PENICILLIN DERIVATIVES

Overview

• Heavily used
• Excellent drugs
• Relatively safe

Classes of Penicillins

• Natural penicillins
• Aminopenicillins
• Penicillinase-resistant penicillins (Antistaphylococcal Penicillins)
• Extended spectrum penicillins (Antipseudomonal Penicilllins)
• Beta-lactamase Inhibitors

Natural penicillins

• Members
• Penicillin G (same as Benzylpenicillin) -- Parenteral
• Penicillin V (same as Phenoxymethylpenicillin) -- Oral
• Spectrum
• gram-positive organisms
• gram-positive anaerobes (NOT Bacteroides fragilis )
• Spirochetes
• Penicillin V not for serious infections -- Use Pen-G IM or IV

Aminopenicillins

• Members
• Ampicillin
• Amoxicillin
• Hetacillin
• Dose forms
• Parenteral (IV/IM)
• PO
• ampicillin -- F = 35-50%
• amoxicillin -- F = 70-90%
• Spectrum
• relatively broad -- G+ & G-
• Not good B. fragilis
• beta-lactamase sensitive
• often with clavulanic acid

Beta-lactamase resistant penicillins (Antistaphylococcal penicillins)

• Members
• Methicillin (prototype)
• Cloxacillin
• Dicloxacillin
• Nafcillin
• Oxacillin
• Dose forms
• All have PO dose forms
• Some IV/IM
• Some intramammary
• Spectrum
• Primarily for beta-lactamase producing staphyloccal infections
• Other drugs generally perferred otherwise

Extended spectrum penicillins (Antipseudomonal penicillins)

• Members
• Azlocillin
• Carbenicillin
• Mezlocillin
• Piperacillin
• Ticarcillin
• Dose forms
• IV/IM
• indanyl form of carbenicillin - PO
• Spectrum
• Includes Pseudomonas aeruginosa and other problem gram negative bacteria
• Other penicillins better for typical gram positive organisms
• Beta-lactamase sensitive

Beta-lactamase inhibitors

• Members
• clavulanic acid
• sulbactam
• Action vs model infection in mice
• (Figure -- Staphylococcus aureus infection )
• Pen G -- no protection
• Clavulanic acid -- no protection
• Only combination protected
• Irreversible inhibitors
• Both inhibit many, but not all beta-lactamases

Pharmacokinetics

Absorption

• PO dose forms
• Penicillin V
• Ampicillin
• Amoxicillin
• Indanyl carbenicillin
• Others destroyed by HCl or poorly absorbed
• Do not use for serious infections
• IV dose forms
• Most
• Must be water soluble
• IM dose forms to circumvent short half-life
• Ampicillin -- sodium -- trihydrate (earlier lecture)
• Penicillin G
• Figure -- IM injections of following: Plasma concentration / time profiles
• Sodium / Potassium salts -- highly water soluble -- 4-6h
• Procaine salt -- poorly water soluble -- 12-24h
• Benzathine salt -- very poorly soluble -- 5d +
• What kinds of plasma levels produced???

Distribution

• Protein binding - hi only with dicloxacillin & relatives (97%)
• Good
• Most extracellular sites
• bone
• Poor
• eye
• cells
• mammary gland
• CNS
• BUT -- inflammation / high dose
• Probenecid -- increases
  (not used therapeutically in VM)

• ---

  Effect of probenecid on serum and CSF penicillin G concentrations. Rabbits were given an injection of aqueous crystalline penicillin G (100,000 U/Kg, i.m.) with or without simultaneous probenecid (25 mg/Kg, i.m.,). Open symbols are controls. Closed symbols are in the presence of probenecid. Squares represent CSF and circles represent serum penicillin G concentration. Tight & White, Antimicrob Agents Chemother 17:229, 1980.

  ---

Elimination

• Half-life
• SHORT -- 0.4 to 1.5 h
• Impaired renal function
• Ampicillin: Normal 1 to 1.3h --> Impaired 10-15 h
• Pen-G: Normal 0.5 to 0.7h --> Impaired 2.5 to 10h
• Route
• Bile -- some high enough to be therapeutic, e.g., ampicillin
• Biotransformation not significant factor
• Renal -- 80-90%
• Glomerular filtration -- minor
• Carrier mediated transport -- major
• Probenecid competition
• Potential for dose-dependent kinetics

Adverse Effects

• Major categories
• Biological
• ampicillin
• Toxic
• Seizures if on brain
• Potassium salt -- hyperkalemia
• Massive doses -- if poor renal function
• Rapid injection -- asystole
• Allergy
• Anaphylactic shock -- kills 300 humans/year
• Allergy in humans 1% (0.05 may have anaphylaxis)
• 10% have history but most not react to skin test or penicillin use
• Incidence increases in viral infections
• Infectious mononucleosis -- 90% !!!
• Cross sensitivity among beta-lactams
• Major and minor determinants and skin tests

Study Questions

1. What is the potential importance of clavulanic acid in penicillin therapy?
2. Is it proper to use penicillin G topically? Why not?
3. What is the difference in indications and routes for the various salt forms (e.g., sodium, potassium, procaine, benzathine, trihydrate as appropriate for each drug) of penicillin G and ampicillin? Think about maximum achievable plasma concentrations and reasons for needing to vary absorption rates.
4. You should know the major family groups of the penicillins? What is the relative importance of each? How do the new derivatives, e.g. those in the antipseudomonas group, compare to the classical penicillin G with respect to activity on sensitive gram positive organisms?
5. What is the importance of noting whether a derivative of a drug is acid resistant? Name two acid resistant penicillins, one each from the natural penicillins and one from the aminopenicillins.
6. You should know that methicillin is the classical anti-staphylococcal pencillin derivative. Yet staphylococci can become resistant to it. What is the basis of this resistance and what does it predict for the potential effectiveness of other beta-lactam antimicrobials against the resistant organism?
7. Do penicillins distribute widely throughout the body, i.e. achieve therapeutic concentrations? Into cells?
8. What is the basis of the use of probenecid to increase the concentration of penicillin (and, presumably certain other beta-lactams) in the CSF? Would you expect probenecid to have the same effect on cephalosporins if biotransformation were not a factor?
9. What is the major route of excretion of the penicillins? Why was probenecid used in conjunction with penicillin in earlier days? This is an example of the kind of mechanism pharmacologists love to talk about.
10. What is the only significant adverse reaction to penicillin per se? Why is the specificity (selectivity) of the penicillins so high? Note that penicillins applied directly to the brain can cause seizures, but this is not a typical use.
11. What effect might the rapid iv injection of massive doses of potassium penicillin have on cardiac function. Note that 200,000 units of penicillin G potassium (1.6 units/ug, MW = 372), a modest dose for a 10 kg dog or child, contains 0.34 mEq of potassium. Verify this with your own calculation. At this dose, the potassium is not important unless there is renal failure, but consider a 10 to 20 fold increase in dose as may be used in some cases. Also, consider the effect of a rapid iv injection when a very high concentration of potassium may reach the heart. After im or slow iv administration the cardiac effect of the potassium would probably be insignificant if renal function is adequate.