Page 850 - Basic _ Clinical Pharmacology ( PDFDrive )

836 SECTION VIII Chemotherapeutic Drugs

C. Topical Agents and sulfamethoxazole is often bactericidal, compared with the
Sodium sulfacetamide ophthalmic solution or ointment is effec- bacteriostatic activity of a sulfonamide alone.
tive in the treatment of bacterial conjunctivitis and as adjunctive NH OCH
therapy for trachoma. Another sulfonamide, mafenide acetate, is N 2 3
used topically but can be absorbed from burn sites. The drug and
its primary metabolite inhibit carbonic anhydrase and can cause H 2 N CH 2 OCH 3
metabolic acidosis, a side effect that limits its usefulness. Silver N
sulfadiazine is a less toxic topical sulfonamide and is preferred to OCH 3
mafenide for prevention of infection of burn wounds. Trimethoprim

Adverse Reactions NH 2

Historically, drugs containing a sulfonamide moiety, including N
antimicrobial sulfas, diuretics, diazoxide, and the sulfonylurea hypo- H N CI
2
glycemic agents, were considered to be cross-allergenic. However, N
more recent evidence suggests cross-reactivity is uncommon and H
many patients who are allergic to nonantibiotic sulfonamides toler- C 2 5
ate sulfonamide antibiotics. The most common adverse effects are Pyrimethamine
fever, skin rashes, exfoliative dermatitis, photosensitivity, urticaria, Resistance
nausea, vomiting, diarrhea, and difficulties referable to the urinary
tract (see below). Stevens-Johnson syndrome, although relatively Resistance to trimethoprim can result from reduced cell perme-
uncommon (<1% of treatment courses), is a particularly serious ability, overproduction of dihydrofolate reductase, or production
and potentially fatal type of skin and mucous membrane eruption of an altered reductase with reduced drug binding. Resistance
associated with sulfonamide use. Other unwanted effects include can emerge by mutation, although more commonly it is due to
stomatitis, conjunctivitis, arthritis, hematopoietic disturbances (see plasmid-encoded trimethoprim-resistant dihydrofolate reductases.
below), hepatitis, and, rarely, polyarteritis nodosa and psychosis. These resistant enzymes may be coded within transposons on con-
jugative plasmids that exhibit a broad host range, accounting for
A. Urinary Tract Disturbances rapid and widespread dissemination of trimethoprim resistance
Sulfonamides may precipitate in urine, especially at neutral or acid among numerous bacterial species.
pH, producing crystalluria, hematuria, or even obstruction. This is
rarely a problem with the more soluble sulfonamides (eg, sulfisoxa- Pharmacokinetics
zole). Sulfadiazine and sulfamethoxazole are relatively insoluble in Trimethoprim is usually given orally, alone or in combination with
acidic urine and can cause crystalluria, particularly when given in sulfamethoxazole, which has a similar half-life. Trimethoprim-
large doses or if fluid intake is poor. Crystalluria is treated by admin- sulfamethoxazole can also be given intravenously. Trimethoprim is
istration of sodium bicarbonate to alkalinize the urine and fluids well absorbed from the gut and distributed widely in body fluids
to increase urine flow. Sulfonamides have also been implicated in and tissues, including cerebrospinal fluid.
various types of nephrosis and in allergic nephritis. Because trimethoprim is more lipid-soluble than sulfamethoxa-
zole, it has a larger volume of distribution than the latter drug.
B. Hematopoietic Disturbances Therefore, when 1 part of trimethoprim is given with 5 parts of
Sulfonamides can cause hemolytic or aplastic anemia, granulocy- sulfamethoxazole (the ratio in the formulation), the peak plasma con-
topenia, thrombocytopenia, or leukemoid reactions. Sulfonamides centrations are in the ratio of 1:20, which is optimal for the combined
may provoke hemolytic reactions in patients with glucose- effects of these drugs in vitro. About 30–50% of the sulfonamide and
6-phosphate dehydrogenase deficiency. Sulfonamides taken near 50–60% of the trimethoprim (or their respective metabolites) are
the end of pregnancy increase the risk of kernicterus in newborns. excreted in the urine within 24 hours. The dose should be reduced by
half for patients with creatinine clearances of 15–30 mL/min.
Trimethoprim (a weak base) concentrates in prostatic fluid and
TRIMETHOPRIM & TRIMETHOPRIM- in vaginal fluid, which are more acidic than plasma. Therefore, it
SULFAMETHOXAZOLE MIXTURES has more antibacterial activity in prostatic and vaginal fluids than
many other antimicrobial drugs.
Mechanism of Action
Trimethoprim, a trimethoxybenzylpyrimidine, selectively inhib- Clinical Uses
its bacterial dihydrofolic acid reductase, which converts dihy- A. Oral Trimethoprim
drofolic acid to tetrahydrofolic acid, a step leading to the Trimethoprim can be given alone (100 mg twice daily) in acute
synthesis of purines and ultimately to DNA (Figure 46–2). urinary tract infections. Many community-acquired organisms are
Trimethoprim is a much less efficient inhibitor of mammalian susceptible to the high concentrations that are found in the urine
dihydrofolic acid reductase. The combination of trimethoprim (200–600 mcg/mL).