Pharmacology

• Chemotherapeutic Drugs


  (Cell wall inhibitors)
• Drugs that inhibit cell wall synthesis


  • β-lactam antibiotics
  • Penicillins
  • Cephalosporins
  • Carbapenems
  • Monobactams

  
• All β-lactam antibiotics contain a β-lactam ring in their structure

  
• Penicillins


  • Bactericidal agents that inhibit the synthesis of peptidoglycan
  • Naturally derived from penicillin moulds like benzylpenicillin, but the majority are synthesized now a day
  • Members of this family differ from each other in the R substituent attached to the 6-aminopenicillanic acid residue
  • The nature of this side chain affects the antimicrobial spectrum, stability to stomach acid, and susceptibility to bacterial degradative enzymes (β-lactamases)

  
• Classification of Penicillins


  • Natural Penicillins
  • Benzyl penicillin (penicillin G)
  • Phenoxymethylpenicillin (penicillin V)
  • β-lactamase-resistant penicillins: "Antistaphylococcal penicillins"
  • Extended Spectrum Penicillins: (also known as aminopenicillins)
  • Antipseudomonal penicillins
• Mechanism of action


  1. Penicillins interfere with the last step of bacterial peptidoglycan synthesis (transpeptidation or cross-linkage)

  2. Cell lysis can then occur, either through osmotic pressure or through the activation of autolysins

  3. Penicillins inactivate numerous proteins on the bacterial cell membrane called penicillin-binding proteins (PBPs)

  4. Some PBPs catalyze formation of the cross-linkages between peptidoglycan chains, penicillins inhibit this transpeptidase-catalyzed reaction

  5. Many bacteria produce degradative enzymes (autolysins) that participate in the normal remodeling of the bacterial cell wall, in the presence of a penicillin, the degradative action of the autolysins proceeds in the absence of cell wall synthesis

  
• Antibacterial spectrum


  • Gram-positive microorganisms have cell walls that are easily traversed by penicillins
  • Gram-negative microorganisms have an outer lipopolysaccharide membrane (envelope) surrounding the cell wall that presents a barrier to the water-soluble penicillins
  • Gram-negative bacteria have proteins inserted in the lipopolysaccharide layer that act as water-filled channels (called porins) to permit transmembrane entry
• Natural penicillins


  • Penicillin G (benzyl penicillin)
  • Penicillin V (Phenoxymethylpenicillin)
• Penicillin G (benzyl penicillin)


  • Cornerstone of therapy for infections caused by a number of G +ve and G -ve cocci, G +ve bacilli, anaerobic organisms and spirochetes
  • Susceptible to inactivation by β-lactamases (penicillinases)

  
• Clinical use of Penicillin G


  • Non B-lactamase producing staphylococcus
  • Streptococcus and pneumococcus (pneumonia)
  • Neisseria meningitids (meningococcal meningitis)
  • Bacillus anthracis (anthrax)
  • Clostridium perfringens (gas gangrene)
  • Clostridium tetani (tetanus)
  • Corynebacterium diphtheriae (diphtheria)
  • Treponema pallidum (syphilis)
  • Leptospira spp. (leptospirosis)
  • Actinomyces israelii (Actinomycosis)
  • Borrelia burgdorferi (Lyme disease)
  • Enterococcus faecalis (endocarditis, combined with aminoglycoside)
  • Gonorrhea (with probenecid)
  • Streptococcal infections prophylaxis in rheumatic heart disease

  
• Penicillin V (Phenoxymethylpenicillin)


  • Has a spectrum similar to that of penicillin G, but it is not used for treatment of severe infections because of its higher minimum bactericidal concentration (MBC)
  • More acid-stable than penicillin G, often employed orally in the treatment of infections

  
• Antistaphylococcal penicillins


  • Cloxacillin and other members use is restricted to the treatment of infections caused by penicillinase-producing staphylococci including MSSA
  • Methicillin is not used clinically except to identify resistant strains of S. aureus, MRSA is usually susceptible to vancomycin

  
• Extended-spectrum penicillins


  • Ampicillin
  • Amoxicillin
• Amoxicillin


  Structural analogue of ampicillin but better absorbed from GIT, better bioavailability, and less diarrhea
• Clinical use of extended-spectrum penicillins


  • Treatment of respiratory infections
  • Infections with susceptible G -ve bacilli (Proteus Mirabilis, Salmonella Typhi, Escherichia coli, Haemophilus influenzae)
  • Listeria monocytogenes (cause pneumonia in neonates)
  • Prophylaxis for patients with abnormal heart valves undergoing oral surgery
  • Eradication of Helicobacter Pylori
• Resistance to extended-spectrum penicillins is now a major clinical problem because of inactivation by β-lactamase

  
• Co-Amoxiclav (combination of amoxycillin + clavulanic acid)


  Clavulanic acid binds to β-lactamase enzymes and competitively protects amoxicillin from breakdown, extending the antimicrobial spectrum

  
• Antipseudomonal penicillins


  • Piperacillin
  • Ticarcillin
  • Formulation with clavulanic acid or tazobactam extends the antimicrobial spectrum
• The antibacterial effects of all the β-lactam antibiotics are synergistic with the aminoglycosides

  
• Penicillins and aminoglycosides should never be placed in the same infusion fluid, because on prolonged contact, the positively charged aminoglycosides form an inactive complex with the negatively charged penicillins

  
• Mechanisms of resistance to penicillins

  • β-Lactamase activity
  • Decreased permeability to the drug
  • Altered penicillin-binding proteins (PBPs)

  
• β-Lactamases


  • Family of enzymes that hydrolyze the cyclic amide bond of the β-lactam ring, resulting in loss of bactericidal activity
  • Can be constitutive or acquired by transfer of plasmids
  • Some β-lactam antibiotics are poor substrates for β-lactamases and resist cleavage

  
• Decreased permeability to the drug


  • Decreased penetration of the antibiotic through the outer cell membrane prevents the drug from reaching the target PBPs
  • The presence of an efflux pump can also reduce the intracellular drug concentration
• Altered PBPs


  Modified PBPs have a lower affinity for β-lactam antibiotics, may explain MRSA

  
• Pharmacokinetics


  • Penicillins can be given orally, i.m. or i.v.
  • Benzylpenicillin is destroyed by gastric acid, so it is not suitable for oral administration

  
• β-Lactamases


  Enzymes that cleave the β-lactam ring, which results in loss of bactericidal activity. They are the major cause of resistance to the penicillins.

  
• β-Lactamases


  • They are either constitutive or, more commonly, are acquired by the transfer of plasmids
  • Some of the β-lactam antibiotics are poor substrates for β-lactamases and resist cleavage, thus retaining their activity against β-lactamase producing organisms

  
• G +ve organisms


  Secrete β-lactamases extracellularly

  
• G -ve bacteria


  Confine the β-lactamase enzymes in the periplasmic space between the inner and outer membranes

  
• Decreased permeability to the drug


  Decreased penetration of the antibiotic through the outer cell membrane prevents the drug from reaching the target PBPs. The presence of an efflux pump can also reduce the amount of intracellular drug.
• Altered PBPs


  Modified PBPs have a lower affinity for β-lactam antibiotics. This mechanism may explain MRSA.

  
• Administration of penicillins


  Penicillins can be given orally, i.m. or i.v. Benzylpenicillin is destroyed by gastric acid and usually given i.v. or i.m., while Phenoxymethylpenicillin is given orally. Intrathecal administration of benzylpenicillin can cause convulsion

  
• Absorption of penicillins


  Most of the penicillins are incompletely absorbed after oral administration, and they reach the intestine in sufficient amounts to affect the composition of the intestinal flora. However, amoxicillin is almost completely absorbed. Consequently, it is not appropriate therapy for the treatment of shigella- or salmonella derived enteritis, because therapeutically effective levels do not reach the organisms in the intestinal crypts.

  
• Distribution of penicillins


  Penicillins are widely distributed in body fluids (joints, pleural and pericardial cavities, bile, saliva, milk) they cross placenta but not BBB, unless the meninges are inflamed.

  
• Elimination of penicillins


  Elimination is rapid and mainly renal (90% through tubular secretion)

  
• Adverse reactions to penicillins


  • Hypersensitivity
  • Diarrhea
  • Nephritis
  • Neurotoxicity
  • Hematologic toxicities
• Hypersensitivity to penicillins


  The major antigenic determinant is its metabolite, penicilloic acid, which reacts with proteins and serves as a hapten to cause an immune reaction. Approximately 5% of patients have some kind of reaction, ranging from maculopapular rash to angioedema and anaphylaxis. Cross-allergic reactions occur among the β-lactam antibiotics.
• Cephalosporins


  β-lactam antibiotics closely related both structurally and functionally to the penicillins. They are produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid.

  
• Cephalosporins vs penicillins


  They have the same mode of action as penicillins, and they are affected by the same resistance mechanisms. However, they are more resistant than the penicillins to β-lactamases.

  
• Generations of cephalosporins


  • First generation
  • Second generation
  • Third generation
  • Fourth generation
  • Advanced generation