Page 849 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 46 Sulfonamides, Trimethoprim, & Quinolones 835

synthase with low sulfonamide affinity is often encoded on a plas-
SO NH 2 COOH mid that is transmissible and can disseminate rapidly and widely.
2
Sulfonamide-resistant dihydropteroate synthase mutants also can
emerge under selective pressure.

Pharmacokinetics
NH 2 NH 2
Sulfonamides can be divided into three major groups: (1)
Sulfanilamide p-Aminobenzoic acid (PABA)
oral, absorbable; (2) oral, nonabsorbable; and (3) topical.
SO NH Oral absorbable sulfonamides are absorbed from the stomach
2
SO NH and small intestine and distributed widely to tissues and body
2
N N fluids (including the central nervous system and cerebrospinal
N
O CH 3 fluid), placenta, and fetus. Protein binding varies from 20%
to over 90%. Therapeutic concentrations are in the range of
NH 2 40–100 mcg/mL of blood. Blood levels generally peak 2–6 hours
NH
NH 2 2 after oral administration.
Sulfadiazine Sulfamethoxazole A portion of absorbed drug is acetylated or glucuronidated in
the liver. Sulfonamides and inactive metabolites are then excreted
in the urine, mainly by glomerular filtration. The dosage of
FIGURE 46–1 Structures of some sulfonamides and
p-aminobenzoic acid. sulfonamides must be reduced in patients with significant renal
failure.
synergistic activity because of sequential inhibition of folate Clinical Uses
synthesis (Figure 46–2).
Sulfonamides are infrequently used as single agents. Many
Resistance strains of formerly susceptible species, including meningococci,
pneumococci, streptococci, staphylococci, and gonococci, are
Some bacteria lack the enzymes required for folate synthesis from now resistant. The fixed-drug combination of trimethoprim-
PABA and, like mammals, depend on exogenous sources of folate; sulfamethoxazole is the drug of choice for infections such
therefore, they are not susceptible to sulfonamides. Sulfonamide as Pneumocystis jiroveci (formerly P carinii) pneumonia,
resistance may also occur as a result of mutations that (1) cause toxoplasmosis, and nocardiosis.
overproduction of PABA, (2) cause production of a folic acid-
synthesizing enzyme that has low affinity for sulfonamides, or A. Oral Absorbable Agents
(3) impair permeability to the sulfonamide. Dihydropteroate
Sulfamethoxazole is a commonly used absorbable agent; however,
in the USA, it is available only as the fixed-dosed combination
trimethoprim-sulfamethoxazole. Typical dosing and indications
are discussed below.
p-Aminobenzoic acid
Administration of sulfadiazine with pyrimethamine is first-
line therapy for treatment of acute toxoplasmosis. Using sulfa-
Sulfonamides
Dihydropteroate − (compete diazine plus pyrimethamine, a potent inhibitor of dihydrofolate
synthase
with PABA) reductase, is synergistic because these drugs block sequential steps
in the folate synthesis pathway (Figure 46–2). However, since
2015, there have been challenges with manufacturing, supply,
Dihydrofolic acid
and pricing of pyrimethamine in the USA. In some cases, clini-
cians have obtained a compounded product through specialty
Dihydrofolate − Trimethoprim pharmacies or prescribed alternate agents, such as trimethoprim-
reductase
sulfamethoxazole. Sulfadoxine is a long-acting sulfonamide that is
coformulated with pyrimethamine (Fansidar). This combination
is no longer commercially available in the USA but may be found
Tetrahydrofolic acid
in other parts of the world where it is used as a second-line treat-
ment for malaria (see Chapter 52).
Purines
B. Oral Nonabsorbable Agents
DNA Sulfasalazine (salicylazosulfapyridine) is widely used in ulcer-
ative colitis, enteritis, and other inflammatory bowel disease (see
FIGURE 46–2 Actions of sulfonamides and trimethoprim. Chapter 62).