Metronidazol Chemische Eigenschaften,Einsatz,Produktion Methoden
R-Sätze Betriebsanweisung:
R40:Verdacht auf krebserzeugende Wirkung.
R46:Kann vererbbare Schäden verursachen.
R45:Kann Krebs erzeugen.
S-Sätze Betriebsanweisung:
S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
S53:Exposition vermeiden - vor Gebrauch besondere Anweisungen einholen.
Beschreibung
Metronidazole is a nitroimidazole antibiotic first isolated in the
1950s. Many nitroimidazoles were being studied at the time,
as the class was found to have trichomonacidal properties.
Metronidazole was of particular interest due to its high activity
against Trichomonas vaginalis and Entamoeba histolytica both
in vitro and in vivo as well as clinical activity against many
anaerobic pathogens including Gram-positive and Gramnegative
bacteria and Giardia lamblia. Metronidazole is often
used clinically for intra-abdominal infections and is the firstline
treatment for Clostridium difficile–associated diarrhea.
Chemische Eigenschaften
Metronidazole is an odorless, white, yellow, or cream-colored crystalline solid. Darkens on exposure to light. Bitter, salty taste (do not test). Soluble in hot water, slightly soluble in ethanol, slightly soluble in water or chloroform, very slightly soluble in ether.
Verwenden
Metronidazole is the drug of choice for amebiases, vaginal trichomonasis and
trichlomonadic urethritis in men, lambliosis, amebic dysentery, and anaerobic infections
caused by microorganisms that are sensitive to the drug. Synonyms of this drug are flagyl,
protostat, trichopol, and vagimid.
Indications
Metronidazole (Flagyl, Metrogel) exerts activity against
most anaerobic bacteria and several protozoa.The drug
freely penetrates protozoal and bacterial cells but not
mammalian cells. Metronidazole can function as an
electron sink, and because it does so, its 5-nitro group is
reduced. The enzyme, pyruvate-ferredoxin oxidoreductase,
found only in anaerobic organisms, reduces
metronidazole and thereby activates the drug. Reduced
metronidazole disrupts replication and transcription
and inhibits DNA repair.
Definition
ChEBI: Metronidazole is a member of the class of imidazoles substituted at C-1, -2 and -5 with 2-hydroxyethyl, nitro and methyl groups respectively. It has activity against anaerobic bacteria and protozoa, and has a radiosensitising effect on hypoxic tumour cells. It may be given by mouth in tablets, or as the benzoate in an oral suspension. The hydrochloride salt can be used in intravenous infusions. Metronidazole is a prodrug and is selective for anaerobic bacteria due to their ability to intracellularly reduce the nitro group of metronidazole to give nitroso-containing intermediates. These can covalently bind to DNA, disrupting its helical structure, inducing DNA strand breaks and inhibiting bacterial nucleic acid synthesis, ultimately resulting in bacterial cell death. It has a role as an antitrichomonal drug, a prodrug, an antibacterial drug, an antimicrobial agent, an antiparasitic agent, a xenobiotic, an environmental contaminant, a radiosensitizing agent and an antiamoebic agent. It is a member of imidazoles, a C-nitro compound and a primary alcohol. It is a conjugate base of a metronidazole(1+).
Acquired resistance
Although resistance in Bacteroides spp. and T. vaginalis is well documented, it is uncommon. Resistance occurs more frequently in H. pylori and failure of treatment with triple drug regimens may be associated with resistance to the metronidazole component.
Allgemeine Beschreibung
White to pale-yellow crystalline powder with a slight odor. Bitter and saline taste. pH (saturated aqueous solution) about 6.5.
Air & Water Reaktionen
Insoluble in water.
Reaktivität anzeigen
Metronidazole darkens on exposure to light. Metronidazole is incompatible with strong oxidizing agents. .
Brandgefahr
Flash point data for Metronidazole are not available; however, Metronidazole is probably combustible.
Pharmazeutische Anwendungen
A 5-nitroimidazole available for oral administration or as a suppository; also formulated as the hydrochloride for intravenous use, and as the benzoate in an oral suspension and a dental gel. Aqueous solubility: 10 g/L at 20°C. Soluble in dilute acids. It is photolabile and preparations should be protected from light. Metronidazole hydrochloride has a low pH (0.5–2.0) when reconstituted, and reacts with aluminum in equipment, including needles, to produce a reddish-brown discoloration. It is incompatible with several agents and other drugs should not be added to intravenous solutions.
Kontakt-Allergie
Metronidazole is a nitro-6-imidazole compound with antiprotozoal and antibacterial properties. Topical exposure may induce allergic contact dermatitis. Sensitization is mainly observed with the treatment of rosacea and rarely occurs from handling of table.
Mechanism of action
Despite the availability of metronidazole since the late 1950s, the mechanism of action of the drug
is still unknown. It generally is agreed that metronidazole is a pro-drug and that anaerobic
organisms reduce the nitro group in metronidazole to a hydroxylamine, as shown in Figure 39.2,
during which a reactive derivative or reactive species are produced that cause destructive effects
on cell components (i.e., DNA, proteins, and membranes). Specifically, DoCampo has reported
that nitroaryl compounds (nitroimidazoles, metronidazole; nitrofurans, nifurtomox) are reduced to
nitro radical anions, which in turn react with oxygen to regenerate the nitroaryl and the superoxide
radical anion. Further reduction of superoxide radical anion leads to hydrogen peroxide
and homolytic cleavage of the latter leads to hydroxyl radical formation. Superoxide radical anion,
hydrogen peroxide, and hydroxyl radicals are referred to as reactive oxygen species (ROS) and
are the reactive substances that are implicated in damage to critical cellular components of the
parasite.
Pharmakologie
Absorption from the intestinal tract is usually good.
Food delays but does not reduce absorption.The drug is
distributed in body fluids and has a half-life of about 8
hours. High levels are found in plasma and cerebrospinal
fluid (CSF). Less than 20% binds to plasma
proteins. Metronidazole is metabolized by oxidation
and glucuronide formation in the liver and is primarily
excreted by the kidneys, although small amounts can be
found in saliva and breast milk. Dose reduction is generally
unnecessary in renal failure.
Clinical Use
Metronidazole is the most effective agent available for
the treatment of individuals with all forms of amebiasis,
with perhaps the exception of the person who is asymptomatic
but continues to excrete cysts. That situation
calls for an effective intraluminal amebicide, such as
diloxanide furoate, paromomycin sulfate, or diiodohydroxyquin.
Metronidazole is active against intestinal
and extraintestinal cysts and trophozoites.
Although quinacrine hydrochloride has been used
for the treatment of giardiasis, many physicians prefer
metronidazole. Furazolidone is an alternate choice.
Metronidazole is the drug of choice in Europe for
anaerobic bacterial infections; concern about possible
carcinogenicity has led to some caution in its use in the
United States.Recently it has been found to be effective
in treating D. medinensis (Guinea worm) infections and
Helicobacter pylori.
Nebenwirkungen
The most frequently observed adverse reactions to
metronidazole include nausea, vomiting, cramps, diarrhea,
and a metallic taste.The urine is often dark or redbrown.
Less frequently, unsteadiness, vertigo, ataxia,
paresthesias, peripheral neuropathy, encephalopathy,
and neutropenia have been reported. Since metronidazole
is a weak inhibitor of alcohol dehydrogenase, alcohol
ingestion should be avoided during treatment. A
psychotic reaction also may be produced. Metronidazole
interferes with the metabolism of warfarin and may potentiate
its anticoagulant activity. Phenobarbital and corticosteroids
lower metronidazole plasma levels by increasing
its metabolism, whereas cimetidine raises levels
by impairing metronidazole metabolism.The drug is not
recommended for use during pregnancy.
Sicherheitsprofil
Confirmed carcinogen
with experimental carcinogenic,
neoplastigenic, tumorigenic, and teratogenic
data. Moderately toxic by ingestion,
intraperitoneal, and subcutaneous routes.
Human systemic effects by ingestion:
paresthesia, nerve or sheath structural
changes, eye changes, tremors, fever,
jaundice and other liver changes, hearingacuity
changes, somnolence, and ataxia.
Experimental reproductive effects. Human
mutation data reported. When heated to
decomposition it emits toxic fumes of NOx.
mögliche Exposition
Metronidazole is an orally administered
drug for the treatment of infections due to entamoeba
histolytica; trichomonas vaginalis; giardia lamblia, and has
also been used for treating Vincent’s infection. It can be
used as a trichomonacide in veterinary medicine. One firm
has petitioned EPA to use metronidazole as a disinfectant
for cooling tower water.
Carcinogenicity
Metronidazole is reasonably anticipated to be a human carcinogenbased on sufficient evidence of carcinogenicity from studies in experimental animals.
Environmental Fate
Due to metronidazole’s use as a pesticide, it may have been
directly released into the environment. It lacks an adequate
chromophore for absorbing light and undergoing photolytic
degradation. In addition, in vitro assays demonstrated the
compound’s robust stability in the atmosphere or aqueous
environments. Metronidazole exhibited a soil half-life between
10 and 27 days.
Stoffwechsel
Metronidazole is available in a variety of dosage forms, including IV, oral, rectal, and vaginal
suppositories. The bioavailability of metronidazole is nearly 100% when administered orally but is
significantly less when administered via the rectal route (67–82%) or the vaginal route (19–56%).
The drug is not bound to plasma protein. Distribution of the drug is fairly uniform through out the
body, including mother's milk.
Liver metabolism of metronidazole leads to two major metabolites: hydroxylation of the 2-methyl
group to 2-hydroxymethylmetronidazole (HM), and oxidation to metronidazole acetic acid. Both
compounds possess biological activity. Additionally, HM is found in the urine as glucuronide and
sulfate conjugates. In addition, a small amount of metronidazole is oxidized to acetamide, a known
carcinogen in rats but not in humans.
Versand/Shipping
UN3249 Medicine, solid, toxic, n.o.s., Hazard
Class: 6.1; Labels: 6.1-Poisonous materials.
Inkompatibilitäten
Incompatible with oxidizers (chlorates,
nitrates, peroxides, permanganates, perchlorates, chlorine,
bromine, fluorine, etc.); contact may cause fires or explosions.
Keep away from alkaline materials, strong bases,
strong acids, oxoacids, epoxides.
Waste disposal
Dispose of contents and
container to an approved waste disposal plant. All federal,
state, and local environmental regulations must be observed.
It is inappropriate and possibly dangerous to the environment
to dispose of expired or waste drugs and pharmaceuticals by
flushing them down the toilet or discarding them to the trash.
Household quantities of expired or waste pharmaceuticals
may be mixed with wet cat litter or coffee grounds, doublebagged
in plastic, discard in trash. Larger quantities shall
carefully take into consideration applicable DEA, EPA, and
FDA regulations. If possible return the pharmaceutical to the
manufacturer for proper disposal being careful to properly
label and securely package the material. Alternatively, the
waste pharmaceutical shall be labeled, securely packaged,
and transported by a state licensed medical waste contractor
to dispose by burial in a licensed hazardous or toxic waste
landfill or incinerator.
Metronidazol Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
