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

Antimicrobial Activity. Enzymes capable of reducing nitrofurantoin
appear to be crucial for its activation. Highly reactive intermediates
are formed, and these seem to be responsible for the observed capacity
of the drug to damage DNA. Bacteria reduce nitrofurantoin more
rapidly than do mammalian cells, and this is thought to account for
the selective antimicrobial activity of the compound. Bacteria that
are susceptible to the drug rarely become resistant during therapy.
Nitrofurantoin is active against many strains of E. coli and enterococci.
However, most species of Proteus and Pseudomonas and
many species of Enterobacter and Klebsiella are resistant.
Nitrofurantoin is bacteriostatic for most susceptible microorganisms
at concentrations of ≤32 μg/mL or less and is bactericidal at concentrations
of ≥100 μg/mL. The antibacterial activity is higher in an
acidic urine.
Pharmacology and Toxicity. Nitrofurantoin is absorbed rapidly and
completely from the GI tract. The macrocrystalline form of the drug
is absorbed and excreted more slowly. Antibacterial concentrations
are not achieved in plasma following ingestion of recommended
doses because the drug is eliminated rapidly. The plasma t 1/2
is
0.3-1 hour; ~40% is excreted unchanged into the urine. The average
dose of nitrofurantoin yields a concentration in urine of ~200
μg/mL. This concentration is soluble at pH >5, but the urine should
not be alkalinized because this reduces antimicrobial activity. The
rate of excretion is linearly related to the creatinine clearance, so in
patients with impaired glomerular function, the efficacy of the drug
may be decreased and the systemic toxicity increased. Nitrofurantoin
colors the urine brown.
The most common untoward effects are nausea, vomiting,
and diarrhea; the macrocrystalline preparation is better tolerated than
traditional formulations. Various hypersensitivity reactions occur
occasionally. These include chills, fever, leukopenia, granulocytopenia,
hemolytic anemia (associated with G6PD deficiency), cholestatic
jaundice, and hepatocellular damage. Chronic active hepatitis is
an uncommon but serious side effect. Acute pneumonitis with fever,
chills, cough, dyspnea, chest pain, pulmonary infiltration, and
eosinophilia may occur within hours to days of the initiation of therapy;
these symptoms usually resolve quickly after discontinuation
of the drug. More insidious subacute reactions also may be noted,
and interstitial pulmonary fibrosis can occur in patients taking the
drug chronically. This appears to be due to generation of oxygen radicals
as a result of redox cycling of the drug in the lung. Elderly
patients are especially susceptible to the pulmonary toxicity of nitrofurantoin.
Megaloblastic anemia is rare. Various neurological disorders
are observed occasionally. Headache, vertigo, drowsiness,
muscular aches, and nystagmus are readily reversible, but severe
polyneuropathies with demyelination and degeneration of both sensory
and motor nerves have been reported; signs of denervation and
muscle atrophy result. Neuropathies are most likely to occur in
patients with impaired renal function and in persons on long-continued
treatment.
The oral dosage of nitrofurantoin for adults is 50-100 mg four
times a day with meals and at bedtime, less for the macrocrystalline
formulation (100 mg every 12 hours for 7 days). Alternatively, the
daily dosage is better expressed as 5-7 mg/kg in four divided doses
(not to exceed 400 mg). A single 50-100-mg dose at bedtime may
be sufficient to prevent recurrences. The daily dose for children is
5 to 7 mg/kg but may be as low as 1 mg/kg for long-term therapy. A
course of therapy should not exceed 14 days, and repeated courses
should be separated by rest periods. Pregnant women, individuals
with impaired renal function (creatinine clearance <40 mL/minute),
and children <1 month of age should not receive nitrofurantoin.
Nitrofurantoin is approved only for the treatment of urinary
tract infections caused by microorganisms known to be
susceptible to the drug. Currently, bacterial resistance to nitrofurantoin
is more frequent than resistance to fluoroquinolones or
trimethoprim-sulfamethoxazole, making nitrofurantoin a secondline
agent for treatment of urinary tract infections (Fihn, 2003).
Nitrofurantoin is not recommended for treatment of pyelonephritis
or prostatitis.
Phenazopyridine. Phenazopyridine hydrochloride
(PYRIDIUM, others) is not a urinary antiseptic. However,
it does have an analgesic action on the urinary tract and
alleviates symptoms of dysuria, frequency, burning, and
urgency.
The usual dose is 200 mg three times daily. The compound is
an azo dye, which colors urine orange or red; the patient should be
so informed. GI upset is seen in up to 10% of patients and can be
reduced by administering the drug with food; overdosage may result
in methemoglobinemia. Phenazopyridine has been marketed since
1925 and has had dual prescription/over-the-counter (OTC) marketing
status since 1951. As part of their ongoing review of OTC drug
products, the Food and Drug Administration (FDA) is currently in
the process of evaluating products containing <200 mg phenazopyridine
to determine whether these products generally are recognized
as safe and effective as urinary analgesics. The outcome of this evaluation
will determine the continued availability of OTC phenazopyridine
products in the U.S. Products containing 200 mg
phenazopyridine are sold by prescription, but their long-term availability
in the marketplace also may be affected by the FDA’s final
OTC ruling. Phenazopyridine is no longer available in Canada.
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CHAPTER 52
SULFONAMIDES, TRIMETHOPRIM-SULFAMETHOXAZOLE, QUINOLONES, AND AGENTS FOR URINARY TRACT INFECTIONS