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Beta – Lactam Antibiotics

Beta – Lactam Antibiotics. Prof. R. K. Dixit Pharmacology and Therapeutics K. G. M. U. Lucknow dixitkumarrakesh@gmail.com. Objectives. After completion of this lecture you will be able to understand What are betalactam antimicrobials Mechanism of action Types of Penicillin, Uses, ADRs

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Beta – Lactam Antibiotics

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  1. Beta – Lactam Antibiotics Prof. R. K. Dixit Pharmacology and Therapeutics K. G. M. U. Lucknow dixitkumarrakesh@gmail.com

  2. Objectives After completion of this lecture you will be able to understand • What are betalactam antimicrobials • Mechanism of action • Types of Penicillin, Uses, ADRs • Classification of Cephalosporin, Uses, ADRs • Members of Carbapenem and Monobactam, Uses, ADRs

  3. Have Beta-lactam ring • Important groups are (PCcM) Paracetamol • Penicillins • Cephalosporins • Carbapenems • Monobactams

  4. Broken by Amidase enzyme Active material Raw material for other penicillin Broken by Betalactamase enzyme Inactive Responsible for hypersensitivity

  5. Active material Raw material for other penicillin Inactive (Major Determinant) Responsible for hypersensitivity

  6. Penicillin Cephalosporins Monobactam Carbapenem Beta Lactamase inhibitor (Claulanic acid and Sulbactam) Suicide Inhibitors Beta Lactamase

  7. Penicillin • First antibiotic to be used clinically in 1941 • One of the least toxic antibiotic even today • Obtained from • Penicillium notatum (Early) • Penicillium chrysogenum (Now, Better Yield) • Scientists- Fleming – Chain – Florey • Original Penicillin – • Penicillin G, Benzyl Penicillin ( R is Benzyl (CH2C6H5) )

  8. Chemistry • Penicillin nucleus consists of • Thiazolidine ring (Ring A)- • Sulphur containing with COOH (Carboxyl group), • Beta lactam ring (Ring B) – (Broken by Betalactamase) • Side chain is attached at position – 6- (NHCOR) • Side chains attached through amide linkage. (Broken by Amidase)

  9. Beta Lactam ring is broken by – • Penicillinase (Beta Lactamase), and by gastric acid. • Resultant Product is Penicilloic acid with • No anti-bacterial activity but • Acts as antigenic determinant (Major determinant) • Penicillins are available as • Na+ or K+ salts . • Amine salts such as Procaine and Benzathine Penicillin.

  10. Natural Penicillin – • -Broken down by Amidase = (Removes Side Chain) • Penicillin – side chain = • 6- Amino-Penicillanic acid (6-APA) • Active moiety • Has intact Betalactam ring (B) • With NH2 group at position 6 joined to thiazolidine ring.

  11. Large amount of 6-APAare produced from culture of P. chrysogenum. (Fungal Amidase hydrolyze side chain at position-6.) • 6-APA is basic raw material • Different types of penicillin are obtained by attaching different groups at position -6. • 6-APA + other side chains = • Different types of semi synthetic Penicillins (Different Pk and Pd)

  12. Sodium or Potassium salts • More stable (Stability decreases after making solution) • Natural Penicillin is • Benzyl penicillin or Penicillin G (PnG) and it is • Thermo and Acid labile

  13. Penicillin Units • One unit of Sodium Benzyl Penicillin = 0.6µg • Or • One mega unit = 0.6 gram • Or • One gram = 1.6 million units

  14. MOA • Bacteria are unique • Don’t have osmotic regulating mechanism • Cell wall controls osmotic changes. • Cell wall is composed of • Peptidoglycans • Cross linked by peptide chains. • NAM – NAG ( N-acetyl muramic acid and N- acetyl glucosamine) • Cross linked by a Pentaglycine cross bridge • (Extending from the L-lysine residue of one peptide chain to the D-alanine residue of another peptide chain).

  15. Cross bridging is transpeptidation reaction. • Transpeptidase and related proteins (Penicillin Binding Proteins) are used for making cross linkage. • Cross linking provides stability, strength.

  16. β-Lactams inhibit Transpeptidase leading to • Damage of cross linking • Weakening of cell wall • Swelling of cell due to Endosmosis • Bacterial membrane bursts • Bacterial lysis • Additional mechanism – • Activation of autolysing enzymes • (Murein Hydrolase and Autolysins) • More lethal during active multiplication

  17. Betalactam Antibiotics

  18. Bactericidal activity of penicillin is more against Gram positive. (Difference in organization of cell wall) • In gram positive • Thick layer of Peptidoglycans and teichoic acid (a polyol phosphate polymer) surrounds the membrane. • Peptidoglycans layer is easily accessible to Beta lactam antibiotics • In gram negative • Two membranes are present. (The cytoplasmic membrane and an outer membrane with thin layer of Peptidoglycans sandwiched between the two). • The outer membrane consists of lipopolysaccharides with narrow porin channels which function as a barrier to permeability of antibiotics

  19. Penicillins which are hydrophilic in nature (Ampicillin and Amoxicillin)can diffuse through porin channels and show activity against negative. • Pseudomonas lacks porins due to which even Ampicillin and amoxicillin can’t act against them. • Aminoglycosides addition is synergistic

  20. Resistance against Penicillin • Natural • Target enzymes and PBPs are deeply located (Lipoprotein barrier in –ve) • PBPs of organisms have low affinity for penicillin • Acquired • Production of Penicillinase (Beta-Lactamase) enzyme, (>300 subtypes). Common organisms producing Beta-Lactamase are • Staphylococcus • Bacillus subtilis • Gonococci • E. coli • Enterococci • Haemophilus influenza • Loss or alteration of Porin channels in gram negative • Modification of penicillin binding proteins (PBPs)- having low affinity . • Activation of antibiotic efflux mechanism- Some gram negative bacteria

  21. Adverse effects • General • Hypersensitivity reactions (including Anaphylaxis) • More with procaine penicillin, • Intradermal Skin sensitivity test • Major Determinant (Penicilloyl moiety in terms of amount) is responsible for hypersensitivity other than anaphylaxis • Minor determinants( Penicillamine and Penicillenate) are responsible for anaphylaxis. The Penicilloyl moiety or major determinant results from reaction of beta-lactam ring with endogenous proteins. The Beta lactam ring spontaneously opens in the body forming a hapten-protein complex, the most abundant but not necessarily most immunogenic.

  22. Hypersensitivity testing

  23. Super infections (Ampicillin) • Nephrotoxicity (Methicillin causing interstitial nephritis) • Increase in Prothrombin time leading to bleeding • Jarisch -Herxheimer Reaction- • Common in secondary syphilis, • Release of Spirochetal lytic products (Heat stable proteins, endotoxins) • Characterized by fever, myalgia, exacerbation of lesions, • Usually occurs within 2 hours of first dose • Treatment- NSAIDs and Corticosteroids • Also in Borelliosis, Leptospirosis, and Brucelosis • Adolf Jarisch an Austrian and Karl Herxheimer a German dermatologist

  24. Jarisch Herxheimer Reaction

  25. Drug Interactions • With Tetracyclines, Chloramphenicol, Erythromycin- • Antagonism • Penicillin with Aminoglycosides- • Synergism. • Penicillin and Aminoglycosides or Penicillin and hydrocortisone in same syringe – • Inactivate each other (Pharmaceutical) • Ampicillin with Allopurinol – • High incidence of non-urticarial maculopapular rashes • Penicillin with Probenecid • Prolongs action of penicillin by decreasing tubular secretion

  26. Uses • General , Plus • Rheumatic fever • SABE (Streptococcal viridans) • Gonorrhea • Syphilis- • 1.2 MU of Procaine penicillin for 12 days or • 2.4 MU of Benzathine Penicillin • Leptospirosis (Weil’s Disease) • Actinomycosis, Listriosis, Lyme Disease, Anthrax, Rat bite fever, Erysipeloid, Gingivostomatitis • Diphtheria • Tetanus • Gas gangrene (Clostridium pefringens (welchii) • Prophylaxis- • Rheumatic fever, SABE, • Agranulocytosis

  27. Thanks

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