Nitroimidazoles: Metronidazole and Tinidazole Mark S. Johnson, Pharm.D., BCPS Associate 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 1 st 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