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Penicillin's
- 1. Penicillin’s Jagir R. Patel AsstProfessor dept. Pharmacology
- 2. Cell wall synthesisinhibitors Some antimicrobial drugs selectively interfere with synthesis of the bacterial “ cell wall”a structure that mammalian cells do not possess. The cell wall is composed of a polymer called peptidoglycan that consists of glycan units joined to each other by peptide cross-links. To be maximally effective, inhibitors of cell wall synthesis require actively proliferating microorganisms; they have little or no effect on bacteria that are not growing and dividing. All bacteria (except mycoplasma) lack sterols stabilizing their inner cell membrane, thus rendering their inner cell membrane extremely vulnerable to osmotic pressure however, these bacteria have a cell wall (again, except mycoplasma) primarily consisting of peptidoglycan intimately surrounding the outside of their inner cell membrane this peptidoglycan protects and stabilizes the inner cell membrane, thus preventing the osmotic lysis of the bacteria
- 5. The peptidoglycanconsists of 2 parts DISACCARIDE BACKBONE : - alternating molecules of N- acetyl glucosamine (“NAG”) and N-acetyl muramic acid (“NAM”) OLIGOPEPTIDE SIDE-CHAINS tetra- or pentapeptides of varying composition extending from both sides of the disaccaride backbone covalently linked to oligopeptide side-chains of adjacent disaccaride backbones Synthesis and remodeling of peptidoglycan is primarily done by 3 groups of enzymes residing within the peptidoglycan layer (“penicillin-binding proteins”, “PBPs”) Penicillin binding proteins: they are bacterial enzymes involved in synthesis of bacterial cell wall and maintenance of the morphologic changes or lysis of susceptible bacteria.
- 6. NAG-NAM POLYMERASE:covalently links alternating NAG and NAM molecules to produce the disaccaride backbone TRANSPEPTIDASE: covalently links the oligopeptide side-chains of adjacent disaccaride backbones AUTOLYSIN: many bacteria specially grm+ve produces “lysozyme” ,degrades parts of the disaccaride backbone during remodeling of peptidoglycan is rapidly inactivated by autolysin inhibitors (“lysozyme inhibitors”) upon completed remodeling PBPs are all involved in the final stages of the synthesis of peptidoglycan, which is the major component of bacterial cell walls. Bacterial cell wall synthesis is essential to growth, cell division (thus reproduction) and maintaining the cellular structure in bacteria. Inhibition of PBPs leads to irregularities in cell wall structure such as elongation, lesions, loss of selective permeability, and eventual cell death and lysis
- 8. Cell wall synthesisinhibitors Agents effecting cell wall Beta lactams Penicillin's Cephalosporin's Carbapenems Monobactams Others Bacitracin Vancomycin Daptomycin
- 9. Beta Lactam antibiotics Beta-lactam antibiotics are substances that contain a beta-lactam ring in their chemical structure a beta-lactam ring is a 4-membered hydrocarbon ring where 1 of the carbons has been exchanged with a nitrogen, and the 2 hydrogen of the carbon adjacent to the nitrogen have been exchanged with a double-bonded oxygen
- 10. Classification of Penicillins 1.Natural penicillins : Penicillin G Penicillin V 2. Penicillinase resistant penicillins: Nafcillin, Oxacillin, Cloxacillin, Dicloxacillin, Flucloxacilin, 3. Extended spectrum penicillins Aminopenicillins: 2nd generations: ampicillin, Bacampicillin, Amoxicillin, Pivampicillins, Methampicillin, Talampicillin Carboxypenicilline: 3rd generations: Carbenicillin, Ticarcillin Uredopenicillins: 4th generations: Piperacillins, Mezlocilin, Azalocillin Beta lactamase inhibitors : clavulanic acid, Sulbactam, Tazobactam Others: Mecillinam, Sulbenicillin
- 11. Anti microbial spectrum It is narrow spectrum antibiotic limited to gram +ve bacteria • Streptococci, enterococci, pneumococci & Staph.aureus • Gram –ve cocci: • Neisseria gonorrhoeae and Neisseria meningitides Cocci • gram +ve: • B.antharacis, Corynebacterium diphtheriae and all Clostridia • ( Clostridia tetani) Bacilli
- 12. Mechanism of action Beta-lactamantibiotics are bactericidal Osmotic lysis of the bacteria Decreased protection, stability and Morphologic changes due to PBP of the inner cell membrane Increased degradation disaccaride backbones Failure of linkage of oligopeptide side-chains of adjacent disaccaride backbones Beta-lactam antibiotics inhibit both Transpeptidase and Autolysin inhibitors and inactivate penicillin binding proteins
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- 15. Mechanism of Resistance NATURAL RESISTANCE: due to the structure of the bacterial cell envelope, 2 mechanisms NO PEPTIDOGLYCAN in mycoplasma does penicillin-binding proteins for the betalactam antibiotics to attack OUTER CELL MEMBRANE in gram-ve bacteria - prohibits uptake of larger beta-lactam antibiotics - only smaller beta-lactam antibiotics may pass through porins of the outer cell membrane
- 16. ACQUIRED RESISTANCE dueto plasmid transfer and/or chromosomal mutations - 3 mechanismsDECREASED UPTAKE • Due to decreased number of porins in the outer cell membrane • limits uptake of even the smaller beta-lactam antibiotics • only in gram –ve bacteria (only gram – bacteria have outer cell membrane) DECREASED AFFINITY • Due to structural alterations of the penicillin binding proteins INCREASED INACTIVATION • due to the presence of beta-lactamases (“penicillinases”)beta-lactamases cleave the beta-lactam ring between the nitrogen and the oxygen-bound carbon, thus inactivating the beta-lactam antibiotics Most gram –ve bacteria (and many gram + bacteria) have beta-lactamases
- 17. Penicillin G Itis also called as “benzyl penicillin” PK: administered orally ( degradation by gastric juice) Intramuscularly( its pain full) IV ( its safe) Distribution :may cross the placental barrier, may cross the blood-brain barrier (but only if the meninges are inflamed ) Excretion: by active tubular secretion
- 18. Adverse effect Hypersensitivityreactions leading to fever, skin rashes, angioedema and/or anaphylactic shock, urticaria, skin rashes, fever, dermatitis etc. Anaphylactic shock: hypotension, bronchospasm, laryngeal edema seizures (if high doses) Precautions for penicillins History of patient for any allergy, hay fever, asthma, allergic rhinitis In such cases penicillins should be avoided Penicillin sensitivity test can be done by intra dermal inj of penicillin on the ventral aspect of forearm of patient, signs of itching erythema, and wheal formation can b watched for. Adrenaline and hydrocortisone should be kept ready before administration of penicillin. For anaphylactic shock
- 19. Drug-Drug interactions Penicillin+ spironolactone : hyperkalemia Penicillin + colestipol = decreases absorption Penicillin + streptokinase = increases risk of bleeding Penicillin + contraceptives = decreased effect of contraceptives
- 20. uses Pneumococcal infections:pneumonia, meningitis Streptococcal infections: streptococcal pharyngitis, otitis media, rheumatic fever Meningococcal meningitis Gonnococal infections : cephalosporin's are preferred or penicillin G Syphilis: Penicillin is drug of choice for Syphilis Diphtheria: acute infections like upper respiratory tract infections Clostridial infections: tetanus and gas gangrene Other infections: anthrax, rat bit fever, listeria infections Draw backs of penicillin G It is acid labile- orally no effective Short duration of action Narrow spectrum
- 22. Penicillin V Acidstable so can be given orally Susceptible to penicillinases It attains very low plasma concentration It is used only for mild streptococcal and Pneumococcal infections
- 23. Oxacillin Absorption: Incompletelyabsorbed from the GI tract, Due to presence of food. Time to peak plasma concentration: 1 hr (oral); 30 min (IM). Distribution: Distributed into synovial, bone, lungs, sputum and bile; cord serum and amniotic fluid. Crosses the placenta and enters breast milk. Plasma protein binding: Approx. 93%. Metabolism: Partially metabolized to active and inactive metabolites in the liver. Excretion: Via urine (oral: approx. 20-30%; IM: >40%) as unchanged drug and metabolites and bile. Plasma half-life: Approx. 30 min. Adverse effect: same as penicillin Indication: Staphylococcal infections resistant to benzyl penicillin Contraindication in hypersensitive to penicillin Interactions: Tetracycline + Oxacillin: antagonistic effect Probenecide + Oxacillin= increased plasma levels
- 24. Ampicillin and Amoxicillin Ampicillin SpectrumIt is active against all organism sensitive to Penicillin G it is more active for pneumococci, meningococci, and gonococci Gram –ve: H. influenza, E.coli, Proteus, Salmonella sp, Shigella Route of admirations Oral, i.m. i.v. Pharmacokinetics Not degraded by acid Food interferes with absorption Partially excreted in bile and reabsorbed Excreted in urine Uses Upper respiratory tract infections Urinary tract infections Meningitis Bacillary dysentery Typhoid fever Amoxicillin It is close congener of Ampicillin, Orally absorption is better as food don’t interfere in absorption Incidence of diarrhoea is lower It is less effective against Shigella and H. influenza
- 26. Carbenicillin Special feature:this penicillin congener is active against Pseudomonas aeruginosa which are no inhibited by Penicillin G and aminopenicillins It is less active for salmonella, E.coli, Enterobacter etc. This congener is neither Penicillinase resistant nor acid resistant It is inactive orally It is used in sodium salts and given I.m. or i.v. Enough sodium should be administered for fluid retention Half life is only 1hr so rapidly excreted in urine Uses: serious infections by Pseudomonas or Proteus i.e. burs, UTI, Septicaemia Side effect: same as penicillin but congestive cardiac failure may be precipitated due to sodium content of Carbenicillin, it can also interfere with platelet function and cause bleeding
- 27. Piperacillin Spectrum Antipseudomonalpenicillin is about 8 times more active then carbenicillin It have good activity against Klebsiella P.K. : administered i.m. or i.v. half life 1hr, rapidly eliminated Uses: burns and UTI
- 28. Azlocillins Azlocillin demonstratesantibacterial activity against a broad spectrum of bacteria, including Pseudomonas aeruginosa, and in contrast to most cephalosporins, exhibits activity against enterococci. Not significantly absorbed from the gastrointestinal tract. Eliminated predominantly by renal mechanisms, but also undergoes biotransformation within body tissues and intraintestinal degradation by bowel bacteria, with high concentrations found in bile. Used in infection caused by Pseudomonas aeruginosa, Escherichia coli, and Haemophilus influenzae. Contraindicated in penicillin hypersensitivity.
- 29. Mecillinam Mecillinam isan extended-spectrum penicillin and is only considered to be active against Gram-negative bacteria. It is given i.m. or i.v. Use: urinary tract infections, and has also been used to treat typhoid and paratyphoid fever. The adverse effect profile of mecillinam is similar to that of other penicillins. Its most common side effects are rash and gastrointestinal upset, including nausea and vomiting Contraindications : Hypersensitivity to penicillins; porphyria. Interactions: Antagonism with bacteriostatic drugs e.g. chloramphenicol, tetracycline's. May prolong bleeding time when used with anticoagulants.