Nitro imidazoles

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

1. NITROIMIDAZOLES -Dr U Bharath kumar 1 st 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

26. 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 dos e 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

27. 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

28. 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)

29. 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

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

31. 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

32. 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.

33. Thank you

34. 5 nitro Metronidazole Tinidazole Panidazole Ornidazole Secnidazole Carnidazole Ternidazole Nimorozole Dimetridazole Ipronidazole 4 nitro Azathioprine 2 nitro Azomycin misonidazole

35. 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.