Transcript Nitroimidazoles: Nitrofurantoin and Tinidazole

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
Metronidazole
dailymed.nlm.nih.gov
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 intraabdominal 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 – 2ndgeneration 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™)
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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