Pharmacology of aminoglycosides

1. Aminoglycosides
& G-CSF
Shahd AlAli
5/13/2016 1

2. Aminoglycosides
• Neomycin
• Tobramycin
• Amikacin
• Gentamycin
• Streptomycin; treatment of TB
5/13/2016 2
NOTAGS

3. 5/13/2016 3

4. Mechanism of Action:
How they’re transported?
They cross the outer membrane and enter the periplasmic space through
aqueous channels formed porin proteins.These drugs are actively
transported through the cell membrane by an oxygen-dependent process
Mechanism of action?
They irreversibly bind to the 30S ribosomal subunit and inhibit the
protein synthesis by blocking the formation of initiation complex, inhibit
translocation step, misread mRNA
5/13/2016 4

5. Resistance
 Block the entry into the cell
 Receptor on 30S ribosome deleted from the bacteria
Production of transferase enzyme which
inactivate the aminoglycosdie
5/13/2016 5

6. Pharmakinetics
 Penetrate most of body fluids well except for CSF, they are highly
concentrated in the renal cortex and endolymph of the inner ear
which could account for their nephrotoxicity and ototoxicity
 They must be given IV or IM because they are not absorbed after oral
administration
 Not well GI absorption, polar
5/13/2016 6

7. Administration
Single dose is preferred
1. Concentration-dependent killing
2. Post-antibiotic effect (which can last
for several hours)
5/13/2016 7

8. Synergism
 With b-lactum or vancomycin
 Synergism is important in case of endocarditis
5/13/2016 8

9. Therapeutic Use
 Ecoli, Klebsiella, Pseudomonas aeruginosa & Enterobacter (PEEK)
 They don’t cover the anaerobes because oxidative metabolism is
required for the uptake of these drugs.
 Usually they are coadiministered with B-lactams to extend the
spectrum.
5/13/2016 9
Streptomycin is very
effective against
enterococcal carditis
in combination with
pencillins

10. Toxicity
 Ototoxicity
Auditory may occur with any aminoglycoside and may be irreversible it’s
more likely with amikacin, ototoxicity is proportional to the plasma level
the toxicity is increased by the use of loop diuretics. It is
contraindicated in pregnancy.
 Nephrotoxicity
Acute tubualr necrosis it is often reversible
 Neuromuscular blockage at high doses (curare-like
effect)
Resulting is respiratory paralysis
5/13/2016 10

11. Preganncy
 Catigoury D’ there is a + evidence of human
fetal risk based on advese reaction but
poteinal benfiits may warrant the usuage of
the drug
5/13/2016 11

12. Clinical use
 Multi-drug resisitant TB
 Aerobic gram – bacteria
 Always with b-lactum combiniation for
1. Synergism
2. Extend to gram +
3. Bacterocidical in endocarditis
5/13/2016 12

13. Granulocyte colony-stimulating factor
 Filgrastim (G-CSF) stimulate the production and function of
neutrophils it also mobilize hematopoietic stem cells (ie, increase
their concentration in peripheral blood)
 stimulates proliferation and differentiation of progenitors already
committed to the neutrophil lineage.
 It also activates the phagocytic activity of mature neutrophils and
prolongs their survival in the circulation.
5/13/2016 13

14. Clinical use
 Used to accelerate the recovery of neutrophils after
 cancer chemotherapy
 aplastic anemia
 congenital and cyclic neutropenia
 Autologous stem cell transplantation
 multiple myeloma
 Given IV/Subcutaneous
 It can cause bone pain
5/13/2016 14

15. Q’s
 Regarding the mechanism of action of aminoglycosides,
the drugs
a) Are bacteriostatic
b) Bind to 50S ribosome subunit
c) Cause misreading of the codon on the mRNA template
d) Stabilize polysomes
5/13/2016 15

16. Amphotericin B
 Is used for fungal systemic infections (flucytosin is also used)
It’s a polyene macrolide which is poorly absorbed (IV)
Mechanism of action: bind to the fungal ergosterol on the cell
membrane and forms pores or channels within the membrane leading to
electrolyte leak out which results in the cell death
5/13/2016 16

17. Clinical usage
 Candidia, cryptococcus, aspergillas
 For fungal meningitis it’s giver intrathecally
 Topical for occular and bladder infections
5/13/2016 17

18. Toxicity (Infusion reaction and
cumulative toxicity)
 Infusion reaction
Fever, chills, spasm, headache and vomiting
Usually test by 1 mg IV to know the severity
To ameloirate it
 Slow the infusion rate
 Decrease the daily dose
 Give antihistamin and steroids
5/13/2016 18

19. Cumulative toxicity
 Renal impairment (renal tubular acidosis, K and
Mg wasting)
 Liver function abnormality
 Anemia due to reduced erythropoitein
(hypochromatic normocytic anemia)
 Seziures after IT therapy
5/13/2016 19