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

1468 Aplastic Anemia. Complete suppression of bone marrow activity with
profound anemia, granulocytopenia, and thrombocytopenia is an
extremely rare occurrence with sulfonamide therapy. It probably
results from a direct myelotoxic effect and may be fatal. However,
reversible suppression of the bone marrow is quite common in
patients with limited bone marrow reserve (e.g., patients with AIDS
or those receiving myelosuppressive chemotherapy).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Hypersensitivity Reactions. The incidence of other hypersensitivity
reactions to sulfonamides is quite variable. Among the skin and
mucous membrane manifestations attributed to sensitization to sulfonamide
are morbilliform, scarlatinal, urticarial, erysipeloid, pemphigoid,
purpuric, and petechial rashes, as well as erythema
nodosum, erythema multiforme of the Stevens-Johnson type,
Behçet’s syndrome, exfoliative dermatitis, and photosensitivity.
These hypersensitivity reactions occur most often after the first week
of therapy but may appear earlier in previously sensitized individuals.
Fever, malaise, and pruritus frequently are present simultaneously.
The incidence of untoward dermal effects is ~2% with
sulfisoxazole, although patients with AIDS manifest a higher frequency
of rashes with sulfonamide treatment than do other individuals.
A syndrome similar to serum sickness may appear after several
days of sulfonamide therapy. Drug fever is a common untoward
manifestation of sulfonamide treatment; the incidence approximates
3% with sulfisoxazole.
Focal or diffuse necrosis of the liver owing to direct drug toxicity
or sensitization occurs in <0.1% of patients. Headache, nausea,
vomiting, fever, hepatomegaly, jaundice, and laboratory evidence of
hepatocellular dysfunction usually appear 3-5 days after sulfonamide
administration is started, and the syndrome may progress to acute
yellow atrophy and death.
Miscellaneous Reactions.Anorexia, nausea, and vomiting occur in 1-2%
of persons receiving sulfonamides, and these manifestations probably
are central in origin. The administration of sulfonamides to newborn
infants, especially if premature, may lead to the displacement of bilirubin
from plasma albumin. In newborn infants, free bilirubin can
become deposited in the basal ganglia and subthalamic nuclei of the
brain, causing an encephalopathy called kernicterus. Sulfonamides
should not be given to pregnant women near term because these drugs
pass through the placenta and are secreted in milk.
Drug Interactions. The most important interactions of the sulfonamides
involve those with the oral anticoagulants, the sulfonylurea
hypoglycemic agents, and the hydantoin anticonvulsants. In each
case, sulfonamides can potentiate the effects of the other drug by
mechanisms that appear to involve primarily inhibition of metabolism
and, possibly, displacement from albumin. Dosage adjustment
may be necessary when a sulfonamide is given concurrently.
TRIMETHOPRIM-SULFAMETHOXAZOLE
The introduction of trimethoprim in combination with
sulfamethoxazole constitutes an important advance in
the development of clinically effective antimicrobial
agents and represents the practical application of a
theoretical consideration; that is, if two drugs act on
sequential steps in the pathway of an obligate enzymatic
reaction in bacteria (Figure 52–2), the result of their
combination will be synergistic (Hitchings, 1961). In
much of the world the combination of trimethoprim
with sulfamethoxazole is known as cotrimoxazole. In
addition to its combination with sulfamethoxazole
(BACTRIM, SEPTRA, others), trimethoprim also is available
as a single-entity preparation.
Chemistry. Sulfamethoxazole was discussed earlier in this chapter,
and its structural formula is shown in Figure 52–1. Trimethoprim, a
diaminopyrimidine, inhibits bacterial dihydrofolate reductase. The
drug’s properties are reviewed in Chapter 49.
TRIMETHOPRIM
Antibacterial Spectrum. The antibacterial spectrum of trimethoprim
is similar to that of sulfamethoxazole, although the former drug
usually is 20-100 times more potent than the latter. Most gramnegative
and gram-positive microorganisms are sensitive to trimethoprim,
but resistance can develop when the drug is used alone.
Pseudomonas aeruginosa, Bacteroides fragilis, and enterococci usually
are resistant. There is significant variation in the susceptibility
of Enterobacteriaceae to trimethoprim in different geographic locations
because of the spread of resistance mediated by plasmids and
transposons (see Chapter 48).
Efficacy of Trimethoprim-Sulfamethoxazole in Combination.
Chlamydia diphtheriae and N. meningitidis are susceptible to
trimethoprim-sulfamethoxazole. Although most S. pneumoniae are
susceptible, there has been a disturbing increase in resistance. From
50-95% of strains of Staphylococcus aureus, Staphylococcus epidermidis,
S. pyogenes, the viridans group of streptococci, E. coli,
Proteus mirabilis, Proteus morganii, Proteus rettgeri, Enterobacter
spp., Salmonella, Shigella, Pseudomonas pseudomallei, Serratia,
and Alcaligenes spp. are inhibited. Also sensitive are Klebsiella spp.,
Brucella abortus, Pasteurella haemolytica, Yersinia pseudotuberculosis,
Yersinia enterocolitica, and Nocardia asteroides.
Mechanism of Action. The antimicrobial activity of the combination
of trimethoprim and sulfamethoxazole results from its actions on
two steps of the enzymatic pathway for the synthesis of tetrahydrofolic
acid. Sulfonamide inhibits the incorporation of PABA into folic
acid, and trimethoprim prevents the reduction of dihydrofolate to
tetrahydrofolate (Figure 52–2). Tetrahydrofolate is essential for onecarbon
transfer reactions (e.g., the synthesis of thymidylate from
deoxyuridylate). Selective toxicity for microorganisms is achieved in
two ways. Mammalian cells use preformed folates from the diet and
do not synthesize the compound. Furthermore, trimethoprim is a
highly selective inhibitor of dihydrofolate reductase of lower organisms:
~100,000 times more drug is required to inhibit human reductase
than the bacterial enzyme. This relative selectivity is vital
because this enzymatic function is essential to all species.