Pharmacology of Aminoglucoside

pharmacology of Aminoglucoside

1. Aminoglycosides Presented By Dr. Manoj Kumar Assistant Professor Department of Pharmacology Adesh Medical College & Hospital Ambala Can’t

2. Amino glycosides A group of bactericidal antibiotics Used to treat aerobic Gram – ve bacteria Hexose ring attached to amino sugars by glycosidic linkages Natural or semi synthetic derivatives compounds produced by the soil actinomycetes Streptomycin was first discovered in 1944 2

3. Properties Highly water-soluble, polar compounds. Not absorbed orally they are given Parenteral. Remain extracellular & poor penetration in CSF . Excreted unchanged by the kidneys. More active in alkaline pH. All are bactericidal. Inhibiting bacterial protein synthesis. Mainly effective against gram – ve organisms. They are ototoxicity and nephrotoxicity 3

4. Classification Systemic Topical Streptomycin Kanamycin Tobramycin Amikacin Gentamicin Sisomicin Netilmicin Neomycin Framycetin 4

5. Mechanism of action 5

6. 6

7. Resistance Alteration of 30S ribosomal unit Inactivation by enzymes Acetyltransferase , phosphotransferase , adenylyltransferase Decreased transport into bacterial cell Mutation of porin channels 7

8. Pharmacokinetics Highly polar basic drugs Water soluble Not absorbed from GIT Given IM, IV infusion, topical route Poor CNS penetration, eye Intrathecal or intraventricular injection More active in alkaline pH Injection not mixed with any other drug 8

9. Absorption & transport Passive diffusion via porin channels across cell wall Enhanced transport: by cell wall-active drugs such as penicillin or vancomycin Active transport across cell membrane into cytoplasm by an O 2 -dependent process Inhibition of transport: by low extracellular pH, anaerobic conditions by reducing gradient 9

10. Pharmacokinetics Excretion through kidneys Directly proportional to creatinine clearance Corrected dose = Normal dose x pt CrCl CrCl 10

11. Anti-bacterial spectrum Active against aerobic gram - ve organisms E.coli , Shigella , Proteus, Pseudomonas, Klebsiella Few gram + ve : S.aureus , S.viridans , S.fecalis Not effective against anaerobes, salmonella 11

12. Aminoglycosides Synergistic action with βlactam antibiotics Weaken or inhibit bacterial cell wall synthesis AGs can penetrate through porin channels by diffusion Combination used in serious infections with gram-negative bacteria Supra-additive killing 12

13. Aminoglycosides Concentration dependent killing Post antibiotic effect Lasts for several hours Given as a single daily dose (even as short t 1/2 : 2-3 hrs ) Advantages : less labour intensive, more feasible Exceptions : renal insufficiency, when given for synergism with β- lactams for enterococcal endocarditis 13

14. . 14

15. Therapeutic uses Gram negative bacillary infection Septicemia, pelvic, abdominal sepsis Bacterial endocarditis Enterococcal , streptococcal, staphylococcal infection of heart valves Tuberculosis Pneumonia Plague, Brucellosis Tularemia 15

16. Therapeutic uses Topical : Neomycin, Framycetin Infections of conjunctiva, external ear To sterilize bowel of patients who receive immunosuppressive therapy, before surgery Hepatic coma 16

17. Adverse effects Narrow margin of safety Nephrotoxicity Ototoxicity Neuromuscular blockade Hypersensitivity reactions Skin rash, fever, anaphylactic shock 17

18. Adverse effects More likely to be encountered when Continued for >5 days Given at higher doses In elderly In renal insufficiency Other nephrotoxic drugs 18

19. Nephrotoxicity S. creatinine levels >1.5mg/dl Responsible for 10-15% of all renal failure cases Reversible Tubular damage Low GFR, albuminuria 19

20. Nephrotoxicity Inhibition of intracellular lysosomal phospholipase A 2 in renal brush border Lysosomal distension, rupture, release of acid hydrolases, free AGs in cytosol Free AGs bind to organelles: displaces Ca 2+ in mitochondria  mitochondrial necrosis 20

21. Nephrotoxicity Agents which decrease nephrotoxicity of AGs Verapamil Ca +2 Polyaspartic acid Disadv : decrease antibacterial activity 21

22. Ototoxicity Irreversible Impairment of 8 th cranial nerve function Accumulate in endolymph , periplymph  Vestibular & Cochlear damage   22 Vertigo, ataxia, loss of balance Hearing loss, tinnitus Streptomycin, Gentamicin Neomycin , Kanamycin, Amikacin Netilimicin is LEAST OTOTOXIC Aminoglycoside

23. Precautions Avoided in pregnancy Risk of fetal ototoxicity CI Patients with perforated ear drum Ototoxicity Caution Elderly Renal impairment Other ototoxic, nephrotoxic drugs 23

24. Neuromuscular blockade At very high doses Displace Ca +2 from NMJ Block post-synaptic N M receptors Inhibit release of ACh from motor nerve Clinical aspect Aggravate weakness in patients of m.gravis Potentiate the action of SMRs More with Streptomycin, Neomycin Reversed by IV Calcium gluconate , IM Neostigmine 24

25. . 25

26. Streptomycin From S.griseus Sensitive to Nocardia , M.tb , Yersinia , Rapid IM absorption Uses TB (2 nd line): 0.5-1 g IM/IV OD * 1-2 moths SABE: + Penicillin * 2 weeks Plague, tularemia, brucellosis (+ tetracycline) Current status: Gentamicin preferred Development of resistance 26

27. GentamIcin Most commonly used More potent, cheap Broader spectrum Effective against Pseudomonas, E.coli , Klebsiella Ineffective against M.tb , S.pyogenes More ototoxic Dosage: 3-5 mg/kg/d, IM/IV Uses : respiratory infections in ICU, UTI, burns 27

28. Amikacin A semi synthetic derivative of kanamycin Widest AMA spectrum 15 mg/Kg/d IM/IV Uses TB: MDR-TB, Atypical mycobacteria 28

29. Neomycin Highly ototoxic : Not given systemically Topical use (Ointments, creams, powder) Uses : hepatic coma, bowel preparation for elective surgery 29

30. Tobramycin Used in pseudomonal infections Can also be given through Inhalational Route Used in P. aeruginosa lower respiratory tract infections complicating cystic fibrosis patients 30

31. Spectinomycin Structurally related to AGs Active against many gram-positive & gram-negative organisms Used as an alternative treatment for drug-resistant gonorrhea or gonorrhea in penicillin-allergic patients 31

32. Spectinomycin Rapidly absorbed after IM injection Adverse effects Pain at injection site Fever Nausea Nephrotoxicity Anemia rare 32

33. Used Often combined with β -lactam antibiotics Used in severe, complicated infections Serious gram negative infections especially to Pseudomonas, Enterobacter , Klebsiella , Serratia UTIs Bacteremia Meningitis Infected burns Pneumonia Osteomyelitis Ear infections Single large dose more effective & less toxic than multiple small doses 33