Pharmacy review: Metronidazole and adverse drug reactions

Metronidazole (1H-imidazole-1-ethanol, 2-methyl-5-nitro-) is an organic compound that is sparingly soluble in water. A crystalline powder, white to pale yellow in color, it darkens on exposure to light. It is available in oral, topical, and parenteral formulations in the United States and Canada under varying brand names, such as Flagyl, Metrogyl, etc.

Dosage forms of metronidazole on the market include tablets: 250 mg, 375 mg, 500mg, and 750 mg ER; lotions: 0.75%; creams: 1% and 0.75%; and gels: topical gel 0.75% and vaginal gel 0.75%. It is also available as an injection for intravenous infusion only. Of note, the parenteral formulation of metronidazole is typically a ready-to-use 100-ml IV single-dose container of sterile, nonpyrogenic metronidazole hydrochloride equivalent to 500 mg of active principle.

Use

Metronidazole is widely used in medical and dental practices for the eradication of anaerobic bacteria, amoebae, and parasitic infections. In the Asian subcontinent, for example, it has been successfully used in combination with mebendazole in the treatment of Taenia species of tapeworm and for guinea worm eradication. In its spectrum of activity, metronidazole encompasses the following micro-organisms:

·      Anaerobic Gram-Positive bacilli: Clostridium species and strains of Eubacterium.

·      Anaerobic Gram-Negative bacilli: Bacteroides fragilis, B. vulgatus, B. ovatus, B. distasonis, B. thetaiotaomicron, and Fusobacterium species.

·      Anaerobic Gram-Positive Cocci: Peptococcus species and Peptostreptococcus species. Gardnerella vaginalis, Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis, Helicobacter pylori, Blastocystis hominis.

Adverse events

In alcoholics or patients with compromised liver function, in pregnant women, and in children, metronidazole ingestion may trigger debilitating adverse reactions; therefore it is advisable that its use be limited to when it is clearly needed for the eradication of infections.

All healthcare practitioners, including physicians, need more advanced learning on drug-drug interactions and adverse drug reactions connected with metronidazole. FDA requires a boxed warning that notes the possibility, discovered in data from animal studies, of carcinogenicity. Metronidazole is contraindicated in the first trimester of pregnancy and must be used with caution in patients with end-stage renal disease; dosage reduction is warranted if CrCl<10ml/min.

One classic adverse reaction from metronidazole ingestion is the disulfiram reaction, first noted by two Danish physicians. Like disulfiram (Antabuse; Wyeth-Ayerst), metronidazole blocks the hepatic oxidation of acetaldehyde, an intermediate step in the metabolism of alcohol, causing an accumulation of acetaldehyde in the blood, with resultant severe nausea and vomiting.¹ Pharmaceutical products containing alcohol, however small the amount, will induce this manner of severe adverse reaction in patients who are on concurrent metronidazole therapy.

Examples of medications that may trigger this reaction include:

·      Lopinavir/ritonavir oral solution (Kaletra; Abbott), which contains 42% alcohol

·      Oral cough/cold preparations containing benzyl alcohol as a base/preservative (Edwards et al¹ have described a case in which a patient given clindamycin and metronidazole at different times in the day still developed intractable nausea and vomiting)

·      Tipranavir capsules, which contain 7% w/w of alcohol, will cause a disulfiram-like reaction with metronidazole.

Clindamycin

In The Journal of Midwifery & Women’s Health², C.J. Krulewitch described an unusual adverse reaction of severe nausea and vomiting in a 26-year old female (GA P1021 at 40 4/7 weeks), who presented to the labor and delivery ward for induction of labor due to decreased amniotic fluid.

The patient had previously been on a 7-day course of metronidazole for a diagnosis of bacterial vaginosis and had taken her last dose on the day of admission. At 5 a.m. the following morning, the patient was given pitocin and clindamycin 800 mg IV for GBS prophylaxis at 7 a.m., and she had a normal spontaneous vaginal delivery at 9:40am.

However, she developed an intractable and severe nausea and vomiting post-partum that lasted 20 hours and was unrelieved by courses of metoclopramide, prochlorperazine, and diphenhydramine.

The cause of this patient’s adverse reaction was attributed to the benzyl alcohol preservative content of the intravenous clindamycin given to her, which elicited a drug-drug interaction with the metronidazole course she had been on.

Warfarin

In another case study, Howard-Thompson A, Hurdle AC, Arnold LB, et al, ³ recounted the case of a 78-year-old white woman who had visited a walk-in clinic and  received prescriptions for metronidazole (250 mg Q8H for five days) and levofloxacin (500 mg QD for six days). The patient did not inform the physician that she was on 7 mg warfarin therapy daily. Nine days later, she was admitted for profuse nosebleeds, with an INR value of 8.0.

According to the authors, this adverse event was attributable to a metronidazole-induced elevation in plasma warfarin levels, because it inhibits the in-vivo metabolism of S-warfarin, the most active isomer in the warfarin racemic mixture. Metronidazole is an inhibitor of the CYP2C9 enzyme, which is one of the cytochrome P450 enzyme system that is responsible for s-warfarin metabolism.

Organ function

The consistent and very frequent use of metronidazole in gynecological clinics and for the treatment of b. fragilis infections of the GI tract presents a number of risks for the occurrence of adverse drug reactions, especially in patients who are social drinkers, in those with undiagnosed hepatic disease, and in those with renal dysfunction. Metronidazole volume of distribution and systemic clearance are reduced by 21% and 66% respectively in liver failure, causing an elimination half-life prolongation of 152 %.⁴

If metronidazole is given concurrently with mebendazole, the risks of toxic epidermal necrolysis and Stevens-Johnson syndrome are heightened. Similarly, if it is given with busulphan, there is a 79%–87% elevation of busulphan trough concentrations. Therefore dose adjustments are necessary wherever these drugs are required for treatment of a patient on metronidazole.

Carcinogenicity

Unlike chloramphenicol, metronidazole does not cause irreversible hematological toxicities, but it has been shown to be carcinogenic in studies of animals, although not of humans.

Studies in experimental animals (rats and mice) have proven metronidazole carcinogenicity.^5,6 The hydroxy metabolite, which is more potent than the parent compound, has been implicated in many lab animals.

The WHO International Agency for Research on Cancer and the U.S. National Toxicology Program both list metronidazole as a possible carcinogen, although the relationship of metronidazole exposure to cancer in humans has not been clearly established.

Side effects

Some more commonly seen side effects of metronidazole include numbness, tingling sensations in hands or feet, irritability, hallucinations, headaches, convulsions, dizziness, drowsiness, sore throat, loss of appetite, cloudy urine, loss of bladder control, joint or muscle pain, skin rash, chills, black or tarry stool, skin redness, blistering, peeling, or loosening of the skin, vaginal irritation, eye pain, fever, continuing diarrhea, Stevens-Johnson syndrome, bladder inflammation, and acute pancreatic inflammation.

Drugs that must be avoided during metronidazole treatments include disulfiram, carbocisteine, BCG vaccine, pimozide, and ethyl alcohol. Drugs that may be used with extreme caution during metronidazole treatments include mycophenolate, fosphenytoin, systemic fluorouracil, calcineurin inhibitors, aripiprazole, tegafur, dofetilide, phenobarbital, ritonavir, and tipranavir. Some medications and vaccines that may be used with close monitoring during metronidazole therapy include typhoid vaccine, vitamin K antagonist, lomitapide, mebendazole, busulphan, and sodium picosulfate.

References

1. Edwards DL, Fink PC, Van Dyke PO. Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole. Clin Pharm. 1986 Dec;5(12):999–1000.

2. Krulewitch C.J. An Unexpected Adverse Drug Effect. The Journal of Midwifery & Women’s Health, 2003;48(1),

3. Howard-Thompson A, Hurdle AC, Arnold LB, et al. Intracerebral hemorrhage secondary to a warfarin-metronidazole interaction, Am J Geriatr Pharmacother. 2008 Mar;6(1):33–36.

4. Farrell G, Baird-Lambert J, Cvejic M, et al. Disposition and Metabolism of Metronidazole in patients with liver failure. Hepatology. 1984; 4(4): 722–726.

5. Bendesky A, Menendez D, Ostrosky-Wegman P. Is Metronidazole Carcinogenic? Mutat Res. 2002 Jun; 511(2):133-144.

6. Menndez D, Bendesky A, Rojas E, et al. Role of P53 functionality in the genotoxicity of metronidazole and its hydroxy metabolite. Mutat Res. 2002 Apr 25;501(1–2):57–67.

Oluwole Williamspractices pharmacy in the Philadelphia, Penn., area. Contact him at pharmwillie@yahoo.co.uk.