comprehensive review of nitroimidazoles , it is first of its kind. extracted from reasearching many articles.

1. NITROIMIDAZOLES
-Dr U Bharath kumar
1st year pg trainee.
Moderator:
Dr G Sudhakar, Reader

2. Contents
• Introduction
• Classification
• Mechanism of action
• Pharmacology
• Indications / contraindications
• Effects on various systems
• Applications
• Resistance
• Conclusion
• References

3. Introduction
• Accidental discovery of nitroimmidazoles
• Initially for treatment of protozoa
• Streptomyces spp6670 (late fifties)
• Accidental discovery of antibacterial spectrum(1962)
• Anaerobic conditions.

4. Nitroimidazoles
• 2 – nitroimidazoles
• 4 – nitroimidazoles
• 5 - nitroimidazoles

5. Metronidazole
• Drug of choice for
• Anaerobic bacteria
• Protozoan infections
• Prodrug
• Synthetic derivative of azomycin
• Nitro functional group (-NO2) at the fifth
position
• Oxygen (furan) or sulphur (thiazole) at
position 1 for variants.

6. Kinetics
• Absorption:
– Rapidly and almost completely absorbed from the
small intestine.
– Food delays absorption. Time to peak plasma
concentration: 1-2 hours (oral); 20 minutes (IV)
– Bioavailability: 60-80% .
• Distribution:
– Crosses blood-brain barrier.
– Readily crosses the placenta and enters breast
milk.
– High volume of distribution.

7. …
• Metabolism:
– Mainly metabolised in the liver via hydroxylation, oxidation, and glucuronidation to
active hydroxyl metabolite.
• Excretion:
– Via urine (60-80% as unchanged drug and metabolites;)
– faeces (6-15%).
– Elimination half-life: Approx 8 hours.

8. Mechanism of action
• Inactive drug
• Cellular respiration
• Pyruvate dehydrogenase
• Pyruvate oxidoreductase (POR)
• Ferridoxin reduction
• oxygen free radicles

9. Intermediate compounds
• Free radicle ion
– Covalant bonding to DNA
• 5 - Nitroso
– GC conversions
• 5 – (N hydroxy)amino
– Act on DNA repair enzymes
• In addition these mechanisms
ATP is depleated

10. Oral dosages
• Anaerobic bacterial infections
Adult: Initially, 800 mg followed by 400 mg 8 hourly usually
for about 7 days.
Child: <8 weeks 15 mg/kg once daily or divided into 7.5 mg/kg
12 hourly.
>8 weeks to 12 years 20-30 mg/kg as a single dose or divided
into 7.5 mg/kg 8 hourly for 7 days
The daily dose may be increased to 40 mg/kg based on the
severity of the infection.
Hepatic impairment: Severe: Reduce dose by 50%.

11. • Prophylaxis of Postoperative anaerobic bacterial infections
Adult: 400 mg 8 hourly in the 24 hours before /after surgery followed by IV
or rectal dosage post-operatively until oral therapy is possible.
Max: 4,000 mg daily.
Child: Newborn <40 weeks 10 mg/kg as single dose before surgery.
<12 years 20-30 mg/kg as a single dose given 1-2
hours before surgery.
Hepatic impairment: Severe: Reduce dose by 50%.

12. • Acute ulcerative gingivitis
Adult: 200 mg tid for 3 days.
Child: 1-3 years 50 mg tid for 3 days.
>3-7 years 100 mg bid for 3 days;
>7-10 years 100 mg tid for 3 days.
>10 years Same as adult dose.
Hepatic impairment: Severe: Reduce dose by 50%.
• Acute dental infections
Adult: 200 mg tid (or)
400 mg bid for 3-7 days.
Hepatic impairment: Severe: Reduce dose by 50%.

13. intravenous
Anaerobic bacterial infections
• Adult: 1,000-1,500 mg once daily as single dose. Alternatively, 500 mg 8
hourly via infusion at a rate of 5 mL/min over 20-60 minutes usually for
about 7 days.
• Max: 4,000 mg daily. Substitute oral therapy as soon as possible.
• Child: I><8 weeks 15 mg/kg once daily or divided into 7.5 mg/kg 12
hourly. >8 weeks to 12 years 20-30 mg/kg as a single dose or divided into
7.5 mg/kg 8 hourly.
• Treatment duration: Usually, 7 days. Daily dose may be increased to 40
mg/kg based on the severity of the infection.
• Hepatic impairment: Severe: Reduce dose by 50%.

14. Prophylaxis of postoperative anaerobic bacterial
infections
• Adult: 1,000-1,500 mg once daily for 30-60 minutes
preoperatively. Alternatively, 500 mg immediately prior,
during or after operation, then 500 mg 8 hourly for 24
hours.
• Child: <12 years 20-30 mg/kg as single dose given 1-2
hours prior surgery.
• Hepatic impairment: Severe: Reduce dose by 50%

15. Special considerations
• Patient with or history seizure disorder,
• blood dyscrasias (e.g. agranulocytosis,
leukopenia, neutropenia)
• Cockayne syndrome. Hepatic impairment and
severe renal impairment or ESRD.
• Pregnancy and lactation.

16. Monitoring Parameters
• Monitor CBC with differential count.
• Monitor LFT in patients with Cockayne
syndrome.
• Monitor neurologic symptoms.

17. Contraindications
• Hypersensitivity to metronidazole
and other nitroimidazoles.
• Concomitant use with disulfiram
within the last 14 days.
• Coadministration with alcohol or
propylene glycol containing
products.
• Pregnancy during the 1st trimester in
the treatment of trichomoniasis.

18. Adverse Drug Reactions
• Neurological disturbances
– encephalopathy,
– convulsive seizures,
– aseptic meningitis,
– peripheral and optic neuropathy,
– paraesthesia;
• Blood and lymphatic system disorders:
Leucopenia, especially neutropenia.
• Cardiac disorders: Chest pain, tachycardia.

19. Adverse Drug Reactions
• Investigations: Flattening of T wave on ECG.
• Ear and labyrinth disorders: Tinnitus.
• Eye disorders: Light sensitivity, nystagmus.
• Gastrointestinal disorders: Nausea, dry mouth,
vomiting, constipation, abdominal pain diarrhoea,
sharp unpleasant metallic taste.
• Metabolism and nutrition disorders: Anorexia.
• Musculo skeletal and connective tissue
disorders: Myalgia.

20. Adverse Drug Reactions
• Psychiatric disorders: Confusion, hallucination.
• Reproductive system : Genital pruritus.
• Respiratory, thoracic and mediastinal disorders: Pharyngitis, sinusitis.
• Skin subcutaneous tissue disorders: Erythematous rash, urticaria, dry skin.
• Vascular disorders: Syncope.

21. Potentially Fatal
• Stevens-johnson syndrome
• Toxic epidermal necrolysis
• Severe hepatotoxicity/acute
hepatic failure in patients with
cockayne syndrome.

22. Drug Interactions
• Disulfiram
• warfarin.
• lithium.
• phenobarbital or phenytoin.
• Ritonavir
• cyclosporin and busulfan.
• 5-fluorouracil.
• cimetidine

23. Lab Interference
• interfere with AST, ALT,
• triglycerides,
• glucose hexokinase,
• LDH testing.

24. Disease interactions
• Colitis
• Hypertension
• Blood dyscrasias
• Liver diseases
• Dialysis

25. Applications
• Acute necrotizing ulcerative gingivitis (ANUG )
• Facial abscess (anaerobic bacterial infections)
• Pericoronitis
• Pseudomembranous enterocolitis
• H. pylori infections
• Ameobiasis
• Giardiasis
• Trichomonas vaginitis
• Extraction of Dracunculus medinensis

29. Other drugs
• TINIDAZOLE:
– Congener of metronidazole
– Contraindicated in pregnancy and lactation
– Incombination with ciprofloxacin/norfloxacin
– Slower metabolism
– t1/2 is 12hrs
– Better tolerance
– Lower incidence of side effects
– Used most commonly for
• Acute necrotising ulcerative gingivitis 2 g as single dose
• Anaerobic bacterial infections 2 g on 1st day, then 1 g/day or 500 mg bid, for 5-6 days.
• Prophylaxis of post-op anaerobic bacterial infections 2 g, 12 hr before surgery

30. Secnidazole
• Rapid oral absorption.
• Slower metabolism.
• Plasma t1/2 is 17-29 hrs.
• Can be used as an alternative to metronidazole.
• Contraindicated in pregnancy and lactation.
• Used for
– PO Amoebiasis: 1.5gm/day for 5 days.
– Trichomoniasis : single dose of 2gm

31. ORNIDAZOLE:
• Longer t1/2 - 12-14 hrs
• Can be used in pregnancy with
caution
• Slow metabolism
• Commonly used for
– Surgical prophylaxsis 1gm 30min before
surgery
– Anaerobic bacterial infections Initial:
0.5-1 g, then 1 g/day in 1-2 divided doses
for 5-10 days
– Trichomonalis : 1.5 gm once daily
SATRANIDAZOLE:
• Longer t1/2 - 14hrs
• Greater potency
• Better tolerated
• Contraindicated in pregnancy
• Most commonly used for
– Amoebic liver abscess (300mg BD
10 days)
– Giardiasis (600mg single dose)

32. Resistance
• Gene mutation to PFOR, HYD, NIMR
• Decreased uptake of metronidazole
• Increased excretion of metronidazole
• Alternate pathway pyruvate fermentation
• Decreased intake of ferric ions (FeoAB)
• Increase/alter DNA repair mechanisms(DNA gyrase, RecQ)
• Reduction inactivation

33. Alternatives
Anti bacterials
• Moxifloxacin , but
• Beta lactems like
– Carbipenem
– Ticarcillin
– Piperacillin
• Cefadroxil
• Clindamycin
Anti protozoan
• Emetine , Dehydroxyemetine
• Chlorquine
• Tetracyclines , paromomycin

34. conclusion
• Nitroimidazoles are potent against anaerobic infections and
only popular options but,
• a surgeon should prescribe with caution while keeping in mind
its drug interactions and adverse effects and most importantly
resistance, as there is no gold standard alternate choice for the
anaerobic bacteria

35. References
• KD tripathi
• Sathoshkar
• CIMS online database
• Topazian
• Metronidazole: an update on metabolism, structure–cytotoxicity and resistance mechanisms Simon A.
Dingsdag1–3* and Neil Hunter1–3
• MINIREVIEW
Why Metronidazole Is Active against both Bacteria and Parasites JOHN SAMUELSON*
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115.

36. Thank you

39. 5 nitro
• Metronidazole
• Tinidazole
• Panidazole
• Ornidazole
• Secnidazole
• Carnidazole
• Ternidazole
• Nimorozole
• Dimetridazole
• Ipronidazole
4 nitro
Azathioprine
2 nitro
Azomycin
misonidazole

40. • Cockayne syndrome is a
rare disorder characterized by an
abnormally small head size
(microcephaly), a failure to gain
weight and grow at the expected
rate (failure to thrive) leading to
very short stature, and delayed
development with hepatic
dysfunction.