NITALOX TABLETS

Mechanism of action

The most widely accepted mechanism of nitazoxanide is the disruption of energy metabolism in anaerobic microbes by inhibition of the pyruvate:ferredoxin/flavodoxin oxidoreductase (PFOR) cycle. It induces lesions in cell membranes and depolarizes the mitochondrial membrane, inhibiting enzymes such as quinone oxidoreductase NQO1, nitroreductase-1, and protein disulfide isomerase. Additionally, it inhibits glutathione-S-transferase, modulates the Avr-14 gene in nematodes, and exhibits various antibacterial mechanisms, including inhibition of pyruvate dehydrogenase in E. coli and disruption of Mycobacterium tuberculosis membrane potential. Nitazoxanide also suppresses viral replication by inhibiting maturation of viral hemagglutinin and activating antiviral intracellular proteins.

Pharmacodynamics

Nitazoxanide prevents microbial activity by disrupting essential energy pathways necessary for survival and proliferation. It exhibits antiprotozoal activity by interfering with the PFOR-dependent electron transfer reaction, crucial for anaerobic energy metabolism. This interference inhibits the sporozoites of Cryptosporidium parvum and trophozoites of Giardia lamblia, relieving diarrhea symptoms. The disruption of the PFOR enzyme-dependent reaction is one of several pathways through which nitazoxanide exerts its antiprotozoal effects.

Pharmacokinetics

Nitazoxanide is rapidly absorbed and extensively metabolized in the liver to its active metabolite, tizoxanide. The drug is excreted primarily in the urine and feces. The pharmacokinetics of nitazoxanide can be influenced by factors such as age, liver function, and co-administration of other medications. The half-life of nitazoxanide is approximately 1 to 3 hours, while tizoxanide has a longer half-life, allowing for

Adverse effects

• Abdominal pain
• Diarrhea
• Nausea
• Headache
• Dizziness

Precautions

• Use with caution in patients with hepatic impairment
• Monitor for gastrointestinal side effects

Pregnancy

Nitazoxanide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data on the use of nitazoxanide in pregnant women is limited.

Breast-feeding

It is not known whether nitazoxanide is excreted in human milk. Caution should be exercised when administering to breastfeeding women.

Storage

Store at room temperature, away from light and moisture. Keep out of reach of children.

Formulations

• Oral suspension
• Tablet

Indications

• Bacterial vaginosis
• Amoebiasis
• Giardiasis
• Trichomoniasis
• Infections caused by anaerobic bacteria

Dosage

Children: Dosing in children is determined based on weight and the specific indication. Refer to the BNF for Children for appropriate dosing guidelines.

Adults: The usual adult dose is 1.5 g orally once daily for 5 days for bacterial vaginosis or 1 g orally once daily for 3 days for amoebiasis. Refer to the BNF for specific indications and adjustments.

Mechanism of action

Ornidazole exerts its antimicrobial effects through the reduction of its nitro group by anaerobic bacteria and protozoa, resulting in the formation of reactive intermediates that interact with microbial DNA. This leads to the disruption of DNA synthesis and ultimately causes cell death. The drug's activity is primarily directed towards anaerobic organisms, including certain protozoa.

Pharmacodynamics

Ornidazole demonstrates a concentration-dependent bactericidal effect against susceptible organisms. Its activity is influenced by the reduction potential of the nitro group, which is crucial for its antimicrobial action. Ornidazole has a broad spectrum of activity, particularly against anaerobes and protozoa, and has been shown to be effective in both in vitro and in vivo models of infection.

Pharmacokinetics

Ornidazole is rapidly and completely absorbed following oral administration, achieving peak plasma concentrations within 1 to 3 hours. It is widely distributed throughout the body, including the central nervous system. The drug is metabolized mainly in the liver, with a half-life of approximately 8 to 10 hours. Excretion occurs primarily through the urine, with a small fraction eliminated unchanged.

Contra-indications

• Hypersensitivity to ornidazole or any of its components
• History of neurological disorders, particularly seizures

Adverse effects

• Nausea
• Vomiting
• Headache
• Dizziness
• Dry mouth
• Metallic taste
• Peripheral neuropathy

Interactions

• Alcohol: Concurrent use may lead to disulfiram-like reactions including flushing, tachycardia, and vomiting
• Anticoagulants: May enhance the effects of warfarin and other anticoagulants
• Other neurotoxic agents: Increased risk of neurological side effects

Precautions

• Use with caution in patients with a history of seizures
• Monitor liver function in patients with hepatic impairment
• Discontinue if neurological symptoms occur

Pregnancy

Ornidazole is not recommended during pregnancy unless the benefit outweighs the risk, particularly in the first trimester.

Breast-feeding

Ornidazole is excreted in breast milk, caution is advised when administering to nursing mothers.

Storage

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

Formulations

• Tablets: 500 mg
• Infusion: 100 mg/100 mL

Mechanism of action

The most widely accepted mechanism of NTZ is believed to be the disruption of the energy metabolism in anaerobic microbes by inhibition of the pyruvate: ferredoxin/flavodoxin oxidoreductase (PFOR) cycle. In parasitic-protozoa, Nitazoxanide also induces lesions in the cell membranes and depolarizes the mitochondrial membrane while inhibiting quinone oxidoreductase NQO1, nitroreductase-1 and protein disulphide isomerase enzymes. In addition, this drug also inhibits the glutathione-S-transferase (a major detoxifying enzyme) and modulates the Avr-14 gene, encoding for the alpha-type subunit of glutamate-gated chloride ion channel present in nematodes. Aside from its well understood non-competitive inhibition of the PFOR in anaerobic bacteria, NTZ also demonstrates various other antibacterial mechanisms. It inhibits pyruvate dehydrogenase in E Coli, disrupts the membrane potential and pH homeostasis in the Mycobacterium tuberculosis, suppresses the chaperone/usher (CU) pathway of the gram-negative bacteria, and stimulates host macrophage autophagy in tuberculosis patients. NTZ also suppresses viral replication by inhibiting the maturation of the viral hemagglutinin and the viral transcription factor immediate early 2 (IE2) as well as by activating the eukaryotic translation initiation factor 2α (an antiviral intracellular protein). Lastly, NTZ exhibits an inhibitory effect on tumor cell progression by altering drug detoxification (glutathione-S-transferase P1), unfolded protein response, autophagy, anti-cytokines activity, and c-Myc inhibition.

Pharmacodynamics

The general effect of this medication is the prevention of microbe activity through disruption of important energy pathways for survival and proliferation. Nitazoxanide exhibits antiprotozoal activity by interfering with the pyruvate ferredoxin/flavodoxin oxidoreductase dependent electron transfer reaction, an essential reaction need for anaerobic energy metabolism of various microorganisms. Sporozoites of Cryptosporidium parvum and trophozoites of Giardia lamblia are therefore inhibited, relieving symptoms of diahrrea. Interference with the PFOR enzyme-dependent electron transfer reaction may only be one of the many pathways by which nitazoxanide exhibits antiprotozoal activity.