METRONIDAZOLE Jawad Ahmad FY2

Outline•Anaerobic Infections•Introduction•Dosage forms and Trade names•Pharmacokinetics•Mechanism of action•Indications•Side effects•Drug Interactions•Important things to remember•References

ANAEROBIC BACTERIA OF MEDICAL INTEREST

MORPHOLOGY GRAM STAIN GENUS Spore forming (+) ClostridiumNon-Spore Forming Bacilli

(+)

(-)

Actinomycetes,Bifidobacterium,Eubacte-rium,Propionibacerium,Mobilncus,Lactobacillus

Bacteroides,FusobacteriumPrevotella,Porphyromonas

Non-Spore Forming Cocci (+)

(-)

Peptococcus,Pepto-streptococcusStreptococcus

Veilonella

SITES AND INFECTION PRODUCED BY ANAEROBES

CLASSIFICATION OF AMEBICIDAL DRUGS

According to the site where the drug is effective, the amebicidal drugs are classified as:• Luminal amebicides (Act on the organisms in the lumen of bowel)• Systemic amebicides (Against amebas in intestinal wall & liver)• Mixed amebicides ( Against both the luminal and systemic form of diseases).

Introduction•Metronidazole (Flagyl) is a synthetic antiprotozoal and antibacterial agent,( l-β-hydroxyethyl)-2-methyl-5-nitroimidazole, which has the following structural formula:

•It belongs to the group of Nitro Imidazoles.•It is a Mixed Amebicidal which means it has both Luminal and Extra-Luminal effect.

•Other members related to metronidazole are Tinidazole and others.

Dosage forms and Trade names

•Trade names: Flagyl, Flagyl ER. Dosage Forms: Tablet, Gel, Cream, Capsule, Tablet, Suspension•Flagyl tablets contain 200 mg or 500 mg of metronidazole.• Inactive ingredients include cellulose, hydroxypropyl cellulose.

BRANDS

PHARMACOKINETICS•Absorption• Bioavailability: 80% absorption from GI tract (PO)• Protein binding (<20%)• Peak serum time: 1-2 hr

•Distribution• Widely distributed; similar pattern for PO and IV

•Metabolism• Liver• Enzymes inhibited: Hepatic CYP2C9

•Elimination• Half-life: 25-75 hr (neonates); 8 hr (others); prolonged in patients with hepatic impairment

• Excretion: Urine (77%); feces (14%)

Mechanism of Action• Metronidazole acts by inhibiting nucleic acid synthesis by disrupting the DNA of microbial cells.

• This function only occurs when metronidazole is partially reduced, and because this reduction usually happens only in anaerobic cells, it has relatively little effect upon human cells or aerobic cells.

•Metronidazole is activated (reduced) by the microbial proteins flavodoxins and ferredoxins found in anaerobic bacteria and certain protozoans Mammalian cells are unharmed because they lack flavodoxins and ferredoxins that reduce the nitro group of metronidazole

•Flavodoxins and Ferredoxins are electron-transfer proteins that serve as electron donors in the reductive activation of anaerobic ribonucleotide reductase, biotin synthase,…etc

•Once activated, the drug (a short-lived reduction product, most probably the protonated one electron nitro radical anion) oxidizes DNA causing strand breaks and subsequent cell death.

Mechanism of Action

IndicationsAnaerobe infections C. difficileH. pylori(triple regime)Bacterial vaginosisTrichomonas vaginitisAmebiasisGiardiasisDental AbscessesProphylactic after surgery

1.AMEBIASIS

Metronidazole is the drug of choice for the treatment of all tissue infections with Entamoeba histolytica

It is not reliably effective against luminal parasites and so must be used with a luminal amebicide to ensure eradication of the infection

Tinidazole, a related nitroimidazole, appears to have similar activity and a better toxicity profile than metronidazole

2.GIARDIASIS

Metronidazole is the treatment of choice for GiardiasisThe dosage for Giardiasis is much lower— and the drug thus

better tolerated—than that for AmoebiasisEfficacy after a single treatment is about 90%Tinidazole is equally effective

3.TRICHOMONIASISMetronidazole is the treatment of choice. A single dose of

2grams is effective or 200mg TDS for 7days.Metronidazole-resistant organisms may lead to treatment

failuresTinidazole may be effective against some of these infectionsT. vaginalis infection is a venereal disease. Therefore,

asymptomatic sexual partners of treated patients should be treated simultaneously if the organism has been found to be present, in order to prevent re-infection of the partner

4.BACTERIAL INFECTIONS

Metronidazole has potent antibacterial activity against anaerobes, including bacteroides and clostridium species

Metronidazole is indicated for treatment of anaerobic or mixed intra-abdominal infections, vaginitis (bacterial vaginosis), antibiotic-associated enterocolitis, acute gingivitis and other dental infections

Metronidazole is indicated for treatment of vaginitis due to bacterial Gardnerella or Mycoplasma hominis infection in symptomatic patients

Helicobacter pylori eradication therapy, as part of a multi-drug regimen in peptic ulcer disease

SIDE EFFECTS OF METRONIDAZOLE

Nausea, vomiting, diarrhea, epigastric distress, abdominal cramping and constipation. Taking the drug with meals lessens gastrointestinal irritation

A sharp, unpleasant Metallic taste, furry tongue, glossitis, dry mouth and stomatitis. These may be associated with a sudden overgrowth of Candida which may occur during therapy

Proliferation of Candida in the vagina, dysuria, polyuria, Dark urine, cystitis, incontinence and proctitis

Reversible neutropenia (leukopenia) and reversible thrombocytopeniaAlthough teratogenic in some animals, metronidazole has not been associated with this

effect in humansMetronidazole and its metabolites are mutagenic in bacteria. Chronic administration of

large doses led to Tumorigenicity in mice and ratsConvulsive seizures and peripheral neuropathy (with prolonged use) are serious

adverse effects, however they are rare

SIDE EFFECTS OF METRONIDAZOLE

Epigastric distressMetallic taste in mouthDarkening of urinePancreatitisHepatitisFeverPeripheral neuropathySeizuresReversible neutropenia

SIDE EFFECTS OF METRONIDAZOLE

Gastrointestinal Haematological

Genitourinary: Neurolological

DRUG INTERACTIONSDRUG INTERACTIONALCOHOL Mild disulfiram like reaction (Nausea,

headache, vomiting, abdominal cramps)ANTICOAGULANTS (WARFARIN) Prolonged PT(Prothrombin time)CIMETIDINE Prolong half life & decrease clearance of

MetronidazolePHENYTOIN & PHENOBARBITONE Decrease serum concentration and

increase metabolism of Metronidazole

PREGNANCY AND LACTATION•Pregnancy category: B•Lactation•Excreted in human milk; not recommended•Following PO administration, concentrations in human milk are similar to concentrations in plasma, therefore advice patient to stop breast feeding whilst taking metronidazole and for 12-24 hours after.

PREGNANCY CATEGORY-BCategory A: Means that controlled studies have found no risk to the fetus when the mother takes the medication during any trimester of pregnancy. Category B: Means that controlled studies in pregnant women have not shown an increased risk of fetal abnormalities, although some adverse findings have occurred in animals

IMPORTANT THINGS TO REMEMBER BEFORE DISPENSING METRONIDAZOLE

•Patient should be asked about other medications he/she is taking as well as other important questions like allergies and intolerances.

•Any woman in child bearing age should be asked if she is pregnant.

•Any old man should be asked about history of chronic illness, especially hepatic and renal diseases.

•Social history must inquire alcohol consumption of the patient. Patient advised not to take alcohol whilst taking this medicine and for48 hours after finishing the course.

REFERENCES•Katzung & Trevor's Pharmacology Examination and Board Review,13th Edition (Katzung & Trevor's Pharmacology Examination & Board Review), ISBN-13: 978-0071789233

•Lippincott Illustrated Reviews: Pharmacology 6th edition (Lippincott Illustrated Reviews Series), ISBN-13: 978-1451191776

•www.reference.medscape.com •www.webmd.com•www.medicinenet.com•BNF Online

•www.nice.org.uk

THE DUTY OF A DOCTOR

TO CURE SOMETIMES

TO RELIEVE OFTEN

TO CARE ALWAYS ABOVE ALL, DO NO HARM