MC - III, Unit - 1, Part 7 - Aminoglycosides.pdf

MC - III, Unit - 1, Part 7 - Aminoglycosides.pdf

• 1.
  MEDICINAL CHEMISTRY-III (BP-601T)- B Pharmacy - VI Sem ARUNAI COLLEGE OF PHARMACY - Tiruvannamalai Unit 1 - ANTIBIOTIC Part 7 – AMINOGLYCOSIDE’S Approved by PHARMACY COUNCIL OF INDIA – New delhi Affiliated to THE TAMILNADU DR MGR MEDICAL UNIVERSITY - Chennai Prepared & Lecture by Mr. Murugan (Associate professor)
• 2.
  β β β β - - - - Syllabus: Historical background,Nomenclature, Stereochemistry, Structure activity relationship, Chemical degradation, classification and important products of the following classes. Aminoglycosides(AGL): Streptomycin (STN), Neomycin, Kanamycin Pervious The Tamilnadu Dr MGR Medical university exam question Sep 2021 Write a note on Aminoglycosides (5 mark) May 2022 Write the mechanism of action and SAR of aminoglycosides (5 mark) Dec 2023 Write the structure and uses of Streptomycin and Kanamycin (5 mark)
• 3.
  Definition: Aminoglycosides antibiotics arethe group of bactericidal and broad-spectrum antibiotics derived from species of streptomyces or micromonosporum bacteria and modified semi-synthetically. structurally contain amino sugar connected with glycoside linkage is called as amino cyclitol moiety. which are effective against aerobic gram -ve and gram +ve bacteria by inhibit the protein synthesis. Example: Streptomycin, Neomycin, Kanamycin Uses: used for the treatment of bacterial infection in GIT, RT, UT, Ear, Eye and skin etc. ADR: produce undesirable toxic effects like Ototoxicity, Nephrotoxicity and Neuromuscular blockade etc Nomenclature:  The aminoglycosides which are derived from streptomyces genus are named with the suffix ‘mycin’  While those derived from micromonospora are named with the suffix ‘micin’  How ever this nomenclature system is not specific for aminoglycosides
• 5.
  Aminoglycoside antibiotics arealso referred as aminocyclitol antibiotics, because structurally it contains of two or more amino sugars joined in glycoside linkage to an aminocyclitol (non-sugar moiety - highly substituted hydroxyl groups in 1,3- diamino cyclohexane), which is a centrally placed ring. The ring is a 2-deoxystreptamine (1,3-diamino inositol) in all aminoglycosides except streptomycin and dihydrostreptomycin, where it is streptidine (1,3-diguanidino inositol) All aminoglycosides in this class possess one amino hexose sugar. but some antibiotics like Streptomycin, neomycin, possess a pentose sugar. Kanamycin and gentamycin families, two amino sugars are attached to 2-deoxy streptamine. Streptomycin, two amino sugars are attached to strepidine. Neomycin family, three amino sugars attached to 2-deoxy streptamine
• 7.
   Aminoglycosides arepolycations, highly polar in nature and soluble in water. basic in nature and form salts with acids (generally forms sulphate salt)  All aminoglycoside antibiotics are absorbed very poorly after oral administration,  Most aminoglycosides are quickly broken in the stomach, can't be given orally.  Few aminoglycoside (kanamycin, neomycin) are administered by oral route to treatment of GI infections.  well absorbed when given parentally.  Aminoglycosides can cross the placental barrier. unable to cross blood brain barrier  Aminoglycosides - potent broad spectrum antimicrobial agent, used for the treatment of systemic infections. Aminoglycosides undesirable side effects, particularly ototoxicity and nephrotoxicity
• 8.
   Ring A:Guanidino groups streptidine ring are essential, Replacement of guanidino groups reduces the antibacterial activity.  Ring B: Reduction of aldehyde to alcohol results - dihyrostreptomycin activity is similar, but produce severe hair loss side effects.  Oxidation of CHO group to oxime, semicarbazone, phenylhydrazone Schiff base derivatives results in inactive analogues.  Oxidation of –CH3 group to methylene hydroxy gives an active analogous but has no advantage over STM.  Ring C: Modification of amino methyl group in the glucosamine by demethylation and replace by larger alkyl groups reduces activity.  N-methyl-L-glucosamine( –NHCH3 group) is very essential for the activity.
• 9.
  Ring I (A)is important for broad spectrum antibacterial activity. Amino functions at 6 and 2 are increase the activity than other groups. Kanamycin-B (6-NH2, 2-NH2) > kanamycin-A (6-NH2, 2- OH) > kanamycin-C (6-OH, 2-NH2). Methylation at either 6-carbon or 6-NH2 positions increase the enzyme resistance and same antibacterial activity. Removal of OH group 3 or 4 or both in the kanamycins does not reduce antibacterial potency. (e.g., 3,4- dideoxykanamycin B or dibekacin). Modification of Ring II (B) NH2 at 1 can be acylated ( amikacin) with retention of activity and increase resistance Substitution of OH group at 2 can increase the activity Modification of Ring III (C) change in functional groups are less sensitive
• 10.
  Aminoglycosides diffuse throughporin channels in outer membrane and transport across the cytoplasmic (inner) membrane reach into inside the bacterial cell, which binds to 30S ribosomes and interfere with protein synthesis by causing misreading and premature termination of mRNA translation, finally microbes dead.
• 11.
  Aminoglycosides are broad-spectrumantibiotics effective in:  Systemic Infections caused by aerobic G(-) bacillus (klebsiella, proteus, enterobacters).  Tuberculosis, Brucellusis, Tularaemia and yersinia infections.  Amoebic dysentery, shigellosis and salmonellosis.  Pneumonia and urinary infections caused by Pseudomona aeroginosa.  G(+) and G(-) aerobic cocci except staphylococci and anaerobic bacteria are less susceptible  Effective against Aerobic Gm -ve bacteria (Citrobacter, Enterobacter, E. coli, proteus, shigella, Pseudomonas, Enterococci and Staphylococcus aureus)  Streptomycin and kanamycin are active against mycobacterium tuberculosis also  while amikacin, gentamicin and tobramycin are active against S. faecalis and P. aeruginosa.  Aminoglycosides are mostly ineffective against G+ve bacilli, G-ve cocci and anaerobic bacteria, fungi, and viruses
• 12.
   The mostfrequent therapy for serious infections such as septicaemia, pelvic & abdominal sepsis  treatment of cystic fibrosis (CF), RTI, UTI and intra-abdominal infections  Infections of conjunctiva or external ear  To sterilize the bowel of patients who receive immunosuppressive therapy, before surgery & in hepatic coma  useful primarily in infections of aerobic gram –ve bacteria like Pseudomonas, actinobacter and Enterobacter  used in conjunction with beta-lactam antibiotics in streptococcal infections, particularly in enocarditis.  Streptomycin can also be used for the treatment of tularemia, plague and leprosy  Topical use of aminoglycosides: gentamicin drops to treat ophthalmic infections, neomycin and Framycetin in topical formulation with corticosteroids, tobramycin aerosolized to treat respiratory infections
• 13.
   All aminoglycosidesfrequent occurrence of nephrotoxicity and ototoxicity during treatment  Neuromuscular blockade  Other adverse effects - Hypersensitivity reactions, superinfection, CNS effects and GI disturbances.  Ototoxicity and nephrotoxicity are more likely to be encountered when therapy is continued for more than 5 days, at higher doses, in the elderly and renal insufficiency.  Simultaneous use with loop diuretics (eg, furosemide) or other nephrotoxic antimicrobial agents (vancomycin, amphotericin) can potentiate nephro-toxicity and should be avoided.  Ototoxicity - auditory damage - result hearing loss initially, vestibular damage - vertigo, loss of balance.  Nephrotoxicity - rising serum creatinine levels or reduced creatinine clearance.  neuromuscular blockade - very high doses - produce a curare-like effect that results in respiratory paralysis.  Hypersensitivity occurs infrequently.