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

1474 were also receiving theophylline or a nonsteroidal anti-inflammatory
drug. Ciprofloxacin and pefloxacin inhibit the metabolism of
theophylline, and toxicity from elevated concentrations of the
methylxanthine may occur (Schwartz et al., 1988). Nonsteroidal antiinflammatory
drugs may augment displacement of γ-aminobutyric acid
(GABA) from its receptors by the quinolones (Halliwell et al.,
1993). Rashes, including photosensitivity reactions, also can occur.
Achilles tendon rupture or tendinitis is a recognized adverse effect,
especially in those >60 years old, patients taking corticosteroids, and
in solid organ transplant recipients (Mandell, 2003). All these agents
can produce arthropathy in several species of immature animals.
Traditionally, the use of quinolones in children has been contraindicated
for this reason. However, children with cystic fibrosis given
ciprofloxacin, norfloxacin, and nalidixic acid have had few, and
reversible, joint symptoms (Burkhardt et al., 1997; Sabharwal &
Marchant, 2006). Therefore, in some cases the benefits may outweigh
the risks of quinolone therapy in children. Ciprofloxacin
should not be given to pregnant women.
Leukopenia, eosinophilia, and mild elevations in serum
transaminases occur rarely. QT c
interval (QT interval corrected for
heart rate) prolongation has been observed with sparfloxacin and to
a lesser extent with gatifloxacin and moxifloxacin. Quinolones probably
should be used only with caution in patients on class III (amiodarone)
and class IA (quinidine, procainamide) antiarrhythmics
(Chapter 29).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
ANTISEPTIC AND ANALGESIC AGENTS
FOR URINARY TRACT INFECTIONS
Urinary tract antiseptics are concentrated in the renal
tubules where they inhibit the growth of many species
of bacteria. These agents cannot be used to treat systemic
infections because effective concentrations are
not achieved in plasma with safe doses; however, they
can be administered orally to treat infections of the urinary
tract. Furthermore, effective antibacterial concentrations
reach the renal pelves and the bladder.
Treatment with such drugs can be thought of as local
therapy: Only in the kidney and bladder, with the rare
exceptions mentioned below, are adequate therapeutic
levels achieved (Hooper, 2005b).
Methenamine. Methenamine is a urinary tract antiseptic
and pro-drug that owes its activity to its capacity to
generate formaldehyde.
N
N
N
Chemistry. Methenamine is hexamethylenetetramine (hexamethylenamine).
The compound decomposes in water to generate formaldehyde,
according to the following reaction:
NH 4
(CH 2
) 6
+ 6H 2
O + 4H + → 4NH 4+
+ 6HCHO
At pH 7.4, almost no decomposition occurs; the yield of
formaldehyde is 6% of the theoretical amount at pH 6 and 20% at
pH 5. Thus, acidification of the urine promotes formaldehyde formation
and the formaldehyde-dependent antibacterial action. The
decomposition reaction is fairly slow, and 3 hours are required to
reach 90% completion.
Antimicrobial Activity. Nearly all bacteria are sensitive to free
formaldehyde at concentrations of ~20 μg/mL. Urea-splitting
microorganisms (e.g., Proteus spp.) tend to raise the pH of the urine
and thus inhibit the release of formaldehyde. Microorganisms do not
develop resistance to formaldehyde.
Pharmacology and Toxicology. Methenamine is absorbed orally, but
10-30% decomposes in the gastric juice unless the drug is protected
by an enteric coating. Because of the ammonia produced,
methenamine is contraindicated in hepatic insufficiency. Excretion
in the urine is nearly quantitative. When the urine pH is 6 and the
daily urine volume is 1000-1500 mL, a daily dose of 2 g will yield
a urine concentration of 18-60 μg/mL of formaldehyde; this is more
than the MIC for most urinary tract pathogens. Various poorly
metabolized acids can be used to acidify the urine. Low pH alone is
bacteriostatic, so acidification serves a double function. The acids
commonly used are mandelic acid and hippuric acid (UREX, HIPREX).
GI distress frequently is caused by doses >500 mg four times a
day, even with enteric-coated tablets. Painful and frequent micturition,
albuminuria, hematuria, and rashes may result from doses of 4 to
8 g/day given for longer than 3-4 weeks. Once the urine is sterile, a
high dose should be reduced. Because systemic methenamine has low
toxicity at the typically used doses, renal insufficiency does not constitute
a contraindication to the use of methenamine alone, but the acids
given concurrently may be detrimental; methenamine mandelate is contraindicated
in renal insufficiency. Crystalluria from the mandelate moiety
can occur. Methenamine combines with sulfamethizole and perhaps
other sulfonamides in the urine, which results in mutual antagonism;
therefore, these drugs should not be used in combination.
Therapeutic Uses and Status. Methenamine is not a primary drug for
the treatment of acute urinary tract infections, but it is of value for
chronic suppressive treatment (Fihn, 2003). The agent is most
useful when the causative organism is E. coli, but it usually can
suppress the common gram-negative offenders and often S. aureus
and S. epidermidis as well. Enterobacter aerogenes and Proteus vulgaris
are usually resistant. Urea-splitting bacteria (mostly Proteus)
make it difficult to control the urine pH. The physician should strive
to keep the pH <5.5.
Nitrofurantoin. Nitrofurantoin (FURADANTIN, MACROBID,
others) is a synthetic nitrofuran that is used for the prevention
and treatment of infections of the urinary tract.
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METHENAMINE
NITROFURANTOIN