 Osteomyelitis
 Middle ear infection
 Septicemia

43. Meningitis caused by gram negative bacilli
 Third genration cephalosporins with
aminoglycoside is used
Subacute bacterial endocarditis(SABE)
 Gentamicin 1 mg/kg 8 hrly i.m. with
penicillin/ampicilllin/vancomycin
Added to peritoneal dialysate to prevent or treat
peritonitis

44. Streptomycin
• Oldest aminoglycoside obtained from
sreptomyces griseus
Spectrum
 H.Ducreyi, Brucella, Yersinia, Nocardia,
Campylobacter granulomatis, Francisella
tularensis, M. Tuberculosis

45. 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 of choice for this rare
disease

46. Contd.
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

47. 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

48. Tobramycin
• Similar to gentamycin
• Used pseudomonas and proteus resistant to
gentamycin
• Ototoxicty and nephrotoxicity is less

49. Amikacin
• Semisynthetic derivative of kanamycin
• Resistance to bacterial aminoglycoside
inactivating enzymes.
• Has widest spectrum of activity

50. Contd.
 Use:
 Empirical treatment of hospital acquired gram
negative bacillary infection where gentamycin
resistant is very high
 Multidrug resistant T.B.
 More hearing loss than vestibular disturbance

51. 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

52. Neomycin
• Wide spectrum
Use
 Topically combine with polymixin and
bacitacin)
• Infected wound
• Ulcers
• Burns
• External ear infections
• Conjuctivitis

53. Contd
 Orally
a) Preparation for bowel surgery:3 doses of 1g along with
metronidazole 0.5 g on day before surgery reduce
postoperative infection
b) Hepatic coma:
• By suppressing intestinal flora it decrease NH3
production
• Because of toxicity lactulose is used

54. 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

55. Framycetin
• Similar to neomycin
• Used mainly topically

56. Paromomycin
• Chemically related to neomycin
Additional activity against:
• E.histolytica
• Giardia lamblia
• Trichomonas vaginalis
• Crytosporidum
• Leishmania

57. Contd.
Uses
 Hepatic coma
 Intestinal amoebiasis
 Giardiasis
 Kala azar
 Crytosporidosis
 Trichomonas infection

58. Contd.
• Dose: 500 mg TDS for 7days
Side effects
 Nausea,vomiting
 Abdominal cramps
 Diarrhoea
 Rarely rashes

59. Spectinomycin
• Obtained from streptomyces
• Not true aminoglycoside chemically
• Single dose 40 mg/kg i.m. used for
gonorrhoea alternative to penicillin
• Nephrotoxicity and ototoxicity very rare

60. Clinical summary
• The role of aminoglycosides in the treatment of
bacterial infections has diminished steadily as
alternative drugs have become available
• Compared with other antibacterials, aminoglycosides
are among the most toxic
• These agents are first-line therapy for only a limited
number of very specific, often historically prominent
infections:
 plague,
 tularemia
 tuberculosis.

61. Contd.
• Gentamicin or amikacin may have a role as a in
the treatment of nosocomial infections caused
by multidrug-resistant gram-negative
pathogens :
Pseudomonas or Acinetobacter
• Because more effective and less toxic
alternatives usually are available:

62. Contd.
• Aminoglycosides should be used sparingly and
reserved for specific indications
• Duration of therapy should be kept to a
minimum to avoid toxicity, and serum
concentrations should be monitored