Metronidazole
Encyclopedia
Metronidazole (icon) is a nitroimidazole
antibiotic
medication used particularly for anaerobic bacteria and protozoa
. Metronidazole is an antibiotic, amebicide, and antiprotozoal.
It is the drug of choice for first episodes of mild-to-moderate Clostridium difficile
infection.
It is marketed by Pfizer
under the trade name Flagyl in the US, by Sanofi-Aventis
globally under the same tradename Flagyl, in Pakistan and Bangladesh it is also available with the brand name of Nidagyl manufactured and marketed by Star Laboratories. In Thailand it is marketed as Mepagyl by Thai Nakhorn Patana. They are also marketed in UK by Milpharm Limited and Almus Pharmaceuticals. Metronidazole was developed in 1960.
Metronidazole is used also as a gel preparation in the treatment of the dermatological
conditions such as rosacea
(Rozex and MetroGel by Galderma
) and fungating
tumours (Anabact, Cambridge Healthcare Supplies).
, amongst other risk factors including the presence of cervicovaginal fetal fibronectin (fFN). A randomised controlled trial demonstrated that metronidazole was ineffective in preventing preterm delivery in high-risk pregnant women and, conversely, the incidence of preterm delivery was actually higher in women treated with metronidazole.
In a study it has been found that metronidazole is not the right antibiotic to administer in these circumstances and that it was often administered too late to be of use. Clindamycin
administered early in the second trimester to women who test positive for bacterial vaginosis
seemed to be more effective.
in dogs, cats, and other companion animals, although it does not reliably clear infection with this organism and is being supplanted by fenbendazole for this purpose in dogs and cats. Metronidazole or simply "Metro" is used in the aquarium hobby to treat ornamental fish as a wide spectrum treatment for bacterial and protozoan infections. It is also used to treat human enteric (gi) and systemic infections. The U.S. Food and Drug Administration
(FDA) prohibits the use of metronidazole in food animals.
s (≥1% of patients) associated with systemic
metronidazole therapy include: nausea
, diarrhea
, and/or metallic taste in the mouth. Intravenous administration is commonly associated with thrombophlebitis
. Infrequent adverse effects include: hypersensitivity
reactions (rash, itch, flushing, fever), headache, dizziness, vomiting
, glossitis
, stomatitis
, dark urine, and/or paraesthesia.
High doses and/or long-term systemic treatment with metronidazole is associated with the development of
leukopenia
, neutropenia
, increased risk of peripheral neuropathy
and/or CNS
toxicity.
Metronidazole is listed by the US National Toxicology Program
(NTP) as reasonably anticipated to be a human carcinogen
. , oral exposure has been shown to cause cancer in experimental animals. The relationship between exposure to metronidazole and human cancer is unclear. One study (Beard et al. 1988) found an excess in lung cancer among women (even after adjusting for smoking), while other studies (IARC 1987; Thapa et al. 1998) found either no increased risk, or a statistically insignificant
risk.
It appears to have a fairly low potential for cancer risk and under most circumstances the benefits of treatment outweigh the risk. Metronidazole is listed as a possible carcinogen according to the WHO
International Agency for Research on Cancer
(IARC).
Due to its potential carcinogenic properties, metronidazole is banned in the EU and the USA for veterinary use in the feed of animals and is banned for use in any food animals in the USA.
In the USA, this type of restriction is covered under the Delaney clause
.
Earlier studies suggested a relation between metronidazole and various birth defects. Those studies are now considered flawed and more recent studies "do not support a significant increased risk for birth defects or other adverse effects on the fetus."
Common adverse drug reactions associated with topical metronidazole therapy include local redness, dryness, and/or skin irritation; and eye watering (if applied near eyes).
and dentate nuclei. Metronidazole toxicity is rare (though the actual incidence is not known with certainty). Patients present with nausea, vomiting, dysarthria
, vertigo
, and confusion. Other side effects of the metronidazole can include dry mouth, diarrhea, headache, dizziness, or peripheral neuropathy
. An examination of a patient reveals that the patient is confused and has dysarthria
(difficult or unclear articulation of speech that is otherwise linguistically normal), ataxia
(loss of full control of bodily movements), abnormal eye movements including nystagmus
and ophthalmoparesis
. Magnetic resonance imaging (MRI) most often shows bilateral symmetric fluid-attenuated inversion recovery (FLAIR
) hyperintense lesions of the dentate nuclei (which is one of the deep cerebellar nuclei), as well as symmetric lesions of the corpus callosum
and basal ganglia
. The brain lesions seen on the MRI rarely enhance and may be Diffusion-Weighted Imaging (DWI
) hyperintense. It has a subacute to acute course. Most reports have been seen in patients who receive approximately one gram a day of metronidazole for over 30 days.
Metronidazole can rarely cause central nervous system toxicity; it does not seem to be a dose- or duration-related phenomenon. Most patients will have MRI abnormalities. Prognosis is excellent with metronidazole cessation.
(alcohol) while using metronidazole has long been thought to have a disulfiram
-like reaction with effects that can include nausea
, vomiting
, flushing
of the skin, tachycardia
(accelerated heart rate), and shortness of breath, however there are studies calling that notion into question.
Consumption of alcohol should be avoided by patients during systemic metronidazole therapy and for at least 48 hours after completion of treatment. However, the mechanism of this reaction in the clinical setting has recently been questioned by some authors,
and a possible central toxic serotonin reaction for the alcohol intolerance suggested.
.
is not fully understood. The complex drug interaction can happen after a couple days or take up to months. The exact mechanism is not known, a theory of serotonin dysfunction helps explain how the syndrome presents and how it is to be treated. Signs and symptoms are muscle rigidity, headache, elevated blood pressure, and changes in blood chemistry. The only direct treatment is to discontinue the offending drugs. Recently, there have been reported cases of SSRI/SNRI
antidepressant drugs and metronidazole induced serotonin syndrome
, this information is not included on the metronidazole patient information leaflet. SSRI and SNRI antidepressants include Prozac, Lexapro, Celexa, Zoloft, Effexor, Cymbalta, etc.
. Once taken up by anaerobes, it is non-enzymatically reduced by reacting with reduced ferredoxin
, which is generated by pyruvate oxido-reductase. Many of the reduced nitroso intermediates will form sulfinamides and thioether linkages with cystein bearing enzymes deactivating these critical enzymes. As many as 150 separate enzymes are affected.
In addition or alternatively, the metronidazole metabolites are taken up into bacterial DNA, and form unstable molecules. This function only occurs when metronidazole is partially reduced, and because this reduction usually happens only in anaerobic cells, it has relatively little effect upon human cells or aerobic bacteria.
, or from ethylenediamine and acetic acid
, followed by treatment with lime
, then Raney nickel
. 2-Methylimidazole nitrated to give 2-methyl-4(5)-nitroimidazole (2), which is in turn alkylated
with ethylene oxide
or 2-chloroethanol
to give metronidazole (3):
Nitroimidazole
4-Nitroimidazole is an imidazole derivative that contains a nitro group.Several derivatives of nitroimidazole constitute the class of nitroimidazole antibiotics that have been used to combat anaerobic bacterial and parasitic infections. Perhaps the most common example is metronidazole . Other...
antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
medication used particularly for anaerobic bacteria and protozoa
Protozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...
. Metronidazole is an antibiotic, amebicide, and antiprotozoal.
It is the drug of choice for first episodes of mild-to-moderate Clostridium difficile
Clostridium difficile
Clostridium difficile , also known as "CDF/cdf", or "C...
infection.
It is marketed by Pfizer
Pfizer
Pfizer, Inc. is an American multinational pharmaceutical corporation. The company is based in New York City, New York with its research headquarters in Groton, Connecticut, United States...
under the trade name Flagyl in the US, by Sanofi-Aventis
Sanofi-Aventis
Sanofi S.A. is a multinational pharmaceutical company headquartered in Paris, France, the world's fourth-largest by prescription sales. Sanofi engages in the research and development, manufacturing and marketing of pharmaceutical products for sale principally in the prescription market, but the...
globally under the same tradename Flagyl, in Pakistan and Bangladesh it is also available with the brand name of Nidagyl manufactured and marketed by Star Laboratories. In Thailand it is marketed as Mepagyl by Thai Nakhorn Patana. They are also marketed in UK by Milpharm Limited and Almus Pharmaceuticals. Metronidazole was developed in 1960.
Metronidazole is used also as a gel preparation in the treatment of the dermatological
Dermatology
Dermatology is the branch of medicine dealing with the skin and its diseases, a unique specialty with both medical and surgical aspects. A dermatologist takes care of diseases, in the widest sense, and some cosmetic problems of the skin, scalp, hair, and nails....
conditions such as rosacea
Rosacea
Rosacea is a chronic condition characterized by facial erythema . Pimples are sometimes included as part of the definition. Unless it affects the eyes, it is typically a harmless cosmetic condition...
(Rozex and MetroGel by Galderma
Galderma
Galderma is a global leading pharmaceutical company specializing in the research, development and marketing of innovative medical solutions in dermatology...
) and fungating
Neoplasia
Neoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia is the abnormal proliferation of cells. The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the...
tumours (Anabact, Cambridge Healthcare Supplies).
Bacterial
- Bacterial vaginosisBacterial vaginosisBacterial vaginosis or less commonly vaginal bacteriosis is a disease of the vagina caused by bacteria. The U.S. Centers for Disease Control and Prevention states it is not clear what role sexual activity plays in the development. However, it is known that BV is associated with having a new sex...
, commonly associated with overgrowth of GardnerellaGardnerellaGardnerella is a genus of gram-variable-staining facultative anaerobic bacteria of which G. vaginalis is the only species.Once classified as Haemophilus vaginalis and afterwards as Corynebacterium vaginalis, Gardnerella vaginalis grows as small, circular, convex, gray colonies on chocolate agar; it...
species and coinfective anaerobes (Mobiluncus, Bacteroides), in symptomatic patients
- Pelvic inflammatory diseasePelvic inflammatory diseasePelvic inflammatory disease is a generic term for inflammation of the uterus, fallopian tubes, and/or ovaries as it progresses to scar formation with adhesions to nearby tissues and organs. This may lead to infections. PID is a vague term and can refer to viral, fungal, parasitic, though most...
in conjunction with other antibiotics such as ofloxacinOfloxacinOfloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class considered to be a second-generation fluoroquinolone. The original brand, Floxin, has been discontinued by the manufacturer in the United States on 18 June 2009, though generic equivalents continue to be...
, levofloxacinLevofloxacinLevofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class and is used to treat severe or life-threatening bacterial infections or bacterial infections that have failed to respond to other antibiotic classes. It is sold under various brand names, such as Levaquin and...
, or ceftriaxoneCeftriaxoneCeftriaxone is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. In most cases, it is considered to be equivalent to cefotaxime in terms of safety and efficacy...
- Anaerobic infectionAnaerobic infectionAnaerobic infections are caused by anaerobic bacteria. Anaerobic bacteria do not grow on solid media in room air ; facultative anaerobic bacteria can grow in the presence as well as in the absence of air. Microaerophilic bacteria do not grow at all aerobically or grow poorly, but grow better under...
s such as Bacteroides fragilis, sppBacteroidesBacteroides is a genus of Gram-negative, bacillus bacteria. Bacteroides species are non-endospore-forming, anaerobes, and may be either motile or non-motile, depending on the species. The DNA base composition is 40-48% GC. Unusual in bacterial organisms, Bacteroides membranes contain sphingolipids...
, Fusobacterium sppFusobacteriumFusobacterium is a genus of filamentous, anaerobic, Gram-negative bacteria, similar to Bacteroides.Fusobacterium contribute to several human diseases, including periodontal diseases, Lemierre's syndrome, and topical skin ulcers...
, Clostridium sppClostridiumClostridium is a genus of Gram-positive bacteria, belonging to the Firmicutes. They are obligate anaerobes capable of producing endospores. Individual cells are rod-shaped, which gives them their name, from the Greek kloster or spindle...
, Peptostreptococcus sppPeptostreptococcusPeptostreptococcus is a genus of anaerobic, Gram-positive, non-spore forming bacteria. The cells are small, spherical, and can occur in short chains, in pairs or individually. Peptostreptococcus are slow-growing bacteria with increasing resistance to antimicrobial drugs.The most frequently...
, Prevotella sppPrevotellaPrevotella is a genus of bacteria.Bacteroides melaninogenicus has recently been reclassified and split into Prevotella melaninogenica and Prevotella intermedia....
, or any other anaerobes in intra-abdominal abscess, peritonitisPeritonitisPeritonitis is an inflammation of the peritoneum, the serous membrane that lines part of the abdominal cavity and viscera. Peritonitis may be localised or generalised, and may result from infection or from a non-infectious process.-Abdominal pain and tenderness:The main manifestations of...
, diverticulitisDiverticulitisDiverticulitis is a common digestive disease particularly found in the large intestine. Diverticulitis develops from diverticulosis, which involves the formation of pouches on the outside of the colon...
, empyemaEmpyemaPleural empyema is an accumulation of pus in the pleural cavity. Most pleural empyemas arise from an infection within the lung , often associated with parapneumonic effusions. There are three stages: exudative, fibrinopurulent and organizing. In the exudative stage, the pus accumulates...
, pneumoniaPneumoniaPneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
, aspiration pneumoniaAspiration pneumoniaAspiration pneumonia is bronchopneumonia that develops due to the entrance of foreign materials into the bronchial tree, usually oral or gastric contents...
, lung abscessLung abscessLung abscess is necrosis of the pulmonary tissue and formation of cavities containing necrotic debris or fluid caused by microbial infection....
, diabetic foot ulcer, meningitis and brain abscessBrain abscessBrain abscess is an abscess caused by inflammation and collection of infected material, coming from local or remote infectious sources, within the brain tissue...
es, bone and joint infections, septicemia, endometritisEndometritisEndometritis refers to inflammation of the endometrium, the inner lining of the uterus. Pathologists have traditionally classified endometritis as either acute or chronic: acute endometritis is characterized by the presence of microabscesses or neutrophils within the endometrial glands, while...
, or endocarditisEndocarditisEndocarditis is an inflammation of the inner layer of the heart, the endocardium. It usually involves the heart valves . Other structures that may be involved include the interventricular septum, the chordae tendineae, the mural endocardium, or even on intracardiac devices...
- Pseudomembranous colitisPseudomembranous colitisPseudomembranous colitis, a cause of antibiotic-associated diarrhea , is an infection of the colon. It is often, but not always, caused by the bacterium Clostridium difficile. Because of this, the informal name C. difficile colitis is also commonly used. The illness is characterized by...
due to Clostridium difficileClostridium difficileClostridium difficile , also known as "CDF/cdf", or "C...
- Helicobacter pyloriHelicobacter pyloriHelicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
eradication therapy, as part of a multi-drug regimen in peptic ulcer disease
- Dental infection of bacterial origin, such as periapical abscess, periodontal abscess, acute pericoronitis of impacted or partially erupted teeth; often used in conjunction with AmoxicillinAmoxicillinAmoxicillin , formerly amoxycillin , and abbreviated amox, is a moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral...
Protozoal
- AmoebiasisAmoebiasisEntamebiasis is a term for the infection more commonly known as amoebiasis.It became the preferred term in MeSH in 1991, but the term amoebiasis is used by the World Health Organization and by those working in the field of amoebiasis research....
: Infections caused by Entamoeba histolyticaEntamoeba histolyticaEntamoeba histolytica is an anaerobic parasitic protozoan, part of the genus Entamoeba. Predominantly infecting humans and other primates, E. histolytica is estimated to infect about 50 million people worldwide...
.
- GiardiasisGiardiasisGiardiasis or beaver fever in humans is a diarrheal infection of the small intestine by a single-celled organism Giardia lamblia. Giardiasis occurs worldwide with a prevalence of 20–30% in developing countries. In the U.S., 20,000 cases are reported to the CDC annually, but the true annual...
: infection of the small intestine caused by the ingestion of infective cysts of protozoan Giardia lambliaGiardia lambliaGiardia lamblia is a flagellated protozoan parasite that colonizes and reproduces in the small intestine, causing giardiasis. The giardia parasite attaches to the epithelium by a ventral adhesive disc, and reproduces via binary fission...
.
- TrichomoniasisTrichomoniasisTrichomoniasis, sometimes referred to as "trich", is a common cause of vaginitis. It is a sexually transmitted disease, and is caused by the single-celled protozoan parasite Trichomonas vaginalis producing mechanical stress on host cells and then ingesting cell fragments after cell death...
: infection caused by Trichomonas vaginalisTrichomonas vaginalisTrichomonas vaginalis is an anaerobic, flagellated protozoan, a form of microorganism. The parasitic microorganism is the causative agent of trichomoniasis, and is the most common pathogenic protozoan infection of humans in industrialized countries. Infection rates between men and women are the...
, which is a common cause of vaginitisVaginitisVaginitis is an inflammation of the vagina. It can result in discharge, itching and pain, and is often associated with an irritation or infection of the vulva. It is usually due to infection. The three main kinds of vaginitis are bacterial vaginosis , vaginal candidiasis, and trichomoniasis. A...
and is the most frequently presenting new infection of the common sexually transmitted diseases.
Nonspecific
- Prophylaxis for those undergoing potentially contaminated colorectal surgery or appendectomies and may be combined with neomycinNeomycinNeomycin is an aminoglycoside antibiotic that is found in many topical medications such as creams, ointments, and eyedrops. The discovery of Neomycin dates back to 1949. It was discovered in the lab of Selman Waksman, who was later awarded the Nobel Prize in Physiology and medicine in 1951...
- Crohn's diseaseCrohn's diseaseCrohn's disease, also known as regional enteritis, is a type of inflammatory bowel disease that may affect any part of the gastrointestinal tract from mouth to anus, causing a wide variety of symptoms...
with colonic or perianal involvement (non-FDA approved) believed to be more effective in combination with ciprofloxacinCiprofloxacinCiprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
- Topical metronidazole is indicated for the treatment of rosaceaRosaceaRosacea is a chronic condition characterized by facial erythema . Pimples are sometimes included as part of the definition. Unless it affects the eyes, it is typically a harmless cosmetic condition...
, and in the treatment of malodorous fungatingNeoplasiaNeoplasm is an abnormal mass of tissue as a result of neoplasia. Neoplasia is the abnormal proliferation of cells. The growth of neoplastic cells exceeds and is not coordinated with that of the normal tissues around it. The growth persists in the same excessive manner even after cessation of the...
wounds.
Preterm births
Metronidazole has also been used in women to prevent preterm birth associated with bacterial vaginosisBacterial vaginosis
Bacterial vaginosis or less commonly vaginal bacteriosis is a disease of the vagina caused by bacteria. The U.S. Centers for Disease Control and Prevention states it is not clear what role sexual activity plays in the development. However, it is known that BV is associated with having a new sex...
, amongst other risk factors including the presence of cervicovaginal fetal fibronectin (fFN). A randomised controlled trial demonstrated that metronidazole was ineffective in preventing preterm delivery in high-risk pregnant women and, conversely, the incidence of preterm delivery was actually higher in women treated with metronidazole.
In a study it has been found that metronidazole is not the right antibiotic to administer in these circumstances and that it was often administered too late to be of use. Clindamycin
Clindamycin
Clindamycin rINN is a lincosamide antibiotic. It is usually used to treat infections with anaerobic bacteria but can also be used to treat some protozoal diseases, such as malaria...
administered early in the second trimester to women who test positive for bacterial vaginosis
Bacterial vaginosis
Bacterial vaginosis or less commonly vaginal bacteriosis is a disease of the vagina caused by bacteria. The U.S. Centers for Disease Control and Prevention states it is not clear what role sexual activity plays in the development. However, it is known that BV is associated with having a new sex...
seemed to be more effective.
Veterinary use
Metronidazole is not labeled for animal use but is widely used to treat infections of GiardiaGiardia
Giardia is a genus of anaerobic flagellated protozoan parasites of the phylum Metamonada in the supergroup "Excavata" that colonise and reproduce in the small intestines of several vertebrates, causing giardiasis, commonly known as Beaver fever...
in dogs, cats, and other companion animals, although it does not reliably clear infection with this organism and is being supplanted by fenbendazole for this purpose in dogs and cats. Metronidazole or simply "Metro" is used in the aquarium hobby to treat ornamental fish as a wide spectrum treatment for bacterial and protozoan infections. It is also used to treat human enteric (gi) and systemic infections. The U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) prohibits the use of metronidazole in food animals.
Adverse effects
Common adverse drug reactionAdverse drug reaction
An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...
s (≥1% of patients) associated with systemic
Systemic
Systemic refers to something that is spread throughout, system-wide, affecting a group or system such as a body, economy, market or society as a whole. Systemic may also refer to:-In medicine:...
metronidazole therapy include: nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
, and/or metallic taste in the mouth. Intravenous administration is commonly associated with thrombophlebitis
Thrombophlebitis
Thrombophlebitis is phlebitis related to a thrombus . When it occurs repeatedly in different locations, it is known as "Thrombophlebitis migrans" or "migrating thrombophlebitis".-Signs and symptoms:...
. Infrequent adverse effects include: hypersensitivity
Hypersensitivity
Hypersensitivity refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. These reactions may be damaging, uncomfortable, or occasionally fatal. Hypersensitivity reactions require a pre-sensitized state of the host. The four-group classification...
reactions (rash, itch, flushing, fever), headache, dizziness, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, glossitis
Glossitis
Glossitis is inflammation of the tongue. It causes the tongue to swell and change color. Finger-like projections on the surface of the tongue may be lost, causing the tongue to appear smooth....
, stomatitis
Stomatitis
Stomatitis is an inflammation of the mucous lining of any of the structures in the mouth, which may involve the cheeks, gums, tongue, lips, throat, and roof or floor of the mouth...
, dark urine, and/or paraesthesia.
High doses and/or long-term systemic treatment with metronidazole is associated with the development of
leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
, increased risk of peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
and/or CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
toxicity.
Metronidazole is listed by the US National Toxicology Program
National Toxicology Program
The National Toxicology Program is an inter-agency program run by the United States Department of Health and Human Services to coordinate, evaluate, and report on toxicology within public agencies....
(NTP) as reasonably anticipated to be a human carcinogen
Carcinogen
A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in causing cancer. This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes...
. , oral exposure has been shown to cause cancer in experimental animals. The relationship between exposure to metronidazole and human cancer is unclear. One study (Beard et al. 1988) found an excess in lung cancer among women (even after adjusting for smoking), while other studies (IARC 1987; Thapa et al. 1998) found either no increased risk, or a statistically insignificant
Statistical significance
In statistics, a result is called statistically significant if it is unlikely to have occurred by chance. The phrase test of significance was coined by Ronald Fisher....
risk.
It appears to have a fairly low potential for cancer risk and under most circumstances the benefits of treatment outweigh the risk. Metronidazole is listed as a possible carcinogen according to the WHO
Who
Who may refer to:* Who , an English-language pronoun* who , a Unix command* Who?, one of the Five Ws in journalism- Art and entertainment :* Who? , a 1958 novel by Algis Budrys...
International Agency for Research on Cancer
International Agency for Research on Cancer
The International Agency for Research on Cancer is an intergovernmental agency forming part of the World Health Organisation of the United Nations....
(IARC).
Due to its potential carcinogenic properties, metronidazole is banned in the EU and the USA for veterinary use in the feed of animals and is banned for use in any food animals in the USA.
In the USA, this type of restriction is covered under the Delaney clause
Delaney clause
The Delaney Clause is a 1958 amendment to the Food, Drugs, and Cosmetic Act of 1938, named after Congressman James Delaney of New York.It said:...
.
Earlier studies suggested a relation between metronidazole and various birth defects. Those studies are now considered flawed and more recent studies "do not support a significant increased risk for birth defects or other adverse effects on the fetus."
Common adverse drug reactions associated with topical metronidazole therapy include local redness, dryness, and/or skin irritation; and eye watering (if applied near eyes).
Metronidazole toxicity of the brain
Toxic levels of metronidazole can cause symmetrical lesions in the brain in the corpus callosumCorpus callosum
The corpus callosum , also known as the colossal commissure, is a wide, flat bundle of neural fibers beneath the cortex in the eutherian brain at the longitudinal fissure. It connects the left and right cerebral hemispheres and facilitates interhemispheric communication...
and dentate nuclei. Metronidazole toxicity is rare (though the actual incidence is not known with certainty). Patients present with nausea, vomiting, dysarthria
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
, vertigo
Vertigo
Vertigo is a form of dizziness.Vertigo may also refer to:* Vertigo , a 1958 film by Alfred Hitchcock**Vertigo , its soundtrack** Vertigo effect, or Dolly zoom, a special effect in film, named after the movie...
, and confusion. Other side effects of the metronidazole can include dry mouth, diarrhea, headache, dizziness, or peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
. An examination of a patient reveals that the patient is confused and has dysarthria
Dysarthria
Dysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
(difficult or unclear articulation of speech that is otherwise linguistically normal), ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
(loss of full control of bodily movements), abnormal eye movements including nystagmus
Nystagmus
Nystagmus is a condition of involuntary eye movement, acquired in infancy or later in life, that may result in reduced or limited vision.There are two key forms of Nystagmus: pathological and physiological, with variations within each type. Nystagmus may be caused by congenital disorders,...
and ophthalmoparesis
Ophthalmoparesis
Ophthalmoparesis or ophthalmoplegia refers to paralysis of one or more extraocular muscles which are responsible for eye movements. It is a physical finding in certain neurologic illnesses.-Classification:...
. Magnetic resonance imaging (MRI) most often shows bilateral symmetric fluid-attenuated inversion recovery (FLAIR
Flair
Flair can refer to:*Ric Flair , a professional wrestler*David Flair , his older son, also a professional wrestler*Reid Flair , his younger son, also a professional wrestler*The Flairs, an American doo-wop group in the 1950s...
) hyperintense lesions of the dentate nuclei (which is one of the deep cerebellar nuclei), as well as symmetric lesions of the corpus callosum
Corpus callosum
The corpus callosum , also known as the colossal commissure, is a wide, flat bundle of neural fibers beneath the cortex in the eutherian brain at the longitudinal fissure. It connects the left and right cerebral hemispheres and facilitates interhemispheric communication...
and basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
. The brain lesions seen on the MRI rarely enhance and may be Diffusion-Weighted Imaging (DWI
DWI
DWI is an acronym which means:* Driving while intoxicated, see Driving under the influence* Driving while impaired* Danish West Indies* Diffusion-weighted imaging, a technique used in magnetic resonance imaging* Drinking Water Inspectorate...
) hyperintense. It has a subacute to acute course. Most reports have been seen in patients who receive approximately one gram a day of metronidazole for over 30 days.
Metronidazole can rarely cause central nervous system toxicity; it does not seem to be a dose- or duration-related phenomenon. Most patients will have MRI abnormalities. Prognosis is excellent with metronidazole cessation.
Interaction with alcohol
Consuming ethanolEthanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
(alcohol) while using metronidazole has long been thought to have a disulfiram
Disulfiram
Disulfiram is a drug discovered in the 1920s and used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. Trade names for disulfiram in different countries are Antabuse and Antabus manufactured by Odyssey Pharmaceuticals...
-like reaction with effects that can include nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
of the skin, tachycardia
Tachycardia
Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
(accelerated heart rate), and shortness of breath, however there are studies calling that notion into question.
Consumption of alcohol should be avoided by patients during systemic metronidazole therapy and for at least 48 hours after completion of treatment. However, the mechanism of this reaction in the clinical setting has recently been questioned by some authors,
and a possible central toxic serotonin reaction for the alcohol intolerance suggested.
Stevens–Johnson syndrome with mebendazole
Metronidazole alone rarely causes Stevens–Johnson syndrome but is reported to occur at high rates when combined with mebendazoleMebendazole
Mebendazole or MBZ is a benzimidazole drug developed by Janssen Pharmaceutica and marketed as Vermox, Ovex, Antiox, and Pripsen...
.
Potentially fatal serotonin syndrome
It is important to note that serotonin syndromeSerotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
is not fully understood. The complex drug interaction can happen after a couple days or take up to months. The exact mechanism is not known, a theory of serotonin dysfunction helps explain how the syndrome presents and how it is to be treated. Signs and symptoms are muscle rigidity, headache, elevated blood pressure, and changes in blood chemistry. The only direct treatment is to discontinue the offending drugs. Recently, there have been reported cases of SSRI/SNRI
SNRI
SNRI may refer to:* Serotonin–norepinephrine reuptake inhibitor* Strategic Naval Research Institute...
antidepressant drugs and metronidazole induced serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...
, this information is not included on the metronidazole patient information leaflet. SSRI and SNRI antidepressants include Prozac, Lexapro, Celexa, Zoloft, Effexor, Cymbalta, etc.
Shape and color
Metronidazole is available with a prescription under the brand names Flagyl and Protostat. Other brand or generic formulations may also be available.Mechanism of action
Metronidazole, taken up by diffusion, is selectively absorbed by anaerobic bacteria and sensitive protozoaProtozoa
Protozoa are a diverse group of single-cells eukaryotic organisms, many of which are motile. Throughout history, protozoa have been defined as single-cell protists with animal-like behavior, e.g., movement...
. Once taken up by anaerobes, it is non-enzymatically reduced by reacting with reduced ferredoxin
Ferredoxin
Ferredoxins are iron-sulfur proteins that mediate electron transfer in a range of metabolic reactions. The term "ferredoxin" was coined by D.C. Wharton of the DuPont Co...
, which is generated by pyruvate oxido-reductase. Many of the reduced nitroso intermediates will form sulfinamides and thioether linkages with cystein bearing enzymes deactivating these critical enzymes. As many as 150 separate enzymes are affected.
In addition or alternatively, the metronidazole metabolites are taken up into bacterial DNA, and form unstable molecules. This function only occurs when metronidazole is partially reduced, and because this reduction usually happens only in anaerobic cells, it has relatively little effect upon human cells or aerobic bacteria.
Synthesis
2-Methylimidazole (1) may be prepared via the Debus-Radziszewski imidazole synthesisDebus-Radziszewski imidazole synthesis
The Debus-Radziszewski imidazole synthesis is an organic reaction describing the synthesis of an imidazole from a diketone, an aldehyde and ammonia...
, or from ethylenediamine and acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
, followed by treatment with lime
Calcium oxide
Calcium oxide , commonly known as quicklime or burnt lime, is a widely used chemical compound. It is a white, caustic, alkaline crystalline solid at room temperature....
, then Raney nickel
Raney nickel
Raney nickel is a solid catalyst composed of fine grains of a nickel-aluminium alloy, used in many industrial processes. It was developed in 1926 by American]] engineer Murray Raney as an alternative catalyst for the hydrogenation of vegetable oils in industrial processes...
. 2-Methylimidazole nitrated to give 2-methyl-4(5)-nitroimidazole (2), which is in turn alkylated
Alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion or a carbene . Alkylating agents are widely used in chemistry because the alkyl group is probably the most common group encountered in...
with ethylene oxide
Ethylene oxide
Ethylene oxide, also called oxirane, is the organic compound with the formula . It is a cyclic ether. This means that it is composed of two alkyl groups attached to an oxygen atom in a cyclic shape . This colorless flammable gas with a faintly sweet odor is the simplest epoxide, a three-membered...
or 2-chloroethanol
2-Chloroethanol
2-Chloroethanol is an organochlorine compound with the formula HOCH2CH2Cl. This colorless liquid has a pleasant ether-like odor. It is miscible with water...
to give metronidazole (3):