Metronidazole

METRONIDAZOLE

It is the prototype nitroimidazole introduced in 1959 for trichomoniasis and later found to be a highly active amoebicide. It has broad-spectrum cidal activity against protozoa, including Giardia lamblia in addition to the above two. Many anaerobic bacteria, such as Bact. fragilis, Fusobacterium, Clostridium perfringens, Cl. difficile, Helicobacter pylori, Campylobacter, peptococci, spirochetes and anaerobic Streptococci are sensitive. Though, it does not directly inhibit the helminth Dracunculus medinensis, extraction of the worm from under the skin is facilitated. Metronidazole does not affect aerobic bacteria. Clinically significant resistance has not developed among E. histolytica, but decreased responsiveness of T. vaginalis has been observed in some areas. Anaerobic bacteria and G. lamblia also can develop metronidazole resistance, but this is a clinical problem only in the case of H. pylori.

Metronidazole is selectively toxic to anaerobic microorganisms. After entering the cell by diffusion its nitro group is reduced by certain redox proteins operative only in anaerobic microbes to highly reactive nitro radical which exerts cytotoxicity. The nitro radical of metronidazole acts as an electron sink which competes with the biological electron acceptors of the anaerobic organism for the electrons generated by the pyruvate : ferredoxin oxidoreductase (PFOR) enzyme pathway of pyruvate oxidation. The energy metabolism of anaerobes is, thus, disrupted. Aerobic environment attenuates cytotoxicity of metronidazole by inhibiting its reductive activation. Anaerobes which develop metronidazole resistance become deficient in the mechanism that generates the reactive nitro radical from it.

Metronidazole has been found to inhibit cell mediated immunity, to induce mutagenesis and to cause radio-sensitization.

Pharmacokinetics

Metronidazole is almost completely absorbed from the small intestines; little unabsorbed drug reaches the colon. It is widely distributed in the body, attaining therapeutic concentration in vaginal secretion, semen, saliva and CSF. It is metabolized in liver primarily by oxidation and glucuronide conjugation, and excreted in urine. Plasma t½ is 8 hrs.

Adverse Effects

Side effects to metronidazole are relatively frequent and unpleasant, but mostly nonserious.

·     Anorexia, nausea, metallic taste and abdominal cramps are the most common. Looseness of stool is occasional.

·     Less frequent side effects are—headache, glossitis, dryness of mouth, dizziness, rashes and transient neutropenia.

·     Prolonged administration may cause peripheral neuropathy and CNS effects. Seizures have followed very high doses.

·     Thrombophlebitis of the injected vein occurs if the solution is not well diluted.

Contraindications

Metronidazole is contraindicated in neurological disease, blood dyscrasias, first trimester of pregnancy (though no teratogenic effect has yet been demonstrated, its mutagenic potential warrants caution), and chronic alcoholism.

Interactions

A disulfiram-like intolerance to alcohol occurs in some patients taking metronidazole; they should be instructed to avoid drinking. Enzyme inducers (phenobarbitone, rifampin) may reduce its therapeutic effect.

Cimetidine can reduce metronidazole metabolism: its dose may need to be decreased. Metronidazole enhances warfarin action by inhibiting its metabolism. It can decrease renal elimination of lithium.

Preparations

FLAGYL, METROGYL, METRON, ARISTOGYL ALDEZOLE 200, 400 mg tab, 200 mg/5 ml susp. (as benzoyl metronidazole: tasteless); 500 mg/100 ml i.v. infusion; UNIMEZOL 200, 400 mg tabs, 200 mg/5 ml susp.

Uses

Amoebiasis:

Metronidazole is a first line drug for all forms of amoebic infection. Many dosage regimens have been tried; the current recommendations are:

For invasive dysentery and liver abscess—800 mg TDS (children 30–50 mg/kg/day) for 7–10 days. In serious cases of liver abscess 1 g may be infused i.v. slowly followed by 0.5 g every 8–12 hr till oral therapy is instituted.

For mild intestinal disease—400 mg TDS for 5–7 days. Metronidazole is less effective than many luminal amoebicides in eradicating amoebic cysts from the colon, because it is nearly completely absorbed from the upper bowel.

Giardiasis  

It is highly effective in a dose of 400 mg TDS for 7 days. A shorter course of 3 days with 2 g/day is equally effective.

Trichomonas Vaginitis

It is the drug of choice; 400 mg TDS for 7 days achieves nearly 100% cure. Additional intravaginal treatment has been given, but is not necessary except in refractory cases. The male partner should be treated concurrently in cases of recurrent infections.

Nonspecific bacterial vaginosis also responds.

Anaerobic Bacterial Infections

They occur mostly after colorectal or pelvic surgery, appendicectomy, etc. Brain abscesses and endocarditis may be caused by anaerobic organisms.

Metronidazole is an effective drug for these and is generally used in combination with gentamicin or cephalosporins (many are mixed infections). For serious cases i.v. administration is recommended: 15 mg/kg infused over 1 hr followed by 7.5 mg/kg every 6 hrs till oral therapy can be instituted with 400–800 mg TDS. Prophylactic use in high risk situations (colorectal surgery) is recommended.

Other drugs effective in anaerobic infections are clindamycin and chloramphenicol.

Pseudomembranous Enterocolitis due to Cl. difficile is generally associated with use of antibiotics. Oral metronidazole 800 mg TDS is more effective, more convenient, less toxic, and therefore preferred over vancomycin.

Ulcerative Gingivitis, Trench Mouth 200–400 mg TDS (15–30 mg/kg/day) is quite effective because anaerobes are involved. Metronidazole/ tinidazole are the drugs of choice for acute necrotizing ulcerative gingivitis, in which they are often combined with amoxicillin, tetracycline or erythromycin. The response is rapid with disappearance of the spirochetefuso-bacterium complex from the lesions and resolution of pain, bleeding, ulceration and bad breath within 2–3 days; but treatment must be continued for at least 5 days.

Helicobacter Pylori Gastritis/Peptic Ulcer

Metronidazole or tinidazole alone are relatively ineffective in eradicating H. pylori; resistance develops. However, metronidazole 400 mg TDS or tinidazole 500 mg BD is frequently used along with amoxicillin/clarithromycin and a proton pump inhibitor in triple drug 2 week regimens.

Guinea worm infestation  Niridazole is considered to

be the drug of choice, but because it is not available in India, metronidazole is used. A 7 day course with 200– 400 mg TDS produces symptomatic relief. The local reaction to the worm may be suppressed by its anti-inflammatory action, and extraction is facilitated.

Tinidazole

It is an equally efficacious congener of metronidazole, similar to it in every way except:

Metabolism is slower; t½ is ~12 hr; duration of action is longer; dosage schedules are simpler. Thus, it is more suited for single dose or once daily therapy.

Some comparative trials in amoebiasis have reported higher cure rates.

It appears to be better tolerated; the incidence of side effects is lower: metallic taste (2%), nausea (1%), rash (0.2%).

TINIBA 300, 500, 1000 mg tabs; 800 mg/400 ml i.v. infusion; TRIDAZOLE 300, 500 mg tab; FASIGYN 0.5 g and 1 g tab.

Recommended schedules are—

Amoebiasis: 2 g OD for 3 days (children 30–50 mg/ kg/day) or 0.6 g BD for 5–10 days.

Trichomoniasis And Giardiasis: 2 g single dose or 0.6 g OD for 7 days.

Anaerobic Infections:

prophylactic—2 g single dose before colorectal surgery;

therapeutic—2 g followed by 0.5 g BD for 5 days.

H. pylori: 500 mg BD for 2 weeks in triple combination.

Secnidazole

A congener of metronidazole with the same spectrum of activity and potency. Absorption after oral administration is rapid and complete, but metabolism is slower resulting in a plasma t½ of 17–29 hours. After 48 hr of a single 2 g dose, plasma secnidazole concentration still remains within the range of MIC values against sensitive organisms. A single 2 g dose has been found to yield cure rates equal to multiple doses of metronidazole and tinidazole. Side effect profile is similar to metronidazole and reported incidence is 2–10%.

Dose: 2 g single dose (children 30 mg/kg) for intestinal amoebiasis, giardiasis, trichomonas vaginitis and nonspecific bacterial vaginosis; 1.5 g/day for 5 days in hepatic amoebiasis.

SECNIL, SECZOL 0.5, 1.0 g tabs; NOAMEBADS 1.0 g tab.

Ornidazole

Activity similar to metronidazole, but it is slowly metabolized—has longer t½ (12–14 hr). Dose and duration of regimens for amoebiasis, giardiasis, trichomoniasis, anaerobic infections and bacterial vaginosis resemble those for tinidazole. Side effect profile is also similar.

DAZOLIC 500 mg tab, 500 mg/100 ml vial for i.v. infusion.

ORNIDA 500 mg tab, 125 mg/5 ml susp.

Satranidazole

Another nitroimidazole having longer t½ (14 hr). Advantages claimed are: better tolerability—no nausea, vomiting or metallic taste, absence of neurological and disulfiram-like reactions and that it does not produce the acetamide metabolite which is a weak carcinogen.

Dose: Amoebiasis 300 mg BD for 3–5 days, giardiasis and trichomoniasis 600 mg single dose.

SATROGYL 300 mg tab.