METRO-Z ORAL TABLETS

Indications

• Bacterial gastrointestinal infections
• Giardiasis
• Shigellosis
• Salmonellosis

Dosage

Children: Refer to the BNF for Children for specific dosing information based on the child's age and weight.

Adults: Refer to the BNF for specific dosing information based on the condition being treated.

Mechanism of action

Furazolidone and its related free radical products are believed to bind DNA and induce cross-links. This action makes bacterial DNA particularly susceptible to damage, leading to high levels of mutations in the bacterial chromosome, which interferes with DNA replication and protein production.

Pharmacodynamics

Furazolidone exhibits a broad antibacterial spectrum, effectively targeting major gastrointestinal pathogens. Its bactericidal activity is primarily due to interference with DNA replication and protein synthesis in bacteria, which helps reduce the potential for the development of resistant organisms.

Pharmacokinetics

Furazolidone is absorbed well from the gastrointestinal tract. It undergoes metabolism in the liver, and its elimination half-life is relatively short. The drug is primarily excreted in urine, and due to its potential side effects and interactions, monitoring of renal function may be necessary during treatment.

Adverse effects

• Nausea
• Vomiting
• Abdominal pain
• Headache
• Dizziness
• Allergic reactions
• Hemolytic anemia

Precautions

• Use with caution in patients with glucose-6-phosphate dehydrogenase deficiency due to potential for hemolytic anemia.
• Monitor for signs of peripheral neuropathy with prolonged use.
• Caution in patients with liver impairment.

Pregnancy

Furazolidone should be avoided during pregnancy due to potential teratogenic effects.

Breast-feeding

Use during breastfeeding is not recommended, as it may be excreted in breast milk.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Tablets
• Suspension

Indications

• Amebiasis
• Trichomoniasis
• Giardiasis
• Anaerobic bacterial infections
• Bacterial vaginosis
• Clostridium difficile infection

Dosage

Children: For children aged 1 month to 11 years, 7.5 mg/kg every 8 hours for 7 days (maximum dose 400 mg). For children aged 12-17 years, 400 mg every 8 hours for 7 days.

Adults: 1 g three times a day for 3 days, then 1 g twice daily for a total treatment duration of 7 days. In cases of Clostridium difficile infection, treatment may extend to 10 days.

Mechanism of action

The exact mechanism of action of metronidazole is not fully established. However, it is believed that anaerobic bacteria and protozoa reduce metronidazole to reactive intermediates that bind to DNA and inhibit nucleic acid synthesis, leading to cell death. Metronidazole is selectively activated in anaerobic conditions, making it effective against obligate anaerobes.

Pharmacodynamics

Metronidazole exhibits both antibacterial and antiprotozoal activities, effectively treating infections caused by anaerobic bacteria. It demonstrates significant antibacterial activity against most obligate anaerobes but is less effective against facultative anaerobes and obligate aerobes. The drug's cytotoxic effects result from DNA strand damage in susceptible microorganisms, which can lead to cell death. Caution is advised due to the potential for peripheral neuropathy and convulsions, especially at higher doses.

Pharmacokinetics

Metronidazole is well absorbed following oral administration and is distributed widely throughout the body, including the central nervous system. It undergoes hepatic metabolism, primarily through oxidation and conjugation, and is excreted mainly in urine. The pharmacokinetic profile may vary in patients with hepatic impairment, and dosage adjustments may be necessary.

Adverse effects

• Peripheral neuropathy
• Convulsions
• Nausea
• Vomiting
• Diarrhea
• Headache
• Dizziness
• Abdominal cramps
• Metallic taste
• Skin rash

Interactions

• Metronidazole + Coumarins: Increases anticoagulant effect
• Metronidazole + Lithium: Increases concentration
• Metronidazole + Busulfan: Increases risk of toxicity (unknown)
• Metronidazole + Capecitabine: Increases risk of capecitabine toxicity (unknown)
• Metronidazole + Fluorouracil: Increases risk of toxicity (unknown)
• Metronidazole + Alkylating agents: Increases risk of toxicity (unknown)

Precautions

• Caution in patients with history of neurological disorders
• Monitor for signs of peripheral neuropathy
• Use with caution in patients with hepatic impairment
• Avoid excessive alcohol consumption during treatment

Pregnancy

No information available; manufacturer advises avoidance unless essential.

Breast-feeding

Amount in milk probably too small to be harmful.

Storage

Store in a cool, dry place, away from light. Keep out of reach of children.

Formulations

• Metronidazole 0.75% gel
• Metronidazole 0.75% cream
• Metronidazole powder and solvent for nebuliser solution
• Metronidazole injection
• Metronidazole oral tablets (various strengths)

Mechanism of action

Furazolidone and its related free radical products are believed to bind DNA and induce cross-links. Bacterial DNA is particularly susceptible to this drug leading to high levels of mutations (transitions and transversions) in the bacterial chromosome. We are studying the development of unilateral malformations. Several chemicals elicit right sided limb defects both in vivo and in vitro. For example, nitroheterocyclics such as furazolidone (FZ) induce asymmetric defects in rat embryos in vitro. Potential mechanisms include asymmetric drug delivery; intrinsic difference between the cells of the left and right limbs; physiological asymmetry (e.g. in tissue oxygen), secondary to another primary asymmetry (e.g. in limb vasculature). In one series of experiments, we have investigated the role of an asymmetry in drug delivery and/or tissue oxygen. 10.3 days embryonic age rat embryos were explanted and cultured for two hours to allow 'recovery'. Embryos were then exteriorised (removal from yolk sac and amnion, retaining intact circulation) and cultured in the presence of 20 uM FZ with 5% O2 for 24h. The assumption was that exteriorisation would abolish any drug delivery or tissue oxygen asymmetry, by direct embryonic exposure to the medium. As previously described, FZ induced right sided defects (limb, eye and fore-brain) in 42% of intact yolk sac embryos. In contrast, exposure of exteriorised embryos to FZ induced a 34% incidence of abnormalities which were identical, but exclusively left sided. The results do not support a simple hypothesis that asymmetric drug delivery or tissue oxygen levels are responsible for the unilateral defects. We are investigating two potential explanations: a) Exteriorisation specifically reverses limb bud susceptibility, b) A secondary asymmetry e.g. mitochondrial maturity is altered by exteriorisation which then acts to invert the limb response. In a second series of experiments, we have also investigated a possible primary asymmetry in the development of the limb vasculature, using whole mount in situ hybridisation with a probe specific for early endothelial cell precursors (flk-1). The results are being analysed using confocal microscopy to image the limb vascular architecture.

Pharmacodynamics

Furoxone has a broad antibacterial spectrum covering the majority of gastrointestinal tract pathogens including E. coli, staphylococci, Salmonella, Shigella, Proteus, Aerobacter aerogenes, Vibrio cholerae and Giardia lamblia. Its bactericidal activity is based upon its interference with DNA replication and protein production; this antimicrobial action minimizes the development of resistant organisms.

Mechanism of action

The exact mechanism of action of metronidazole has not been fully established, however, it is possible that an intermediate in the reduction of metronidazole which is only made by anaerobic bacteria and protozoa, binds deoxyribonucleic acid and electron-transport proteins of organisms, blocking nucleic acid synthesis. After administration, metronidazole enters cells by passive diffusion. Following this, ferredoxin or flavodoxin reduce its nitro group to nitro radicals. The redox potential of the electron transport portions of anaerobic or microaerophilic microorganisms renders metronidazole selective to these organisms, which cause nitro group reduction, leading to the production of toxic metabolites. These include N-(2-hydroxyethyl) oxamic acid and acetamide, which may damage DNA of replicating organisms. Microbicidal; active against most obligate anaerobic bacteria and protozoa by undergoing intracellular chemical reduction via mechanisms unique to anaerobic metabolism. Reduced metronidazole, which is cytotoxic but short-lived, interacts with DNA to cause loss of helical structure, strand breakage, and resultant inhibition of nucleic acid synthesis and cell death. Metronidazole is bactericidal, amebicidal, and trichomonacidal in action. The exact mechanism of action of the drug has not been fully elucidated. Metronidazole is un-ionized at physiologic pH and is readily taken up by anaerobic organisms or cells. In susceptible organisms or cells, metronidazole is reduced by low-redox-potential electron transport proteins (e.g., nitroreductases such as ferredoxin) to unidentified polar product(s) which lack the nitro group. The reduction product(s) appears to be responsible for the cytotoxic and antimicrobial effects of the drug which include disruption of DNA and inhibition of nucleic acid synthesis. Metronidazole is equally effective against dividing and nondividing cells. In in vivo studies in rats given metronidazole in dosages of 2-4 mg/100 g of body weight, the drug reportedly inhibited the development of formalin-induced edema in the rat paw. In vitro in neutrophils, metronidazole has a dose-dependent inhibitory effect on generation of hydrogen peroxide and hydroxyl radicals, oxidants that may cause tissue injury at the site of inflammation. This antioxidant effect appears to be caused by a direct effect on neutrophil function and may contribute to the drug's anti-inflammatory effect in vivo. Results of in vitro studies using leukocytes obtained from patients with Crohn's disease indicate that exposing the cells to metronidazole concentrations of 10 or 50 mcg/mL improved both spontaneous and induced leukocyte migration in cells that previously exhibited reduced migration; the drug had no effect on leukocytes obtained from healthy adults or patients with Crohn's disease when the cells exhibited normal migration prior to exposure to the drug. This effect on leukocyte migration also was observed in vivo in adults with Crohn's disease who received a single 400-mg dose of metronidazole. It has been suggested that metronidazole may increase leukocyte migration by a direct effect on the leukocytes, possibly by causing the release of surface-bound immune complexes from the cell surface.

Pharmacodynamics

Metronidazole treats amebiasis, trichomoniasis, and giardiasis, exerting both antibacterial and antiprotozoal activities. Metronidazole is an effective treatment for some anaerobic bacterial infections. Metronidazole has shown antibacterial activity against the majority of obligate anaerobes, however, during in vitro studies, it does not demonstrate significant action against facultative anaerobes or obligate aerobes. The nitro group reduction of metronidazole by anaerobic organisms is likely responsible for the drug's antimicrobial cytotoxic effects, causing DNA strand damage to microbes. A note on convulsions and neuropathy and carcinogenesis It is important to be aware of the risk of peripheral neuropathy and convulsions associated with metronidazole, especially at higher doses. If convulsions or numbness of an extremity occur, discontinue the drug immediately. Metronidazole has been found to be carcinogenic in mice and rats. The relevance to this effect in humans is unknown. It is advisable to only administer metronidazole when clinically necessary and only for its approved indications.