3. pencillin


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3. pencillin

  2. 2. Site and Mechanism of action of Antibiotics
  3. 3. • Inside bacterial cell is much concentration of ions and metabolites • It is required for cells to function normally : • to generate energy • Synthesize macromolecules • grow and divide • It cause high osmotic pressure
  4. 4. Antibiotics affecting cell wall Source Therapeutic application Penicillin Pencillium chrysogenum Pencillin notatum Gram +ve coccal infections, syphilis, gonorrhoea, meningo coccal meningitis Cephalosporin Cephalosporium spp Allergic to penicillin Cycloserine Streptomyces TB caused by resistance bacilli Bacitracin Bacillus licheniformis Sterilization of gut before surgery, topical application Vancomycin Streptomyces orientalis Staphylococcal infection resistant to other drugs Fofsomycin Active against +Ve, G-ve.
  5. 5. Peptidoglycan synthesis Cytoplasm Cell Membrane Cell wall undecaprenol sugar UDP-M, UDP-G amino acid Disaccharide pentapeptide 5
  6. 6. Fosfomycin Cytoplasm X X sugar Inactivating the enzyme Pyruvyl transferase enzyme Inhibits formation of UDP-M called a "Park nucleotide" Cycloserine Amino acid UDP-M pentapeptide X X alanine (ala) analog inhibits conversion L-ala to D-ala inhibits formation of D-ala-D-ala 6
  7. 7. TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane Cell wall undecaprenol P P 7
  8. 8. TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane Cell wall undecaprenol P P 8
  9. 9. TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane undecaprenol P P Cell wall
  10. 10. TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell wall Cell membrane undecaprenol P P
  11. 11. TRANSPORT OF PEPTIGOGLYCAN SUBUNIT ACROSS MEMBRANE Cell membrane Cell wall undecaprenol P P
  13. 13. Vancomycin Cell wall Vancomycin ( binds to D-alanyl-D- alanine protion of terminal end of peptidoglycan pentapeptide Makes transglycolase enzyme ineffectual cause inhibition of elongation
  14. 14. Beta lactam antibiotics • penicillins • Cephalosporins/cephamycins • monobactams
  15. 15. Beta lactams •inhibit penicillin binding proteins(Transpeptidase) Cell wall •stop cross-linking •Activate autolysin enzyme There functions are diverse: catalyze the transpeptidase reaction, maintain shape, forms septums during division, Inhibit autolytic enzymes. Penicillin binding protein
  16. 16. BETA LACTAM ANTIBIOTICS • Clinically useful families of beta-lactam compounds include the – Penicillins, – Cephalosporins, – Monobactams – Carbapenems
  17. 17. History • The penicillins were the first antibiotics discovered as natural products from the mold Penicillium. • In 1928, Sir Alexander Fleming, professor of bacteriology at St. Mary's Hospital in London, was culturing Staphylococcus aureus. • He noticed zones of inhibition where mold spores were growing. • He named the mold Penicillium rubrum. • It was determined that a secretion of the mold was effective against Gram-positive bacteria.
  18. 18. CHEMISTRY AND PROPERTIES • 1-THIOZOLIDINE RING • 2-BETA LACTAM RING O S C NH CH CH 2 O C CH3 C CH3 1 N •Beta lactamase • Gastric acid CH COOH •Penicillanic acid
  19. 19. • The penicillin nucleus itself is the chief structural requirement for biological activity; • Metabolic transformation or chemical alteration of this portion of the molecule causes loss of all significant antibacterial activity
  20. 20. Semisynthetic Natural β- lactum sensitive •Narrow spectrum •Acid liable •β- lactum sensitive Long acting •Procaine pencillin •Benzethine Short acting •Pencillin-G Narrow spect •Pencillin- V β- lactum resistance Anti staphylococcal Extended Acid Liable •Methicillin Acid Stable Aminopencillins •Neficillin •Ampicillin •Becampacilllin •Talampicillin •Amoxicillin β- lactum inhibitors Acid Stable •Floxacillin •Oxacillin •Cloxacillin •Dicloxacilin Acid Liable/ Anti pseudomonal •Pencillin- V (Phenoxy methylpencillin) Carboxy pen. •Carbenpencillin •Tricarben pencillin Uridopen. •Azlocillin •Mezlocillin •Pipera pencillin
  21. 21. Antimicrobial spectrum: Penicillin G
  22. 22. Pharmacokinetics Oral administration of Penicillin G: • Acid labile –destroyed by gastric acid • About one-third of an orally administered dose of penicillin G is absorbed from the intestinal tract under favorable conditions. • Gastric juice at pH 2 rapidly destroys the antibiotic. Parenteral Administration of Penicillin G: • From im site absorption is rapid and complete • Peak plasma levels attained in 30min
  23. 23. Pharmacokinetics • Cont… Penicillin G is distributed widely throughout the body, but the concentrations in various fluids and tissues differ widely. • Approximately 60% of the penicillin G in plasma is reversibly bound to albumin. • Significant amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and intestine • Cerebrospinal Fluid. Penicillin does not readily enter the CSF when the meninges are normal. However, when the meninges are acutely inflamed, penicillin penetrates into the CSF more easily. • Little metabolized because rapid excretion
  24. 24. Pharmacokinetics Cont… • The half-time for elimination is about 30 minutes in normal adults (upto 10 hours in renal failure) . • Approximately 10% of the drug is eliminated by glomerular filtration and 90% by tubular secretion. • While probenecid markedly decreases the tubular secretion of the penicillins,
  25. 25. Preparations and dose • Benzylpenicillin (sodium and potassium salts) • Repository preparations: • Insoluble salts, only im injection never iv injection – Procaine penicillin – Benzathine penicillin
  27. 27. Resistance mechansims • Produce β lactamase (penicillinase) – destroys antibiotic • modified penicillin binding proteins – don’t bind antibiotic • modified porins – no internalization of antibiotic 27
  28. 28. Adverse effects • Hypersensitivity Reactions. Hypersensitivity reactions are most common adverse effects noted with the penicillins, and these agents probably are the most common cause of drug allergy. • The basis of which is the fact that degradation products of penicillin combine with host protein and become antigenic. (Penicilloic acid)
  29. 29. Adverse effects Cont… • In approximate order of decreasing frequency, manifestations of allergy to penicillins include maculopapular rash, urticarial rash, fever, bronchospasm, vasculitis, serum sickness, exfoliative dermatitis, Stevens-Johnson syndrome, and anaphylaxis • The overall incidence of such reactions to the penicillins varies from 0.7% to 10% in different studies.
  30. 30. Adverse effects • Very high doses of penicillin G can cause seizures in kidney failure. • Pain at im injection site • Nausea on oral ingestion • Thromboplebitis of injected vein Cont…
  31. 31. Penicillin V • Orally active • Used for the treatment of bacteremia and oral infections • Higher minimum bactericidal concentration
  32. 32. • The major draw backs of benzylpenicillin are: – Inactivation by gastric acid – Short duration of action – Poor penetration into the CSF – Narrow spectrum of activity – Susceptibility to Penicillinase – Development of resistance – Possibility of anaphylaxis
  33. 33. Penicillinase-resistant penicillins (antistaphylococcal penicillins) • These congeners have side chains that protect the beta lactam ring from attack by staphylococcal penicillinase • Indicated in infections caused by penicillinase producing staphylococci (drugs of choice, except in MRSA) – Methicillin, Cloxacillin – Oxacillin, Nafcillin, Dicloxacillin
  34. 34. Extended spectrum penicillins • Active against a variety of gram-negative bacilli as well • Can be grouped according to their spectrum of activity 1. Aminopenicillins: Ampicillins: • Active against all organisms sensitive to PnG; in addition, many gram-negative bacilli
  35. 35. Extended spectrum penicillins Cont…
  36. 36. Extended spectrum penicillins Cont… Pharmacokinetics: • Acid resistant • Oral absorption is incomplete but adequate • Primary excretion is kidney, partly enterohepatic circulation occurs • Plasma half life is 1hr Uses: • UTI, RTI, Meningitis, Gonorrhoea, typhoid fever, bacillary dysentery, Cholisystitis, Subacute bacterial endocarditis and Septicemias
  37. 37. Extended spectrum penicillins Cont… Adverse effects: • Diarrhoea • Rashes • Hypersensitivity Interactions: • Hydrocortisone –inactivates ampicillin if mixed in the iv solution • OC –failure of oral contraception • Probenecid –retards renal excretion
  38. 38. Extended spectrum penicillins Cont… • Bacampicillin –ester prodrug of ampicillin • Talampicillin, Pivampicillin and Hetacillin are other Prodrugs of ampicillin Amoxicillin: • Close congener of ampicillin but not a prodrug • Similar to it in all aspects except: – Better oral absorption – Higher and sustained blood levels are produced – Incidence of diarrhoea is lower – Less effective against Shigella and H. influenzae
  39. 39. Extended spectrum penicillins 2. Carboxypenicillins (Carbenicillin, Ticarcillin) and 3. Ureidopenicillins (Piperacillin) Cont…
  40. 40. Extended spectrum penicillins Cont… • These are called antipseudomonal penicillins • Piperacillin is more potent among these • Carbenicillin is less effective against Salmonella, E. Coli and enterobacter but not active against Klebshiella and gram-positive cocci • Piperacillin has good activity against Klebshiella, and is used mainly in neutropenic/ immunocompromised patients having serious gram-negative infections and in burns
  41. 41. G+Ve cocci Staphylococcus (Boils, bone, joint, infections of wounds) • Non Beta lactamase producing- Pencillin G or V • Beta lactamase producing – Flucloxacillin Streptococcus, haemolytic types( Bacterimia, scarlet fever, toxic shock syndrome) – Pencillin-G or Pencillin V Enterococcus (endocarditis)- Pencillin G + gentamicin Pneimococcus (pneumonia) Pencillin G or Pencillin V or ampicillin or macrolide
  42. 42. G –ve cocci • Morasella catarrhalis(Sinusitis) amoxicillin+clavunic acid • Neisseria gonorrhoeae (gonorrhoea) amoxicillin+clavunic acid G+ve rods • Clostridium (tetanus, gangrene)- Pencillin G • Listeria monocytogenes (Rarely cause meningitis) Amocillin±aminoglycoside
  43. 43. G-ve rods • Haemophilius influenzae (R.T.I, ear, sinuses, meningitis) Ampicillin or cefuroxime • Pasterurella multocida (wound infection, abcess) Amoxicillin+ calvulanic acid • H. pylori Metroindazole + amoxicillin+ Ranitidine Other • Oropharyngeal infection- Pencillin G • Rheumatic fever - Prophylactic
  44. 44. Spirochaetes • Treponema (syphillis, yaws)- Pencillin G • Leptospira (weil’s disease) - Pencillin G • Actinomyces (abscesses) - Benzylpencillin
  45. 45. 2nd line drug for • • • • • • Corynebacterium (diphtheria)- Macrolide- Pencillin G UTIextend spectrum pencillins(Amoxicillin) Shigella (dysentery) – Q -ampicillin Salmonella (typhoid)- Quinolone- amoxicillin Whooping cough – Macrolide - Ampicillin Borella recurrentis (relapsing fever)- Benzylpencillin
  46. 46. Beta-lactamase inhibitors • Clavulanic acid, Sulbactam and Tazobactam • They contain beta-lactam ring but themselves, do not have significant antibacterial activity
  47. 47. Beta-lactamase inhibitors Clavulanic acid: • Obtained from Streptomyces clavuligerus • Called a suicide inhibitor • Pharmacokinetics matches amoxicillin with which it is used Sulbactam: • Semisynthetic beta-lactamase inhibitor • Related chemically as well as in activity to clavulanic acid • It is also a progressive inhibitor • Combined with ampicillin Cont…
  48. 48. Beta-lactamase inhibitors Cont… Tazobactam: • Similar to Sulbactam • Pharmacokinetics matches with Piperacillin with which it is used for used in severe infections like peritonitis, pelvic/urinary/respiratory infections • However, the combination is not effective against piperacillin-resistant Pseudomonas
  49. 49. Ampicillin Amoxycillin Oral incomplete absorption Oral complete absorption Food Dec. absorption No CSF meningitis No Shigella respond No Streptococci viridans respond Respond Bacilliary desentry responds No Gentamicin Synergistic action No Dec. OC pills activity No Salbactum Clavulanic acid 250-500mg of QID Equals to 250-500mg TDS ----- Used in H.Pylori Regimens