DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

microorganisms, including Clostridium spp., are highly sensitive.
Bacteroides fragilis is an exception, displaying resistance to penicillins
and cephalosporins by virtue of expressing a broad-spectrum
cephalosporinase. Some strains of Prevotella melaninogenicus also
have acquired this trait. Actinomyces israelii, Streptobacillus moniliformis,
Pasteurella multocida, and L. monocytogenes are inhibited by
penicillin G. Most species of Leptospira are moderately susceptible to
the drug. One of the most exquisitely sensitive microorganisms is
Treponema pallidum. Borrelia burgdorferi, the organism responsible
for Lyme disease, also is susceptible. None of the penicillins is effective
against amebae, plasmodia, rickettsiae, fungi, or viruses.
Absorption
Oral Administration of Penicillin G. About one-third of an orally
administered dose of penicillin G is absorbed from the intestinal tract
under favorable conditions. Gastric juice at pH 2 rapidly destroys the
antibiotic. The decrease in gastric acid production with aging
accounts for better absorption of penicillin G from the gastrointestinal
(GI) tract of older individuals. Absorption is rapid, and maximal
concentrations in blood are attained in 30-60 minutes. The peak value
is ~0.5 unit/mL (0.3 μg/mL) after an oral dose of 400,000 units
(~250 mg) in an adult. Ingestion of food may interfere with enteric
absorption of all penicillins, perhaps by adsorption of the antibiotic
onto food particles. Thus, oral penicillin G should be administered at
least 30 minutes before a meal or 2 hours after. Despite the convenience
of oral administration of penicillin G, this route should be used
only in infections in which clinical experience has proven its efficacy.
Oral Administration of Penicillin V. The virtue of penicillin V in comparison
with penicillin G is that it is more stable in an acidic medium
and therefore is better absorbed from the GI tract. On an equivalent
oral-dose basis, penicillin V (K + salt) yields plasma concentrations
two to five times greater than those provided by penicillin G. The
peak concentration in the blood of an adult after an oral dose of
500 mg is nearly 3 μg/mL. Once absorbed, penicillin V is distributed
in the body and excreted by the kidney in a manner similar to
that of penicillin G.
Parenteral Administration of Penicillin G. After intramuscular injection,
peak concentrations in plasma are reached within 15-30 minutes. This
value declines rapidly because the t 1/2
of penicillin G is 30 minutes.
Many means for prolonging the sojourn of the antibiotic in
the body and thereby reducing the frequency of injections have been
explored. Probenecid blocks renal tubular secretion of penicillin, but
it is used rarely for this purpose. More commonly, repository preparations
of penicillin G are employed. The compound currently
favored is penicillin G benzathine (BICILLIN L-A, PERMAPEN), which
releases penicillin G slowly from the area in which it is injected and
produces relatively low but persistent concentrations of antibiotic in
the blood. Penicillin G benzathine suspension is the aqueous suspension
of the salt obtained by the combination of 1 mol of an
ammonium base and 2 mol of penicillin G to yield N,N′-dibenzylethylenediamine
dipenicillin G. The salt itself is only 0.02% soluble in
water. The long persistence of penicillin in the blood after a suitable
intramuscular dose reduces cost, need for repeated injections, and
local trauma. The local anesthetic effect of penicillin G benzathine
is comparable with that of penicillin G procaine.
Penicillin G benzathine is absorbed very slowly from intramuscular
depots and produces the longest duration of detectable
antibiotic of all the available repository penicillins. For example, in
adults, a dose of 1.2 million units given intramuscularly produces a
concentration in plasma of 0.09 μg/mL on the first, 0.02 μg/mL on
the fourteenth, and 0.002 μg/mL on the thirty-second day after injection.
The average duration of demonstrable antimicrobial activity in
the plasma is ~26 days. It is administered once monthly for rheumatic
fever prophylaxis and can be given in a single injection to treat
streptococcal pharyngitis.
Distribution. Penicillin G is distributed widely throughout the body,
but the concentrations in various fluids and tissues differ widely. Its
apparent volume of distribution is ~0.35 L/kg. Approximately 60%
of the penicillin G in plasma is reversibly bound to albumin.
Significant amounts appear in liver, bile, kidney, semen, joint fluid,
lymph, and intestine.
Although probenecid markedly decreases the tubular secretion
of the penicillins, this is not the only factor responsible for the
elevated plasma concentrations of the antibiotic that follow its
administration. Probenecid also produces a significant decrease in
the apparent volume of distribution of the penicillins.
Penetration into Cerebrospinal Fluid. Penicillin does not readily enter
the CSF when the meninges are normal. However, when the meninges
are acutely inflamed, penicillin penetrates into the CSF more easily.
Although the concentrations attained vary and are unpredictable, they
are usually in the range of 5% of the value in plasma and are therapeutically
effective against susceptible microorganisms.
Penicillin and other organic acids are secreted rapidly from
the CSF into the bloodstream by an active transport process.
Probenecid competitively inhibits this transport and thus elevates
the concentration of penicillin in CSF. In uremia, other organic acids
accumulate in the CSF and compete with penicillin for secretion;
the drug occasionally reaches toxic concentrations in the brain
and can produce convulsions.
Excretion. Under normal conditions, penicillin G is eliminated rapidly
from the body mainly by the kidney but in small part in the bile
and by other routes. Approximately 60-90% of an intramuscular dose
of penicillin G in aqueous solution is eliminated in the urine, largely
within the first hour after injection. The remainder is metabolized to
penicilloic acid. The t 1/2
for elimination of penicillin G is ~30 minutes
in normal adults. Approximately 10% of the drug is eliminated by
glomerular filtration and 90% by tubular secretion. Renal clearance
approximates the total renal plasma flow. The maximal tubular secretory
capacity for penicillin in the normal adult male is ~3 million
units (1.8 g) per hour.
Clearance values are considerably lower in neonates and
infants because of incomplete development of renal function; as a
result, after doses proportionate to surface area, the persistence of
penicillin in the blood is several times as long in premature infants
as in children and adults. The t 1/2
of the antibiotic in children <1 week
of age is 3 hours; by 14 days of age it is 1.4 hours. After renal function
is fully established in young children, the rate of renal excretion
of penicillin G is considerably more rapid than in adults.
Anuria increases the t 1/2
of penicillin G from a normal value of
0.5 hour to ~10 hours. When renal function is impaired, 7-10% of the
antibiotic may be inactivated each hour by the liver. Patients with renal
shutdown who require high-dose therapy with penicillin can be treated
adequately with 3 million units of aqueous penicillin G followed by
1483
CHAPTER 53
PENICILLINS, CEPHALOSPORINS, AND OTHER β-LACTAM ANTIBIOTICS