Cell Wall Synthesis Inhibitors: 1

Penicillins

Chemistry: Penicillin contains a thiazolidine ring, a Beta-lactam ring, and a side chain. Amidase splits penicillin at the side chain linkage; the side chain is required for antibacterial activity. Penicillinase opens the beta-lactam ring to produce penicilloic acid.

Shortcomings of penicillin G:

1. Short half life (acid labile; weak acid that is both secreted and filtered; probenecid given to decrease secretion; procaine, a PABA derivative, added to delay absorption)

2. Acid instability (penicillin V contains an oxygen atom in the side chain that decreases acid lability);

3. Penicillin-resistant staphylococci (methicillin, oxacillin, cloxacillin, and naficillin are penicillinase-resistant)

4. Narrow spectrum (ampicillin and carbenicillin are broad spectrum).

Degradation products of penicillin: Penicillamine, a cysteine derivative, is a chelating agent used in the treatment of Wilson’s disease, as well as for removing mercury and lead from the body. Penicilloic acid serves as a hapten for antigens.

General toxicities: High therapeutic index; GI distress; neurological problems; hematuria; hemolytic anemia; carbenicillin is administered as a sodium salt, while penicillin G is administered as a potassium salt (caution in patients with electrolyte problems, cardiovascular, or renal disease).

Hypersensitivity reactions: 10-15%; can be immediate, accelerated, or delayed; often results from previous hidden exposure. Skin testing using the antigenic determinant, a penicilloyl derivative of lysine, is useful, but not 100% accurate.

Narrow spectrum penicillins: Penicillin G

Indications: G(+) organisms.

Pharmacokinetics: Approximately 3-5 times more penicillin G must be administered orally than parenterally. To assure maximum and prompt absorption, oral penicillin should be prescribed one hour before or two hours after a meal. Penicillin G poorly penetrates the BBB unless the meninges are inflamed. Excretion is via the kidneys and is blocked by probenecid.

Penicillinase-resistant penicillins: Methicillin, oxacillin, nafcillin, cloxacillin

Indications: G(+) penicillinase-producing organisms (S. aureus).

Pharmacokinetics: Excreted by kidneys; does not penetrate BBB well; methicillin deteriorates rapidly in solution; methicillin has high incidence of nephrotoxicity.

Resistance: Plasmid-mediated.

Broad spectrum penicillins: Ampicillin

Indications: DOC for L. monocytogenes; additional G(+) and G(-) coverage; NOT ACTIVE AGAINST PSEUDOMONAS OR KLEBSIELLA.

Pharmacokinetics: Renal and biliary excretion; high incidence of rash; GI disturbances are common.

Broad spectrum penicillins: Amoxicillin – better absorbed from the gut than ampicillin.

Broad spectrum penicillins: Carbenicillin

Indications: P. aeruginosa, Proteus, E. coli, Enterobacter. NOT ACTIVE AGAINST KLEBSIELLA. Less active than penicillin G against G(+).

Pharmacokinetics: Extra carboxylic acid  caution about salt content when used in large quantities.

Broad spectrum penicillins: Ticarcillin – 2-4 times more active against P. aeruginosa.

Broad spectrum penicillins: Azlocillin – 10 times more effective against P. aeruginosa.

Broad spectrum penicillins: Mezlocillin & Piperacillin – ACTIVE AGAINST KLEBSIELLA AND PSEUDOMONAS.

Murein cell wall synthesis in G(+):

1. Formation of UDP-N-acetyl muramic acid;

2. Formation of UDP-N-acetyl-muramyl pentapeptide;

3. Formation of linear peptide-polysaccharide;

4. Cross linking.

Stages 1&2 occur in the cytoplasm, while stages 3&4 occur in the periplasmic space. Racemase (inhibited by cycloserine) converts L-alanine to D-alanine.

Penicillin MOA: beta-lactam drug attaches to the specific penicillin binding proteins on the bacteria; cell wall synthesis is inhibited by blocking transpeptidation; autolytic enzymes are activated in the cell wall resulting in lesions and bacterial cell death.

Category: Pharmacology Notes