Penicillins (VK)


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  • Penicillins as well as cephalosporins are called beta-lactam antibiotics and are characterized by 3 fundamental structural requirements:
  • A bacterial cell from which da rigid cell wall has been incompletely removed . The bacterium loses its characteristic shape and becomes round
  • an inj of a substance in a vehicle that tends to keep it at the site of inj so that absorption occurs over a prolonged period
  • Penicillins (VK)

    2. 2. Site and Mechanism of action of Antibiotics
    3. 3. Penicillium The name Penicillium comes from Penicillus = brush, and this is based on the  brush-like appearance of the fruiting structures
    4. 4. Introduction  The penicillins constitute one of the most important groups of antibiotics.  Although numerous other antimicrobial agents have been produced since the first penicillin became available, these still are widely used, major antibiotics, and new derivatives of the basic penicillin nucleus still are being produced.  Many of these have unique advantages, such that members of this group of antibiotics are presently the drugs of choice for a large number of infectious diseases.
    5. 5. History  1928 - Alexander Fleming  Bread mold (Penicillium notatum) growing on petri dish  1939 - Florey, Chain, and Associates  Began work on isolating and synthesizing large amounts of Penicillin.  1941 – introduced in antibacterial therapy
    6. 6. Structure the fused beta-lactam structure (shown in the blue and red rings, a free carboxyl acid group (shown in red bottom right), one or more substituted amino acid side chains (shown in black). The lactam structure can also be viewed as the covalent bonding of pieces of two amino acids - cysteine (blue) and valine (red).
    7. 7. thiazolidine ring (A) connected to a b-lactam ring (B), to which is attached a side chain (R).
    8. 8.  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
    9. 9.  Clinically useful families of beta-lactam compounds include the  Penicillins  Cephalosporins  Monobactams  Carbapenems
    10. 10. Mechanisms of Action  All penicillin derivatives produce their bactericidal effects by inhibition of bacterial cell wall synthesis.  Specifically, the cross linking of peptides on the polysaccharide chain is prevented.  If cell walls are improperly made cell walls allow water to flow into the cell causing it to burst.
    11. 11. Penicillin Bind (PBP) on the cell wall of susceptible bacteria Inhibits transpeptidation Prevents peptidoglycan synthesis Cell wall deficient forms spheroplasts & filamentous forms Autolysis Cell death (bactericidal action)
    12. 12. MOA: Cell Wall production  The cell walls of bacteria are essential for their normal growth and development.  Peptidoglycan is a heteropolymeric component of the cell wall that provides rigid mechanical stability by virtue of its highly cross-linked latticework structure  The peptidoglycan is composed of glycan chains, which are linear strands of two alternating amino sugars (N-acetylglucosamine and N-acetylmuramic acid) that are cross-linked by peptide chains. (NAG-NAM).
    13. 13. Mechanisms of Action  Cont… Binding to PBPs results in:  Inhibition of transpeptidase: transpeptidase catalyzes the cross-linking of the pentaglycine bridge with the fourth residue (D-Ala) of the pentapeptide. The fifth residue (also D-Ala) is released during this reaction. Spheroblasts are formed.  Structural irregularities: binding to PBPs may result in abnormal elongation, abnormal shape, cell wall defects.
    14. 14. Comparison of the structure and composition of gram-positive and gram-negative cell walls.
    15. 15. CLASSIFICATION  NARROW SPECTRUM PENICILLINS β -lactamase sensitive(NATURAL PENICILLINS) Acid resistant - Penicillin V (oral) Acid labile - Penicillin-G (benzyl penicillin) (I.M,IV) - Procaine penicillin-G(I.M,depot inj) - Benzathine penicillin-G(I.M, depot inj)
    16. 16. β -lactamase resistant(ANTISTEPHYLOCOCCAL PENICILLINS) Acid resistant - Cloxacillin - Dicloxacillin - flucloxacillin Acid labile - Methicillin (I.M,I.V) - Nafcillin (I.M,I.V)
    17. 17.  EXTENDED SPECTRUM PENICILLINS Acid resistant • Aminopenicillins: Ampicillin, Amoxicillin, Bacampicillin, Talampicillin Acid labile ( ANTIPSEUDOMONAL PENICILLINS) • •  Carboxypenicillins: Carbenicillin, Ticarcillin Ureidopenicillins: Piperacillin, Mezlocillin, Azlocillin BETA LACTAMASE INHIBITORS • Sulbactam, Tazobactam, Clavulanic acid
    18. 18. Natural penicillins  Listed as antistaphylococcal  Obtained from fermentations of the mold Penicillium chrysogenum  Penicillin G (benzylpenicillin) and Penicillin V
    19. 19. Antimicrobial spectrum: Penicillin G
    20. 20. Pharmacokinetics Oral administration of Penicillin G: Acid labile About one-third of an orally administered dose of PenG is absorbed from the intestinal tract under favorable conditions. Gastric juice at pH 2 rapidly destroys the antibiotic. Parenteral Administration of Penicillin G: From I.M site absorption is rapid and complete Peak plasma levels attained in 30min
    21. 21. Pharmacokinetics  Cont… PenG is distributed widely throughout the body, but the concentrations in various fluids and tissues differ widely.  Approx. 60% of the PenG in plasma is reversibly bound to albumin.  Significant amounts appear in liver, bile, kidney, semen, joint fluid, lymph, and intestine  CSF: 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
    22. 22. Pharmacokinetics  Cont… The half-time for elimination is about 30 minutes in normal adults (upto 10 hours in renal failure) .  Approx. 10% of the drug is eliminated by glomerular filtration and 90% by tubular secretion .  While probenecid markedly ↓ss the tubular secretion of the penicillins, this is not the only factor responsible for the elevated plasma concentrations of the antibiotic that follow its administration.
    23. 23. Preparations and dose   Benzylpenicillin (sodium and potassium salts) Repository preparations:    Insoluble salts, only I.M injection never I.V inj Procaine penicillin Benzathine penicillin
    24. 24. Unitage of Penicillin  The IU of penicillin is the specific penicillin activity contained in 0.6 mg of the crystalline sodium salt of penicillin G.  1mg of pure penicillin G sodium thus equals 1667 units; 1mg of pure penicillin G potassium represents 1595 units.  The dosage and the antibacterial potency of the semisynthetic penicillins are expressed in terms of weight.
    25. 25. Therapeutic Uses                Pneumococcal Infections  Pneumococcal Meningitis  Pneumococcal Pneumonia Streptococcal Infections  Streptococcal Pharyngitis (including Scarlet Fever)  Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis Staphylococcal Infections Meningococcal Infections Gonococcal Infections Syphilis, Actinomycosis, Diphtheria, Anthrax Clostridial Infections Fusospirochetal Infections Rat-Bite Fever Listeria Infections Lyme Disease Erysipeloid Surgical Procedures in Patients with Valvular Heart Disease Tetanus and gas gangrene Prophylactic uses:  Rheumatic fever, bacterial endocarditis and agranulocytosis pts
    26. 26. Mechanisms of Bacterial Resistance to Penicillins  Resistance to penicillins and other beta lactams is due to one of four general mechanisms:     Inactivation of the antibiotic by beta lactamase Modification of target PBPs Impaired penetration of drug to target PBPs The presence of an efflux pump.
    27. 27. Other resistance mechanisms    A reduction in the permeability of the outer membrane. Thus there is a decreased ability of the drug to penetrate to the target site. The occurrence of modified penicillin binding sites. This mechanism is responsible in methicillin resistance in Pneumococci.
    28. 28. Adverse effects  Hypersensitivity Reactions  The basis of which is the fact that degradation products of penicillin combine with host protein and become antigenic.
    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 incidence of such reaction is 5-8% of the Pts receiving Penicillins
    30. 30. Adverse effects  Cont… Very high doses of penicillin G can cause seizures in kidney failure.  Pain at I.M injection site  Nausea on oral ingestion  Thromboplebitis of injected vein
    31. 31. Penicillin V  Orally active  Used for the treatment of bacteremia and oral infections  Higher minimum bactericidal concentration
    32. 32. Semisynthetic penicillins  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. Penicillinase-resistant penicillins (antistaphylococcal penicillins)Cont… Methicillin: Acid Not labile used clinically, except to identify resistant strains MRSA is susceptible to Vancomycin/linezolid and rarely Ciprofloxacin
    35. 35. Penicillinase-resistant penicillins (antistaphylococcal penicillins)Cont… Cloxacillin: Acid resistant More active than methicillin Less active against PnG sensitive organisms: should not be used as its substitute Incompletely >90% but dependably absorbed (oral route) protein bound, eliminated primarily by kidney, also partly by liver Plasma half life is about 1hr
    36. 36. 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
    37. 37. Extended spectrum penicillins Cont…
    38. 38. 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
    39. 39. Extended spectrum penicillins Cont… Adverse effects: Diarrhoea Rashes Hypersensitivity Interactions: Hydrocortisone OC –inactivates ampicillin if mixed in the I.V solution –failure of oral contraception Probenecid –retards renal excretion
    40. 40. 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
    41. 41. Extended spectrum penicillins Cont… 2. Carboxypenicillins (Carbenicillin, Ticarcillin) and 3. Ureidopenicillins (Piperacillin)
    42. 42. 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 gramnegative infections and in burns
    43. 43. Beta-lactamase inhibitors  Clavulanic acid, Sulbactam and Tazobactam  They contain beta-lactam ring but themselves, do not have significant antibacterial activity
    44. 44. Beta-lactamase inhibitors Clavulanic acid : Obtained Called from Streptomyces clavuligerus a suicide inhibitor Pharmacokinetics matches amoxicillin with which it is used Sulbactam: Semisynthetic Related It beta-lactamase inhibitor chemically as well as in activity to clavulanic acid is also a progressive inhibitor Combined with ampicillin Cont…
    45. 45. 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
    46. 46. They are available only in fixed combinations with specific penicillins: Ampicillin + Sulbactam (1g+0.5g I.V/I.M inj) Amoxycillin + Clavulanic acid (250mg+125mg tab) Piperacillin + Tazobactam sodium (2g+0.25g I.V/I.M inj)