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

such a combination would yield synergistic antimicrobial
effects has been realized both in vitro and in vivo.
Acquired Bacterial Resistance to Sulfonamides.
Bacterial resistance to sulfonamides presumably originates
by random mutation and selection or by transfer
of resistance by plasmids (Chapter 48). Such resistance,
once it is maximally developed, usually is persistent
and irreversible, particularly when produced in vivo.
Acquired resistance to sulfonamide usually does not
involve cross-resistance to antimicrobial agents of other
classes. The in vivo acquisition of resistance has little or
no effect on either virulence or antigenic characteristics
of microorganisms.
Resistance to sulfonamide probably is the consequence of an
altered enzymatic constitution of the bacterial cell; the alteration may
be characterized by (1) a lower affinity of dihydropteroate synthase
for sulfonamides, (2) decreased bacterial permeability or active
efflux of the drug, (3) an alternative metabolic pathway for synthesis
of an essential metabolite, or (4) an increased production of an
essential metabolite or drug antagonist. For example, some resistant
staphylococci may synthesize 70 times as much PABA as do the susceptible
parent strains. Nevertheless, an increased production of
PABA is not a constant finding in sulfonamide-resistant bacteria,
and resistant mutants may possess enzymes for folate biosynthesis
that are less readily inhibited by sulfonamides. Plasmid-mediated
resistance is due to plasmid-encoded drug-resistant dihydropteroate
synthetase.
Absorption, Fate, and Excretion
Except for sulfonamides especially designed for their
local effects in the bowel (Chapter 47), this class of drugs
is absorbed rapidly from the GI tract. Approximately
70-100% of an oral dose is absorbed, and sulfonamide
can be found in the urine within 30 minutes of ingestion.
Peak plasma levels are achieved in 2-6 hours,
depending on the drug. The small intestine is the major
site of absorption, but some of the drug is absorbed from
the stomach. Absorption from other sites, such as the
vagina, respiratory tract, or abraded skin, is variable and
unreliable, but a sufficient amount may enter the body to
cause toxic reactions in susceptible persons or to produce
sensitization.
All sulfonamides are bound in varying degree to plasma proteins,
particularly to albumin. The extent to which this occurs is
determined by the hydrophobicity of a particular drug and its pK a
; at
physiological pH, drugs with a high pK a
exhibit a low degree of protein
binding, and vice versa.
Sulfonamides are distributed throughout all tissues of the
body. The diffusible fraction of sulfadiazine is distributed uniformly
throughout the total-body water, whereas sulfisoxazole is confined
largely to the extracellular space. The sulfonamides readily enter
pleural, peritoneal, synovial, ocular, and similar body fluids and may
reach concentrations therein that are 50-80% of the simultaneously
determined concentration in blood. Because the protein content of such
fluids usually is low, the drug is present in the unbound active form.
After systemic administration of adequate doses, sulfadiazine
and sulfisoxazole attain concentrations in cerebrospinal fluid that
may be effective in meningeal infections. At steady state, the concentration
ranges between 10% and 80% of that in the blood. However,
because of the emergence of sulfonamide-resistant microorganisms,
these drugs are used rarely for the treatment of meningitis.
Sulfonamides pass readily through the placenta and reach the
fetal circulation. The concentrations attained in the fetal tissues are
sufficient to cause both antibacterial and toxic effects.
The sulfonamides undergo metabolic alterations in vivo,
especially in the liver. The major metabolic derivative is the N4-
acetylated sulfonamide. Acetylation, which occurs to a different
extent with each agent, is disadvantageous because the resulting
products have no antibacterial activity and yet retain the toxic potential
of the parent substance.
Sulfonamides are eliminated from the body partly as the
unchanged drug and partly as metabolic products. The largest fraction
is excreted in the urine, and the t 1/2
of sulfonamides in the body
thus depends on renal function. In acid urine, the older sulfonamides
are insoluble and may precipitate, forming crystalline deposits that
can cause urinary obstruction. Small amounts are eliminated in the
feces, bile, milk, and other secretions.
Pharmacological Properties
of Individual Sulfonamides
The sulfonamides may be classified on the basis of the
rapidity with which they are absorbed and excreted
(Table 52–1):
• agents that are absorbed and excreted rapidly, such
as sulfisoxazole and sulfadiazine
• agents that are absorbed very poorly when administered
orally and hence are active in the bowel lumen,
such as sulfasalazine
• agents that are used mainly topically, such as sulfacetamide,
mafenide, and silver sulfadiazine
• long-acting sulfonamides, such as sulfadoxine, that
are absorbed rapidly but excreted slowly
Rapidly Absorbed and Eliminated Sulfonamides
Sulfisoxazole. Sulfisoxazole is a rapidly absorbed and excreted sulfonamide
with excellent antibacterial activity. Because its high solubility
eliminates much of the renal toxicity inherent in the use of older
sulfonamides, it has essentially replaced the less soluble agents.
Sulfisoxazole is bound extensively to plasma proteins.
Following an oral dose of 2-4 g, peak concentrations in plasma of
110-250 μg/mL are found in 2-4 hours. From 28-35% of sulfisoxazole
in the blood and ~30% in the urine is in the acetylated form.
The kidney excretes ~95% of a single dose in 24 hours.
Concentrations of the drug in urine thus greatly exceed those in
blood and may be bactericidal. The concentration in cerebrospinal
fluid averages about a third of that in the blood.
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CHAPTER 52
SULFONAMIDES, TRIMETHOPRIM-SULFAMETHOXAZOLE, QUINOLONES, AND AGENTS FOR URINARY TRACT INFECTIONS