Nitroimidazoles:Metronidazole and Tinidazole

Mark S. Johnson, Pharm.D., BCPSAssociate Professor and Director of

Postgraduate Education

Metronidazole (Flagyl®)

• Nitroimidazole class• Antiparasitic and antibacterial activity

• MOA• Diffuses into organism by passive diffusion then

interacts with DNA to cause loss of helical DNA structure and strand breakage, which results in inhibition of protein synthesis and cell death

• Needs to be reduced for it’s action• Bactericidal

dailymed.nlm.nih.gov

Metronidazole

Metronidazole (Flagyl®)Spectrum of Activity

• Good– Anaerobes: gram positive and gram negative

• Bacteroides, Fusobacterium, Clostridium, Prevotella

– Protozoa:• Trichomonas, Entamoeba, Giardia

• Moderate– Helicobacter pylori

• Poor– Peptostreptococcus, Actinomyces,

Propionibacterium

Metronidazole (Flagyl®)PKS

• Absorption• BA 100%

• Distribution• Saliva, bile, seminal fluid, bone, liver, liver abcesses, lung,

vagina, crosses BBB• Protein binding 20%

• Metabolism– Hepatic (30-60%)– t1/2 of 6-8h (prolonged in hepatic and ESRD)

• Excretion– Urine (60-80% as unchanged drug)– Feces (6-15%)

Metronidazole (Flagyl®)ADR’s

• GI: – Common: nausea, vomiting, diarrhea, metallic taste – Rarely hepatitis, pancreatitis

• Neurologic– Dose-related peripheral neuropathy

• Can also be optic or autonomic neuropathy– Headache– Rarely confusion, seizures

• Skin—urticaria• Dark Urine• Pregnancy (category B, avoid in 1st trimester)

Metronidazole (Flagyl®)Drug Interactions

• Inhibits 2C9 (weak), 3A4 (moderate)• Disulfiram-like reaction when given with alcohol

(inhibition of aldehyde dehydrogenase)• Warfarin—increased INR• Phenytoin, phenobarbital can decrease

metronidazole levels

Metronidazole (Flagyl®)Clinical Uses

• Anaerobic infections in general, including intra-abdominal infections

• Trichomoniaisis• Bacterial vaginosis, vaginitis• GI infections caused by protozoa (amebiasis,

giardiasis, others)• Pseudomembranous colitis (Clostridium difficile)• Helicobacter pylori infections

Metronidazole (Flagyl®)Dosage Forms

• IV: – 500mg (7.5mg/kg) Q6h-8h – possibly 15mg/kg Q12h– Not to exceed 4gm/d

• Oral– Regular Release: 250mg-500mg PO Q8-12h

(depending on indication)– Extended Release: 750mg QD

• Topical (acne rosacea): 0.75% or 1%

Tinidazole (Tindamax™)

• Structurally similar to metronidazole – 2nd-generation nitroimidazole– Antiprotozoal

• Mechanism: similar to metronidazole• Indications– Intestinal amebiasis and amebic liver absess– Entamoeba

histolytica– Giardiasis – Giardia lamblia– Trichomoniasis – Trichomonas vaginalis– Bacterial vaginosis caused by Bacteroides spp, Gardnerella

vaginalis, Prevotella

Tinidazole (Tindamax™)

• t1/2: 13h (once daily dosing)• Similar ADR’s to metronidazole• Substrate for 3A4• Availability:– 250mg and 500mg tabs– 2gm once daily with food– More expensive