Transcript pharmacology-lect-4-n-3-penicillin

Cell wall inhibitors
Dr. Naza M. Ali
12-12-2016
Lec 4
Cell wall
 The cell wall is a rigid outer layer, it completely surrounds
the cytoplasmic membrane, maintaining the shape of the cell
and preventing the cell lysis from high osmotic pressure.
 Cell wall is composed of a polymer called peptidoglycan that
consists of glycan units joined to each other by peptide crosslinks.
Cell Wall Inhibitors:
Inhibitors of cell wall synthesis require actively
Proliferating microorganisms mean they have little or
no effect on bacteria that are not growing and dividing.
I. Penicillins
 Penicillins are classified as beta-lactam drugs because
of their unique four-membered lactam ring.
 All have a thiazolidine ring (A) is attached to a betalactam ring (B) that carries a secondary amino group
RNH-
• Penicillin are among the most widely effective
antibiotics
• The least toxic drugs, but increased resistance has
limited their use.
• Members of this family differ from one another in
the R substituent attached to the 6-aminopenicillanic
acid residue
 The nature of this side chain affects
1.The antimicrobial spectrum,
2. Stability to stomach acid,
3. Susceptibility to bacterial degradative enzymes betalactamases.
B
A
Mechanism of action
Interfere with last step of bacterial cell wall synthesis,
they are bactericidal
1. Penicillin-binding proteins:
• Penicillins inactivate numerous proteins on the
bacterial cell membrane.
• These PBPs are bacterial enzymes involved in the
synthesis of the cell wall and in the maintenance of
the morphologic features of the bacterium.
• Exposure to these antibiotics can lead to
morphologic changes or lysis of susceptible bacteria.
2. Inhibit of transpeptidase:
• Some PBPs catalyze formation of the cross-linkages
between peptidoglycan chains.
• Penicillins inhibit this transpeptidase-catalyzed
reaction,
• thus hindering the formation of cross-links essential
for cell wall integrity.
• As a result of this blockade of cell wall synthesis.
3. Activation of autolytic enzyme:
•
The gram-positive cocci, produce degradative
enzymes (autolysins) that participate in the normal
remodeling of the bacterial cell wall.
Mechanism of resistance
1. Beta-Lactamase activity:
this family of enzymes hydrolyzes the cyclic amide bond
of the beta-lactam ring, which results in loss of
bactericidal activity.
2. Decreased permeability to the drug:
decreased penetration of the antibiotic through the
Outer cell membrane prevents the drug from reaching
the target PBPs.
3. Altered PBPs: modified PBPs have a lower affinity for
beta-lactam antibiotic.
Antibacterial spectrum
1. Natural penicillins:
are obtained from fermentations of the mold Penicillum
• Penicillin G (benzylpenicillin) is the cornerstone of
therapy for infections caused by a number of
gram-positive cocci , gram-negative cocci,
gram-positive bacilli, spirochetes and
anaerobic.
Penicillin G is susceptible to inactivation by lactamases
(penicillinases).
• Penicillin V has a spectrum similar to that of penicillin G
is more acid-stable than penicillin G.
2. Antistaphylococcal penicillins:
Methicillin
Nafcillin
Oxacillin
Dicloxacillin
 are penicillinase-resistant penicillins
3. Extended-spectrum penicillins: (semisynthetic)
 Ampicillin , Amoxicillin
 Inactivated by Penicillinase
 have an antibacterial spectrum similar to that of
penicillin G but are more effective against
gram-negative bacilli.
 Infections of E. coli,
 H. influnzae,
 P. mirabilis,
 S. typhi
 Ampicillin is the drug of choice for the grampositive bacillus Listeria monocytogenes.
 In the treatment of respiratory infections
 Amoxicillin used prophylactically by dentists for
patients with abnormal heart valves who are to
undergo extensive oral surgery.
4) Antipseudomonal penicillins
Carbenicillin
Ticarcillin
Piperacillin
• Are effective against P. aeruginosa
• because of its constitutive penicillinase
• Formulation with bete-lactamase inhibitors extends
antimicrobial spectrum of these antibiotics to include
penicillinase-producing organisms
have synergistic action when used with aminoglycoside.
• Must be administered IV or IM
Pharmacokinetics
Route of administration is determine
-by the stability of the drug to gastric acid
-by the severity of the infection
 Oral, I.M, I.V
 Depot forms: procaine penicillin G, benzathine
penicillin
Absorption
• They are polar molecules
• Absorption of most all penicillinase- resistant
penicillin is decreased by food.
• Should administered at least 1-2 before or after a
meal because gastric emptying time is lengthened,
and the drugs are destroyed in the acidic
environment.
Distribution:
 They distribute well
 All penicillin's cross placental barrier (not teratogenic)
 Penetration into certain sites ( bone or CSF) is
insufficient for therapy unless these sites are inflamed,
 Penicillin levels in the prostate are insufficient to be
effective against infections.
Enhanced penetration of penicillin into the
cerebral spinal fluid (CSF) during inflammation.
Excretion:
• By tubular secretion system and glomerular
filtration.
• Patients with impaired renal function must have
dosage regimens adjusted.
Adverse Reaction
• Hypersensitivity: due to its metabolite, penicilloic
acid, which reacts with proteins and serves as a
hapten to cause an immune reaction.
5% of patient have maculopapular rash with marked
swelling of lips, tongue & anaphylaxis
• Diarrhea: due to disruption of the normal balance of
intestinal microorganisms, is a common problem.
It occurs to a greater extent with those have extended
antimicrobial spectrum.
• Nephritis: methicillin cause nephrotoxicity.
• Neurotoxicity if injected intrathecally
• Hematologic toxicities
• Cation toxicity: penicillins are administered as
sodium or potassium salt.
Toxicities caused by large quantities of Na or K