Lecture 5: Penicillins Flashcards
Cushman's Section
What is important to know about Gram (+) Bacteria Structure?
- Drugs penetrate easier
- Increased B-lactamases
- Thick cell wall
- One Membrane
- Bridge between L-Lys & D-Ala
What is important to know about Gram (-) Bacteria Structure?
- Excludes Drugs [Has Porins Tho]
- B-lactamases in Periplasmic Space
- Thin cell wall
- Two Membrane [Inner & Outer]
- Bridge between DAP
Explain how Transpeptidase cross-links peptidoglycaon strands together?
- Transpeptidase catalyzes peptidoglycan structure kicking off 1 D-Ala
- Another peptidoglycan amino group binds to the other peptidoglycan structure
- = Peptide-D-Ala-Gly-Gly-Peptide [Crosslinked]
What is the Mechanism of Action for the Penicillins?
- Penicillins act like the Peptidoglycan Structure “fooling” the transpeptidase to bind to it inactiving it [NO CROSS-LINKS]
Why do Penicillins display selective toxicity for bacteria and NOT the host?
- Bacteria contain D-Ala which is not found in host cells
- Host has L-Ala
What are some of the ways that are Resistance to B-Lactams?
- Decreased Uptake of Drug
- Mutation of PBPs
- Efflux Pumps [move drug out]
- B-Lactamases [they will break the B-Lactam ring = inactived]
What is the meachanism of allergenicity of Penicillins?
- B-lactam acts as Hapten [Pharmacophore of drug]
- Allerigies to 1 B-lactam = probably ALL [could try Cephalos or Carbas]
What is the mechanism of Penicillin Degradation under Acidic and Basic conditions?
- Ring breaks open??
In what way does lipophilicity of Penicillins affect serum protein binding?
- Increases ClogP = Increases lipophilicity
- More lipophilic side chains = more protein binding [decreases degradation]
- Reducing bioavailability
- Does not affect half-life
What are the Penicillin excretion mechanisms?
- Excreted renally and biliary [90% Tubular & 10% Glomarular]
- Half life longer in kidney disease
- Penicillins are anioinic [so is probenecid] so increased half life
Nafcilin = Billiary
What is the way that Penicillins are distributed in the Body?
- Basically everywhere except the CSF [if meningitis; use parenteral to enter CSF]
What is the way that Penicillins are synthesized?
- Made by acykation of 6-APA
From Left to Right; what is the Nomenclature of the B-lactam ring system?
- Penam
- Penem
- Carbapenem
- Caphem
- Monobactam
What are the characteristics of Penicillin G [Benzylpenicillin]?
Spectrum? B-lactamase Sens? Dosage? Toxicity? Precautions?
- Spectrum: Gram (+) with N. Gonorrhoeae & H. Influenzae [resistance is common]
- B-lactamase Sens: YES
- Dosage: Oral or Parenteral [most effective]
- Toxicity/Precautions: Allergic reaction –> use with cautions if so
What are the characteristics of Bicillin C-R [Bensylpenicillin Benzathine and Benzylpenicillin Procaine]?
Pharmacokinetics? Administration? Use?
- PK: Low solubility = slow release from IM [Depo]
- Administration: ONLY IM [IV = cardiac death & near nerve = neuro damage]
- Use: Mod - Severe URTi, Scarlet Fever, Skin/Soft Tissue infections…
What is the main difference between Penicillin V and Penicillin G?
Chemical Feature?
- PenV is more stable in acid; ether Oxygen decreasing nucleophilicity of the amide carbonyl side chain
What are the major B-lactamase Resistant Parenteral Penicillins?
Anti-staph?
- Methicillin
- Nafcillin
- Oxacillin
What are the major B-lactamase Resistant Oral Penicillins?
Anti-staph
- Oxacillin [D/C’d]
- Clozacillin [D/C’d]
- Dicloxacillin
What are the B-lactamase Sensitive Broad Spectrum Oral Penicillins?
Amino?
- Ampicillin
- Amoxicillin
What are the B-lactamase Broad Spectrum Parenteral Penicillins?
ureido?
- Azlocillin
- Mezlocillin
- Piperacillin
What is the way that Methicillin confers resistance to hydrolysis by B-lactamases?
- 2 Methoxyls ORTHO to the amide; stop nucleophilic attacks; increasing stablilty
What is the way, chemically, that Methicillin is so unstable to hydrolysis under acidic conditions?
- Electron donation toward the amide cabonyl oxygen by the o-methoxy group, making the amide conbonyl oxygen more nucleophilic
What is the antibiotic spectrum for Methicillin?
- NARROW
- Was used to treat S. Aureus BUT MRSA was formed becase of PBP mutation [PBP2A]
What is the characteristics of Nafcillin with respect to B-lactamase sensitivity and acid stability?
- B-lactamase Sens: NO
- Slightly more stable than methicallin in acid because of big ring [clinically identicial tho]
