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Tetracyclines, chloramphenicol and macrolides antibiotics

Tetracyclines, chloramphenicol and macrolides antibiotics

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Protein synthesis inhibitors Protein synthesis inhibitors Document Transcript

  • 8/6/2012 By- Jitendra Bhangale Assistant Professor & Head, Department of Pharmacology, Smt N. M. Padalia Pharmacy College, Ahmedabad 1 © 2010 Delmar, Cengage Learning By Jitendra BhangaleAsst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad2 © 2010 Smt N. M. Padalia 1
  • 8/6/2012 It was originally obtained from the soil actinomycetes. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad3 © 2010 Smt N. M. PadaliaOxytetracycline is a natural product elaborated by Streptomyces rimosus.Tetracycline is a semisynthetic derivative of chlortetracycline.Demeclocycline is the product of a mutant strain of Strep. aureofaciensMethacycline, doxycycline, and minocycline all are semisynthetic derivatives.The Tetracyclines are close congeners of polycyclic naphthacenecarboxamide.Many others like Chlortetracycline, Methacycline, Rolitetracycline, Lymecycline are no longer commercially available By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad4 © 2010 Smt N. M. Padalia 2
  • 8/6/2012 The peptidyl tRNA at the donor site donates the growing peptide chain to the aminoacyl tRNA at the acceptor site in a reaction catalyzed by peptidyl transferase. The tRNA, discharged of its peptide, is released from the donor site to make way for translocation of the newly formed peptidyl tRNA. The acceptor site is then free to be occupied by the next "charged" aminoacyl tRNA. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad5 © 2010 Smt N. M. PadaliaThe tetracyclines are primarilybacteriostatic; inhibit proteinsynthesis by binding to 30Sribosomes in susceptibleorganism.Inhibit aminoaceyl tRNAattachment to A siteAs a result the peptide chainfails to grow. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad6 © 2010 Smt N. M. Padalia 3 View slide
  • 8/6/2012It is a broad spectrum antibiotic that active against many gram-positive and gram-negative bacteria Cocci Gram-negative bacilli H. ducreyi, N. gonorrhoea Calymmatobacterium N. Meningitidis Granulomatis Gram-positive bacilli V. cholerae, Clostridia Yersinia pestis, Y. enterocolitica Listeria, Campylobacter, Corynebacterta, Helicobacter pylori, Propionibacterium acnes Brucella, B. Anthracis F. tularensis By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad7 © 2010 Smt N. M. PadaliaSpirochetes, including T. pallidum and Borreha are ouite sensitive.All rickettsiae (typhus, etc.) and chlamydiae are highly sensitive.Mycoplasma and Actinomyces are moderately sensitive.Entamoeba histolytica and Plasmodia are inhibited at high concentrations.Resistance microorganismsNotable bacilli that are not inhibited are Pseudomonas aeruginosa, Proteus, Klebsiella, Salmonella typhi and many Bact. fragilis. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad8 © 2010 Smt N. M. Padalia 4 View slide
  • 8/6/2012Absorption:- Absorption after oral administration is approximately 30% for chlortetracycline; 60–70% for tetracycline, oxytetracycline, demeclocycline, and methacycline; 95–100% for doxycycline and minocycline.Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and antacids, which contain multivalent cations; and by alkaline pH. By Jitendra Bhangale Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad9 © 2010 Smt N. M. PadaliaDistribution:- Tetracyclines are widely distributed in the body.Excretion:- Most tetracyclines are primarily excreted in urine by glomerular filtration.Tetracyclines are classified as1. Short-acting (chlortetracycline, tetracycline, oxytetracycline) serum half-lives of 6–8 hours2. Intermediate-acting (demeclocycline and methacycline) serum half-lives of 12 hours3. Long-acting (doxycycline and minocycline) serum half-lives 16–18 hours By Jitendra Bhangale 10 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 5
  • 8/6/2012Hypersensitivity reactions (drug fever, skin rashes)Gastrointestinal effects:- Nausea, vomiting, and diarrhoeaBony Structures and TeethLiver ToxicityKidney ToxicityLocal Tissue ToxicityPhotosensitization Systemic tetracycline administration, especially of demeclocycline, can induce sensitivity to sunlight or ultraviolet light, particularly in fair-skinned persons.Vestibular Reactions:- Dizziness, vertigo, nausea, and vomiting have been particularly noted with doxycycline at doses above 100 mg. By Jitendra Bhangale 11 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 12 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 6
  • 8/6/2012It was originally obtained from the Streptomyces venezuelae 1947. By Jitendra Bhangale 13Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia The peptidyl tRNA at the donor site donates the growing peptide chain to the aminoacyl tRNA at the acceptor site in a reaction catalyzed by peptidyl transferase. The tRNA, discharged of its peptide, is released from the donor site to make way for translocation of the newly formed peptidyl tRNA. The acceptor site is then free to be occupied by the next "charged" aminoacyl tRNA. By Jitendra Bhangale 14Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 7
  • 8/6/2012Chloramphenicol binds to the50S ribosomal subunit at thepeptidyltransferase site andinhibits the transpeptidationreaction.Chloramphenicol binds to the50S ribosomal subunit near thesite of action of clindamycinand the macrolide antibiotics.These agents interfere withthe binding of chloramphenicoland thus may interfere witheach others actions if givenconcurrently. By Jitendra Bhangale 15 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaIt is a broad spectrum antibiotic that active against many gram-positive and gram-negative bacteria H. influenzae, Salmonella typhi Neisseria meningitidis, Escherichia coli S. pneumoniae Klebsiella pneumoniae Enterobacteriaceae Proteus mirabilis V. cholerae By Jitendra Bhangale 16 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 8
  • 8/6/2012Resistance mechanismResistance to chloramphenicol usually is caused by a plasmid- encoded acetyltransferase that inactivates the drug.Acetylated derivatives of chloramphenicol fail to bind to bacterial ribosomes. By Jitendra Bhangale 17 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaAbsorption:- Chloramphenicol is absorbed rapidly from the gastrointestinal tract. Chloramphenicol succinate in plasma are achieved after intravenous and intramuscular administration. Chloramphenicol palmitate is a prodrug that is hydrolyzed in the intestine to yield free chloramphenicol. By Jitendra Bhangale 18 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 9
  • 8/6/2012Distribution:- Chloramphenicol is widely distributed in the body.Excretion:- Chloramphenicol is primarily excreted in urine by glomerular filtration. By Jitendra Bhangale 19 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia Typhoid Fever Bacterial Meningitis Anaerobic Infections Rickettsial Diseases Brucellosis By Jitendra Bhangale 20 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 10
  • 8/6/2012Hypersensitivity reactions (drug fever, skin rashes)Bone marrow depressionVestibular Reactions:- Dizziness, vertigo, nausea, and vomitingGray baby syndrome: - The baby stopped feeding, vomited, became hypotonic and hypothermic, abdomen distended, respiration became irregular; an ashen gray cyanosis developed in many, followed by cardiovascular collapse and death.Blood lactic acid was raised By Jitendra Bhangale 21 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia By Jitendra Bhangale 22 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 11
  • 8/6/2012 Macrolide antibiotics contain a many-membered lactone ring (14-membered rings for erythromycin & clarithromycin and a 15-membered ring for azithromycin) to which are attached one or more deoxy sugars. By Jitendra Bhangale 23 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaNarrow spectrum Erythromycin (Streptomyces erythreus)Broad spectrum Clarithromycin, Roxithromycin Azithromycin are semisynthetic derivatives of erythromycin By Jitendra Bhangale 24 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 12
  • 8/6/2012 The peptidyl tRNA at the donor site donates the growing peptide chain to the aminoacyl tRNA at the acceptor site in a reaction catalyzed by peptidyl transferase. The tRNA, discharged of its peptide, is released from the donor site to make way for translocation of the newly formed peptidyl tRNA. The acceptor site is then free to be occupied by the next "charged" aminoacyl tRNA. By Jitendra Bhangale 25 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaMacrolide antibiotics arebacteriostatic agents that inhibitprotein synthesis by bindingreversibly to the 50S ribosomalsubunits of sensitive organisms.Erythromycin appears to inhibitthe translocation step wherein thenascent peptide chain temporarilyresiding at the A site of thetransferase reaction fails to move tothe P, or donor, site.Alternatively, macrolides maybind and cause a conformationalchange that terminates proteinsynthesis by indirectly interferingwith transpeptidation andtranslocation. By Jitendra Bhangale 26 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 13
  • 8/6/2012It is a broad spectrum antibiotic that active against many gram-positive and gram-negative bacteriaGram-positive organisms ListeriaPneumococciStreptococci Mycobacterium kansasiiStaphylococciCorynebacteria Mycobacterium scrofulaceumMycoplasmaLegionella Bordetella pertussisChlamydia trachomatisC psittaci Bartonella henselaeC pneumoniaeHelicobacter B quintana By Jitendra Bhangale 27 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaAbsorption:-Erythromycin base is destroyed by stomach acid and must be administered with enteric coating.Food interferes with absorption. Stearates and esters are fairly acid-resistant and somewhat better absorbed.Distribution:- Erythromycin are widely distributed in the body.Excretion:- Erythromycin are primarily excreted in urine. By Jitendra Bhangale 28 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 14
  • 8/6/2012Hypersensitivity reactions (drug fever, skin rashes)Gastrointestinal effects:- Nausea, vomiting, and diarrhoeaHepatitis with cholestatic jaundice By Jitendra Bhangale 29 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. PadaliaMycoplasma pneumoniae Staphylococcal Infections Infections Campylobacter InfectionsLegionnaires Disease Helicobacter pylori InfectionChlamydial Infections TetanusDiphtheria SyphilisPertussis Mycobacterial InfectionsStreptococcal Infections By Jitendra Bhangale 30 Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 15
  • 8/6/2012 By Jitendra Bhangale 31Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad © 2010 Smt N. M. Padalia 16