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

microaerophilic bacteria such as Helicobacter and Campylobacter
spp. Metronidazole may facilitate extraction of adult guinea worms
in dracunculiasis even though it has no direct effect on the parasite
(Chapter 51).
Mechanism of Action and Resistance. Metronidazole is a prodrug;
it requires reductive activation of the nitro group by susceptible organisms.
Its selective toxicity toward anaerobic and microaerophilic
pathogens such as the amitochondriate protozoa T. vaginalis,
E. histolytica, and G. lamblia and various anaerobic bacteria derives
from their energy metabolism, which differs from that of aerobic cells
(Land and Johnson, 1997; Samuelson, 1999; Upcroft and Upcroft,
1999). These organisms, unlike their aerobic counterparts, contain
electron transport components such as ferredoxins, small Fe–S proteins
that have a sufficiently negative redox potential to donate electrons
to metronidazole. The single electron transfer forms a highly
reactive nitro radical anion that kills susceptible organisms by radical-mediated
mechanisms that target DNA and possibly other vital
biomolecules. Metronidazole is catalytically recycled; loss of the
active metabolite’s electron regenerates the parent compound.
Increasing levels of O 2
inhibit metronidazole-induced cytotoxicity
because O 2
competes with metronidazole for electrons generated by
energy metabolism. Thus, O 2
can both decrease reductive activation of
metronidazole and increase recycling of the activated drug. Anaerobic
or microaerophilic organisms susceptible to metronidazole derive
energy from the oxidative fermentation of ketoacids such as pyruvate.
Pyruvate decarboxylation, catalyzed by pyruvate:ferredoxin oxidoreductase
(PFOR), produces electrons that reduce ferredoxin, which, in
turn, catalytically donates its electrons to biological electron acceptors
or to metronidazole.
Clinical resistance to metronidazole is well documented for
T. vaginalis, G. lamblia, and a variety of anaerobic and
microaerophilic bacteria but has yet to be shown for E. histolytica.
Resistant strains of T. vaginalis derived from nonresponsive patients
have shown two major types of abnormalities when tested under aerobic
conditions. The first correlates with impaired oxygen-scavenging
capabilities, leading to higher local O 2
concentrations, decreased
activation of metronidazole, and futile recycling of the activated
drug. The second type is associated with lowered levels of PFOR
and ferredoxin, the latter owing to reduced transcription of the ferredoxin
gene. That PFOR and ferredoxin are not completely absent
may explain why infections with such strains usually respond to
higher doses of metronidazole or more prolonged therapy. Studies on
metronidazole-resistant isolates of G. intestinalis indicate that similar
mechanisms may be operating, with PFOR levels reduced 5-fold
compared with susceptible strains (Upcroft and Upcroft, 2001).
Metronidazole resistance has not been found in clinical isolates of E.
histolytica but has been induced in vitro by culturing trophozoites
in gradually increasing concentrations of the drug. Interestingly,
although some decrease in PFOR levels was reported, metronidazole
resistance was mediated primarily by increased expression of
superoxide dismutase and peroxiredoxin in amebic trophozoites
(Wassmann et al., 1999). Resistance of anaerobic bacteria to metronidazole
is being recognized increasingly and has important clinical
consequences. In the case of Bacteroides spp., metronidazole resistance
has been linked to a family of nitroimidazole (nim) resistance
genes, nimA, -B, -C, -D, -E, and -F, that can be encoded chromosomally
or episomally (Gal and Brazier, 2004). The exact mechanisms
underlying resistance are not known, but nim genes appear to encode
a nitroimidazole reductase capable of converting a 5-nitroimidazole
to a 5-aminoimidazole, thus stopping the formation of the
reactive nitroso group responsible for microbial killing.
Metronidazole has been used widely for the treatment of the
microaerophilic organism Helicobacter pylori, the major cause of
ulcer disease and gastritis worldwide. However, Helicobacter can
develop resistance to metronidazole rapidly. Multiple mechanisms
probably are operating, but there are data associating loss-of-function
mutations in an oxygen-independent NADPH nitroreductase
(rdxA gene) with resistance to metronidazole (Mendz and
Mégraud, 2002).
Absorption, Fate, and Excretion. The pharmacokinetic properties
of metronidazole and its two major metabolites have been investigated
intensively (Lamp et al., 1999). Preparations of metronidazole
are available for oral, intravenous, intravaginal, and topical administration.
The drug usually is absorbed completely and promptly after
oral intake, reaching concentrations in plasma of 8-13 μg/mL within
0.25-4 hours after a single 500-mg dose. (Mean effective concentrations
of the compound are ≤8 μg/mL for most susceptible protozoa
and bacteria.) A linear relationship between dose and plasma concentration
pertains for doses of 200-2000 mg. Repeated doses every
6-8 hours result in some accumulation of the drug; systemic clearance
exhibits dose dependence. The t 1/2
of metronidazole in plasma
is ~8 hours; its volume of distribution approximates total body water.
Less than 20% of the drug is bound to plasma proteins. With the
exception of the placenta, metronidazole penetrates well into body
tissues and fluids, including vaginal secretions, seminal fluid, saliva,
breast milk, and CSF.
After an oral dose, >75% of labeled metronidazole is eliminated
in the urine largely as metabolites; ~10% is recovered as
unchanged drug. The liver is the main site of metabolism, and this
accounts for >50% of the systemic clearance of metronidazole. The
two principal metabolites result from oxidation of side chains, a
hydroxy derivative and an acid. The hydroxy metabolite has a
longer t 1/2
(~12 hours) and has ~50% of the antitrichomonal activity
of metronidazole. Formation of glucuronides also is observed.
Small quantities of reduced metabolites, including ring-cleavage
products, are formed by the gut flora. The urine of some patients
may be reddish brown owing to the presence of unidentified pigments
derived from the drug. Oxidative metabolism of metronidazole
is induced by phenobarbital, prednisone, rifampin, and
possibly ethanol. Cimetidine appears to inhibit hepatic metabolism
of the drug.
Therapeutic Uses. The uses of metronidazole for anti-protozoal therapy
have been reviewed extensively (Freeman et al., 1997; Nash,
2001; Stanley, 2003). Metronidazole cures genital infections with T.
vaginalis in both females and males in >90% of cases. The preferred
treatment regimen is 2 g metronidazole as a single oral dose for both
males and females. Tinidazole, which has a longer t 1/2
than metronidazole,
is also used at a 2-g single dose and appears to provide
equivalent or better responses than metronidazole. For patients who
cannot tolerate a single 2-g dose of metronidazole (or 1 g twice daily
in the same day), an alternative regimen is a 250-mg dose given three
times daily or a 375-mg dose given twice daily for 7 days. When
repeated courses or higher doses of the drug are required for uncured
or recurrent infections, it is recommended that intervals of 4-6 weeks
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CHAPTER 50
CHEMOTHERAPY OF PROTOZOAL INFECTIONS