Research in Pharmacy and Health Sciences.2022,8(4):197-204. • https://doi.org/10.32463/RPHS.2022.v09i04.

02 e-ISSN: 2455-5258

REVIEW ARTICLE OPEN ACCESS

Metronidazole: An Overview of the Disease

Priya Sharma*, Jyoti Gupta
IEC School of Pharmacy, IEC University, Baddi, Himachal Pradesh, India
Received: 22 August, 2022 Abstract
Accepted: 12 October, 2022 Metronidazole is an antibiotic that is commonly used in various medical conditions,
including trichoniasis, amoebiasis and giardiasis. In 1950, Metronidazole was first used to
*Correspondence to: treat Trichomonas vaginalis infection, and novel clinical features were subsequently
identified. Metronidazole is currently used to treat Bacteroides, Fusibacterial and
Priya Sharma Clostridian infections, rosacea, oral and dental disorders, bone and joint infections,
gynecological illness, endocarditis, septicemia and inflammation of the respiratory tract.
Email: [email protected] This may also be used during surgical procedures to treat Crohn’s disease, or also as
prophylaxis. Metronidazole has been well tolerated with mild to severe side effects,
Copyright: © the author(s), including nausea, stomach pain and diarrhea. Nevertheless, in rare cases severe
publisher and licensee Indian
neurotoxicity, optic neuropathy, peripheral neuropathy and encephalopathy have been
Academy of Pharmacists. This is an
open-access article distributed recorded. Metronidazole has been known to be a cost-effective drug, regardless of its low
under the terms of the Creative quality, strong efficacy against pathogenic anaerobic bacteria, beneficial pharmacokinetic
Commons Attribution Non- & pharmacodynamic features, and mild adverse effects.
Commercial License, which
permits unrestricted non- KEY WORDS: metronidazole, adverse effects, clinical features, anaerobic bacteria, anti-
commercial use, distribution, and infective.
reproduction in any medium,
provided the original work is
properly cited.

Published by: OZZIE Publishers

Web: www.ozziepublishers.com

1. INTRODUCTION wastewater is widely used for the disposal of hazardous

organic compounds. The adsorption process moves only
Metronidazole is a type of nitroimidazole drug that is widely
contaminants from the water to the solid phase and does not
used to inhibit trichomonade and amoeba protozoa, with a
deteriorate completely[9]. For the diagnosis of Trichomonas
good anti-anaerobic action[1,2] However, the medications
vaginalis, Metronidazole has become the first drug to use. In
nitroimidazole and its derivatives can be potentially
combination with Metronidazole, IgE mediated and non-IgE
carcinogenic, mutagenic and genetic toxic to animals[3]. It is
mediated reactions, including SJS, TEN, serum disease and
a commonly used product owing to its tolerability, high oral
fixed-drug eruptions, were identified[20]. Biotechnology is a
bioavail¬ability, and ability to penetrate deep into tissues,
popular approach for the treatment of antibiotic waste water,
including the central nervous system. Metronidazole is an
but it typically takes some time[10], and it doesn't have a
imidazole used to treat antibacterial and antiprotozoal
strong removal effect. Flocking and centrifugation physical
infections such as bacterial vaginosis and related antibiotic
methods also cause secondary emissions. Oxidation is a very
colitis. Successful regulation of Metronidazole in
powerful procedure, but during the degradation cycle the
pharmaceutical products and the exclusion of Metronidazole
chemical produced may be more harmful[11]. Figure 1 shows
residues in foods and beverages are a primary focus of
the chemical structure of Metronidazole.
research interest[4-8]. Metronidazole can be treated in many
different ways such as activated carbon adsorption, acidic 1. METRONIDAZOLE
catalytic degradation, UV degradation, microscopic
degradation, etc. It is difficult to remove entirely, like IUPAC Name: 2-(2-Methyl-5-nitro-1H-imidazol-1-yl)
Metronidazole wastewater as an industrial wastewater ethanol
specializing in pharmaceutical products with complex Chemical Formula: C6H9N3O3
structure and restricted biodegradability. Adsorption of

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 Metronidazole involves four main steps which lead to the
– intracellular formation of essential redox intermediate
OH
O metabolites[18]. In the first two phases, the compound is
+ N passed into cells by means of passive diffusion, and an electron
N CH3 is passed to the Metronidazole nitro group, leading to a short
O life nitroso free radical, cytotoxic, which can interrelate with
N cellular DNA[19]. This activation process produces a
concentration gradient which increases the organism's
Figure 1. Chemical structure of Metronidazole increased intake of the drug, further enhancing its
antimicrobial activity. The third phase in the action of
Molecular Weight: 171.154 Metronidazole involves the cytotoxic effect of the reduced
Melting point: 160º C drug, as the active compound of Metronidazole can prevent
Predicted water solubility: 5.92 g / L synthesis of DNA and cause DNA damage by oxidation,
Description: Metronidazole is a derivative of nitroimidazole resulting in splits of single and double strand[19]. This causes
used to treat amoebiasis, vaginitis, giardiasis, trichomonas DNA degradation with Metronidazole and death of the cells.
infection. Finally, the inactive end products of the drug have been
Categories: Anti-Infective, Antiprotozoal agents and released[20].
Radiation-sensitizing
The microbial selectively of Metronidazole indicates that
Indication: It is effective in preventing bacterial and protozoal aerobic bacteria are unable to activate the medication because
infections. This drug was used to cure anaerobic infections and they lack sufficiently negative redox potential with the
prophylactically in colonic surgery[12,13] Entamoeba required electron transport proteins[19]. However, the redox
histolytica was often used successfully. In 2015 WHO was potential of the electron transport chain is sufficiently negative
added to the official list of pharmaceutical products. In the in susceptible anaerobic bacteria to reduce the nitro
process of diagnosis with anaerobic and combined diseases, Metronidazole group.
surgical anaerobic prophylaxis, Clostridium difficile-
In anaerobic bacteria, the drug is activated by receiving an
associated diarrhea and colitis, Helicobacter pylori infection
electron of ferredoxins or flavodoxins, which are depleted by
and duodenal ulcer disease, Bacterial vaginosis,
iron-sulphide proteins called pyruvate: ferredoxin
Giardialamblia gastro-enteritis, amoebiasis caused by
oxidoreductase (PFOR)[21]. Depending on the organism, a
Entamoeba histolytica, acne rosacea (topical treatment) and
certain donor of electron active in the reduction of
Trichomonas infections[14].
nitroimidazole. For example, a different mechanism for
HISTORY Metronidazole susceptibility, which requires a 2-electron
transfer step mediated by an oxygen- nitro reductases, occur in
In the 1950s, Metronidazole was first synthesized as an the micro aerophilous Helicobacter pylori. Many
effective antitrichomonal medication in the treatment of microaerophilic protists (Giardia lamblia, Entamoeba
vaginal trichomoniasis was investigated by pharmaceutical histolytica and T. vaginalis) have Metronidazole activated
firm Rhône-Poulenc. bacterium-like enzymes (nitro reductase)[22].
Initially, a crude extract was found to destroy Tricho- vaginalis SPECTRUM OF ACTIVITY
from Streptomyces bacterium and the active portion, which
was previously characterized by nitroimidazole antibiotic, has Metronidazole and associated nitroimidazoles are found in two
been known as azomycin. Metronidazole was a synthetic distinct anaerobic microbes, microaerophilic microbes and
azomycin derivative and was much more potent against T. protozoa. Resistance has been found more and more in certain
vaginalis and less toxic. The first 8823 R.P. was identified. species as discussed later, but it cannot be readily identified,
This result quickly led to successful use of trichomoniasis since the anaerobic susceptibility tests are not carried out
during human clinical trials[15]. systematically. However, the resistance emergence suggests
that current surveillance is important[19].
MECHANISM OF ACTION
Many gram negative anaerobes have a Metronidazole-
Metronidazole and other nitroimidazole (e.g., nimorazole, susceptiblity[23,24]. In general, members of the Bacteroides
Ornidazole, ronidazole, secindazole, tinidazole) are inactive and Parapacteroides genera are metronidazole susceptible with
and are determined by their ability to activate drugs as they are tolerance normally seen in less than 5% of isolate[25- 28]. In
actively diffused into the cell. Their bactericidal and parasite South Africa the Bacteroides Isolates have demonstrated
actions are fast and proportionate to the concentration in the higher resistance levels[29]. Desulfovibrio species, as is
target cell of the activated drugs[16]. The mechanism of action extremely susceptible[30]. Fusobacterium, Porphyromonas,
of Metronidazole defines the other nitroimidazoles. Figure 2 Prevotella, and genera Bilophila are typically susceptible to
shows the Mechanism of action of Metronidazole[17]. The clinical significance[23,31]. However, unsusceptible strains
nitroimidazoles have a heterocyclic form composed of a NO 2 of Prevotella were identified[23]. In oral isolates of
imidazole dependent nucleus. The mechanism of action of Porphyromonas gingivalis[32], metronidazole resistance has

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been recently identified. Reduced sensitivity was also susceptible to Metronidazole due to bacteria infected with
observed in Sutterella isolates and Veillonella gram- Vaginitis[34, 35].
coccus[24,33]. Mobiluncus bacteria are typically not

Ferredoxin (reduced) Metronidazole

Ferredoxin (oxidized)
Metabolites

Bacterium

DNA

DNA Fragmented

Figure 2. Mechanism of action of Metronidazole[17]

PHARMACOLOGY

Metronidazole is sold commercially in different ways, absorbed with recorded bioavailability of 59% to 94% when
including: oral capsules and tablets, (immediate and extended rectally administration; topical and vaginal Metronidazole
release); intravenous fluid, creams, lotions, topical gels and achieve systemic measurable concentrations with 2%to 25%
vaginal gels[16,36]. bioavailability[16,36,47]. Oral Metronidazole administration
in food is recommended to reduce the adverse effects of gastric
Although no commercial oral Metronidazole suspension is intestines and does not affect bioavailability but can delay the
available, it is frequently compounded in the pharmacy by the time to peak serum concentrations. Peak serum concentrations
crush of immediate releases tablets and by the combining of range from 12 to 40 μg/mL and occur 1 to 2 hours after oral
the aqueous suspension solution and buffered oral syrup at a administration and about 3 hours after rectal
ratio of 1:1[37]. Table 1 illustrate that the dosage and duration administration[16,36]. Table 2 shows that Metronidazole is a
of Metronidazole depends on the particular product and lipophilic molecule with low protein binding and moderate to
indication. The package insert suggests an IV loading dose of large distribution volume that allows widespread distribution
15 mg / kg, followed by 7.5 mg / kg every 6 to 8 hours, with a in different tissues[16,36]. It is excellent to penetrate into
maximum daily dose limit of 4 g[16]. The key substance is inflamed cerebrospinal fluid, epithelial lining fluid, saliva and
above normal Bacteroid MICs at the fixed dose of 500 mg IV bile and serum concentrations are identical[16,36,48].
every 8 hours and is effective in treating intra-abdominal Patients with non-inflamed meninges often reach therapeutic
infections[38-40]. It is generally recommended that the concentrations at around 43% of serum[49]. In addition, there
infusion time be 1 hour, but 20 to 30 minutes have been is very high penetration into abscesses, appendix tissue,
used.[41] Due to the long half-life, depending upon peritoneal fluid, and pancreatic tissue, varying from
concentration and high-dose Metronidazole administered as 1 2.3to7.2μg/mL[16,36,50]. However, the amount of drug
to 1.5 g every 24 hours can be a safe, effective alternative at detected in the bile is negligible for patients with obstructive
500 mg every 6 to 8 hours[42,43]. Depending on patient cholecystitis[16,36]. Metronidazole crosses the placental
condition and indication, the standard duration of oral or membrane and enters breast milk, which may be teratogenic in
intravenous Metronidazole courses vary from 1 to 10 days. the first trimester (see “Precautions”)[51]. Concentrations of
Longer durations can be prescribed but due to an increased risk stools during C. difficile colitis at the start of infection are
of peripheral neuropathy or adverse effects on the central highest and taper as inflammation subsides and stools are
nervous system, cautions should be taken for durations produced, but concentrations typically remain well above
exceeding 1 month[44-46]. recoreded MICs[52]. The effect of higher stool concentrations
Oral Metronidazole is absorbed rapidly and almost completely is also observed during Crohn’s disease outbreaks when
with 100% bioavailability[16,36]. Metronidazole is also well diarrhea is present[53].

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 Dosage
Product Strengths Indications Dose & Administration
form
Adults
Acute intestinal amebiasis: 750 mg
Symptomatic trichomoniasis tid for 5-10 days
Metronidazole Tablet
250 mg asymptomatic trichomoniasis, Amebic liver abscess: 500 or 750 mg
(Flagyl)
Tablet 500 mg treatment of asymptomatic consorts, tid for 5-10 days
amebiasis, anaerobic bacterial Anaerobic bacteria: 7.5 mg/kg every
infections, intra-abdominal infections, 6 hr for 7-10 days (may be longer)
skin and skin suture infections, Trichomoniasis:
gynecologic infections, bacterial 250 mg tid daily for 7 days
Metronidazole Capsule
Capsule 375 mg septicemia, bone and joint infections, 375 mg (capsule) bid for 7 days
(Flagyl)
CNS infections, lower respiratory tract 2 g single dose or 1 g bid for 1 day
infections, endocarditis Children:
35-50 mg/kg daily divided into 3 doses
for 10 days
Metronidazole extended-
Extended- 750 mg Bacterial vaginosis Adults:
release tablet (Flagyl
release tablet 750 mg once daily for 7 days
ER)
Adults:
Anaerobic infections:
Anaerobic infections, intra-abdominal Loading dose of 15 mg/kg IV over 1
infections, skin and skin structure hr
500mg/100
Metronidazole infections, gynecologic infections, Maintenance dose: 7.5 mg/kg IV over
Intravenous mL (0.74%
intravenous solution bacterial septicemia, bone and joint 1 hr every 6 hr. Usual duration 7-10
solution NaCl)
(Metro) infections, CNS infections, lower days.
5mg/mL
respiratory tract infections, Colorectal surgery prophylaxis:
(0.74% NaCl)
endocarditis, prophylaxis Initial: 15 mg/kg IV over 30-60 min
about 1 hr before surgery
Maintenance: 7.5 mg/kg IV over 20-60
min at 6 and 12 hr after initial dose
Adults:
Bacterial vaginosis: 1 applicatorful (≈5
Metronidazole gel
Vaginal gel 0.75% Bacterial vaginosis g containing metronidazole 37.5 mg)
(MetroGel Vaginal,
intravaginally once or or twice daily
Vandazole)
for 5 days. For once-a-day dosing,
administer at bedtime.
Adults:
Metronidazole cream
1% strength: apply a thin film once
(MetroCream), Cream 0.75% Rosacea
daily
Rosadan-0.75% 1.0%
0.75% strength: apply a thin film twice
Noritate-1.0%
daily
Adults:
Metronidazole gel 1% strength: apply a thin film once
Gel 0.75% Rosacea
(Metrogel-1.0%) daily
1.0%
(Rosadan-0.75%) 0.75% strength: apply a thin film
twice daily
Adults:
Metronidazole lotion Rosacea
Lotion 0.75% 0.75% strength: apply a thin film twice
(MetroLotion)
daily
Metronidazole Adults:
Metronidazole Kit Rosacea
Kit 0.75% cream 0.75% strength: apply a thin film twice
(Rosadan)
+ wash daily
Table 1. Major Preparations and Indications for Metronidazole: Administration and Dosage[16]

Pharmacologic/Pharmacokinetic
Result Comments
Factor
Absorption
Oral 98%-100%
Rectal 59%-94%
Vaginal cream 20%
Vaginal gel 56%
Topical 2%
Time to Peak
Oral 1-2 hrs
Rectal 3 hrs
Topical 8-12 hrs
Peak Serum Concentrations

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 Intravenous 25 and 18 μg/mL After 15 mg/kg load and 7.5 mg/kg every 6 hr
Oral 6, 12, 21.4, and 40 μg/mL After single dose of 250 mg, 500 mg, 750 mg, and 2000 mg
Rectal 18.5 μg/mL After 500-mg dose
Topical 27.5 μg/mL After application of 1% cream
Volume of Distribution
Adults
0.55 L/kg
Neonates
0.54-0.81 L/kg
Tissue and Fluid Penetration
CSF (inflamed meninges) Approximates serum concentration
CSF (noninflamed meninges) 45% of serum concentration
Bile Approximates serum concentration
Epithelial lining fluid Approximates serum concentration
Saliva Approximates serum concentration
Abscess Variable, but high concentration
Peritoneal fluid High concentrations: 7.2-14.2 μg/mL
Pancreatic tissue High concentration: 5.1-8.5 μg/mL
Metabolism
Oxidation Primary mechanism of elimination
Glucuronidation Secondary mechanism of elimination
Cytochrome P450 Secondary mechanism of elimination
Excretion
Unchanged drug 6%-18%
Metabolites 60%-80%
Haemodialysis Removes 25%-45% over 4 hr
Peritoneal dialysis Removes 10% over 7.5 hr
Protein binding <20%
Pregnancy Avoid in first trimester Category B
Lactation Avoid Significant penetration into breast milk
Table 2. Pharmacokinetic and Pharmacologic Properties of Metronidazole[16,36]

ADVERSE EFFECTS AND PRECAUTIONS conjunctivitis, edema, seizure, superficial skin abnormalities,
ADVERSE EFFECTS and peripheral neuropathy will discontinue treatment before
severe drug-related adverse effects are excluded[16,36].
Metronidazole is commonly well tolerated. Dose dependent,
mild and reversible are the most common adverse effects. In CLINICAL USES
2% to 10% of patients, nausea, diarrhea, dry throat, metallic PARASITIC INFECTIONS
taste, candidal vaginitis, and stomatitis occur[16,36]. Severe
adverse effects of central nervous system (ataxia, Metronidazole has been developed as an antitrichomonal agent
encephalopathy, dysarthria, epilepsy, aseptic meningitis, and for its use. The nitroimidazoles are the most effective
peripheral neuropathy) have been more frequently reported but pharmaceutical class for these diseases, in this regard,
are reversible during prolonged treatments[51,54]. Caution tinidazole appears to be similar or superior to
should be taken in patients with history of epilepsy when Metronidazole[55]. For the use in pregnant women with T.
administering Metronidazole. Certain moderate symptoms in vaginalis infections, Metronidazole appears to be safe.
central nervous systems, such as dizziness, headache, Nitroimidazole drugs such as Metronidazole are mainly used
confusion, vertigo, and insomnia have been identified. In for Giardia infections[55].
Addition, Stevens-Johnson syndrome, pancreatitis,
ophthalmologic toxicity (myopia and blurry vision), ANAEROBIC INFECTIONS
ototoxicity, and hemolytic uremic syndrome are unusual and
severe adverse effects of Metronidazole treatment[16,36]. In view of its potent bactericidal action of Metronidazole
against anaerobes and its beneficial pharmacodynamics profile
PRECAUTIONS (distribution across the body, including the central nervous
system and into abscess cavities), it is effective in treating a
Patients can prohibit the use of Metronidazole, where the myriad of anaerobic infections[16,19]. Metronidazole is
history of hypersensitivity has been present with widely used to treat gastrointestinal anaerobic diseases, central
Metronidazole, parabens or nitroimidazole agents, alcohol nervous system (including meningitis and brain abscess),
consumption within 3 days of therapy, and/or disulfiram gynecologic diseases, bacteremia, endocarditis, infections of
concomitant intake within 2 weeks of Metronidazole therapy. bones and joints, respiratory tract infections, infections of the
Disulfiram-like alcohol reactions can occur along all routes of skin and skin-systems, oral and dental infections, and
administration, including topical and vaginal tetanus[16,19,56].
administration[16,36]. Caution should be done in patients with
peripheral neuropathy, liver disorder, epilepsy history or OTHER NITROIMIDAZOLE ANTIMICROBIALS
diagnosis of vaginal candidiasis due to antibiotics, while
prescribing Metronidazole[16,36]. In Addition, patients Certain members of the 5-
currently undergoing Metronidazole with aseptic meningitis, nitroimidazole class include Tinidazole, Secnidazole and Orn

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idazole. In 2004, Tinidazole was commonly prescribed and threatening anaerobic infections, while the efficacy and safety
approved for use in the United States, both in Europe and in of other nitroimidazole agents was tested on restricted
developing countries. The mechanism of action, spectrum of basis[58,59].
activity, toxicity and adverse effects of all agents of the class
are identical[57]. However, the characteristic feature of agents MARKETED AND COMBINATION PRODUCTS OF
is half-life and less frequent dosage compared to METRONIDAZOLE
Metronidazole is required[57]. Half-life for tinidazole,
Marketed Products of Metronidazole and Combination
secnidazole, and ornidazole is 10 to 15 hours, 17 to 28.8 hours,
and 11 to 14 hours, respectively, for once daily dose. As a product of Metronidazole are summarized in Table 3 and
single-dose alternative for the treatment of intestinal Table 4 respectively.
amebiasis, giardiasis, and bacterial vaginosis, these agents
provide a possible benefit over metronidazole. However,
Metronidazole is considered the drug of choice for life-

Brand Name Dosage form Manufacturer

Aldezole® Tablets 200 mg and 400 mg; Suspension 200 mg; Injection 500 mg Albert David
Antamebin® Tablets 200 mg; Suspension 200 mg Raptakos
Aristogyl® Tablets 200 mg and 400 mg; Suspension 100mg Aristo
Flagyl® Tablets 200 mg and 400 mg; Suspension 200mg NPIL
Tablets 200 mg and 400 mg; Suspension 200 mg; Injection 500 mg;
Metrogyl® J B Chemicals
Dental and Vaginal gel 1%
Metron® Tablets 200 mg and 400 mg; Suspension 100mg Alkem
Metgyl® Tablets 200 mg and 400 mg Jagsonpal
Met® Tablets 400 mg Ind-Swift
Unimezol® Tablets 200 mg and 400 mg; Suspension 200mg Unichem
Table 3. Marketed Products of Metronidazole

Brand Name Combination and Dosage Form Manufacturer

200 mg Metronidazole + 300 mg Nalidixic acid tablets and
Abdogyl-N® Glaxo SmithklineBeechem
suspensions
Amibex® 300 mg Metronidazole + 100 mg Furazolidine tablets Ind-Swift
400 mg Metronidazole + 100 mg Furazolidine+ 50 mg Simethicone
Aristogyl-F® Aristo
tablets
Metrohex® 1% Metronidazole + 0.25% Chlorhexidine gel Dr. Reddy’s laboratory
Metrokind-P® 1% Metronidazole + 5% Povidone iodine gel Mankind
Stedmox-M® 200 mg Metronidazole + 250 mg Amoxicillincapsules Stedman
Dyrade-M® 200 mg Metronidazole + 250 mg Diloxanidetablets and suspensions Cipla
Gramogyl® 100 mg Metronidazole +100 mg Norfloxacin suspension Ranbaxy
Fenigyl® 200 mg Metronidazole + 200 mg Norfloxacintablets and suspensions Finecure
Table 4. Combination Products of Metronidazole

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