5. II. Extra-Luminal AmebicidesA: Systemic or Tissue Amebicides1. Chloroquine2. Emetines : Emetine, DehydroemetineB: Mixed Amebicides /Drugs effective in systemic & Intestinal Amebiasis . (Not reliably effective against luminal infections as luminal concentrations are too low for single drug treatment) Nitroimidazoles Metronidazole Tinidazole Secnidazole.
6. Metronidazole (Flagyl)Most commonly usedMixed tissue amebicide (Intestinal & extra Intestinal) not reliablyeffective against amebae in the lumen as luminal concentrations aretoo low for single drug treatment.Kills only trophozoits in intestinal wall but not the cysts of E.histolytica.
7. Chemically --- Nitroimidazole
8. Pharmacokinetics:Prep: Oral, I/V infusion, topical gel, cream. Abs. well & almost complete from GIT, some unabsorbed drug reaches colon. PPL:1- 3 hrs Dist Rapid & wide. Distributed to all tissues & high concentrations in body fluids– CSF & brain. Also in Vaginal secretions ,saliva. t ½: 7.5 hrs Met: in the liver; may accumulate in hepatic insufficiency Excretion: urine.
9. MOAMetronidazole kills protozoa & is bactericidal for anaerobic bacteria.• Metronidazole is a pro drug. It requires reductive activation of the NITRO group. This occurs in sensitive anaerobic protozoa & anaerobic bacteria by Ferredoxins; which are electron transport proteins.• These proteins can donate electrons to Metronidazole ,which serves as electron acceptor.• The reduced product is cytotoxic, it targets DNA & other biomolecules / proteins, resulting in cell death. Hence it kills the micro-organisms .
10. Resistance: Not a therapeutic problem. Some strains of T. vaginalis are becoming resistance.
11. Antimicrobial SpectrumKills anaerobic protozoa & bacteria• Entameba Histolytica (Trophozoits only) Trichomona Vaginalis Giardia Lamblia Clostridia – C . difficile B. fragilis Helicobacter pylori.Also toxic to hypoxic / anoxic cells
12. Therapeutic Uses Versatile drug1. Amebiasis: DOC in all tissue infections Acute intestinal Amebiasis / Amebic colitis with dysentery. 10 d course with a luminal amebicide Not reliably effective against parasites in lumen, Hepatic Amebiasis :10 d course cures 95 % cases For cases in which initial therapy fails –Aspiration of abscess & addition of Chloroquine / Dehydroemetine or Emetine--- toxic
13. 2. Trichomoniasis : Treatment of choice single dose of 2g. Vaginal & urethral Trichomoniasis. Can be used topically.3. Giardiasis Treatment of choice--- single dose 90 % efficacy.4. Bacterial vaginosis: Can be used topically as a gel.5. Eradication of H. Pylori in Peptic ulcer--a component of 14 days triple therapy regimen. Metronidazole 500mg BD along with a proton pump inhibitor BD, Clarithromycin 500mg BD6. Pseudomembranous enterocolitis by Clostridium difficile. DOC. (Vancomycin is the drug of second choice)
14. 1. Anaerobic/ mixed intra abdominal infections.2. Component of prophylaxis specially for colorectal surgery.3. Brain abscess.4. Acute Ulcerative Gingivitis.5. Facilitates extraction of adult guinea worm in Dranculosis6. Acne rosacae.
16. III. OTHER A/E:2. Disulfiram like action with alcohol.3. Dysuria ,Dark urine.4. Mutagenic in bacteria.5. Carcinogenic in Rodents.6. Hypersensitivity reactions--- rash, neutropeniaIV. Drug interactions- Potentiate Anticoagulant effect of Warfarin.- Metabolism of Metronidazole induced by Phenytoin & Phenobarbitone & Cimetidine may inhibit it.- Metronidazole increases Lithium toxicity.
17. Contraindications Patient with active disease of the CNS. Hepatic Disease/Renal disease, dose adjustment should be done. Pregnancy/ Nursing Mothers.
18. Tinidazole :• It is a second- generation Nitroimidazole.• Congener of Metronidazole• It is similar to Metronidazole in spectrum of activity, MOA , absorption , A/E & D/I.• It is also effective against cysts of E.histolytica.• It is longer acting –once daily dose.• Short course– 2gm daily, single dose-- for 3 days.Secnidazole: Longer acting Single 2gm dose is given
19. EmetinesSource: Emetine --- Alkaloid of Ipecacuanna (Ipecac)Dehydroemetine---Synthetic analogEffective against the trophozoits of Entameba histolytica.
20. Therapeutic Uses :Limited use: Only when Metronidazole can not be used in : Severe Amoebic dysentry Hepatic AmebiasisDehydroemetine is preferrd– better toxic profileDrug should be used S/C or I/M injection in a supervised settingNever given I/VUsed only for minimum period to relieve severe symptoms. Usually 3-5 days.
21. Adverse EffectsMild when used for 3-5 days, increase with time Diarrhea . Central nausea & vomiting Pain & tenderness at site of injection/ sterile abscess. Muscle weakness & discomfort. Minor ECG changesSerious toxicity: Hypotension, Cardiac arrhythmias, Cardiac failure.Contraindications:Cardiac /renal diseaseYoung children , pregnancy.
22. ChloroquineAntimalarial drug –already discussed. Tissue Amebicide specially against Amoebic Hepatitis & Liver Abscess. Concentrated in liver; kills trophozoits of E. histolytica Not effective for amebic colitis or luminal amebae because absorbed in upper intestine.TH.use: Hepatic amebiasis / abscess; not responding to Metronidazole
23. Diloxanide Furoate (Luminal amebicide)Dichloroacetamide derivativePharmacokinetics: Given orally, in gut splits into Diloxanoid & furoic acid. 90% Diloxanoid is absorbed & conjugated to form glucuronide -- excreted in urineMOA: Not understood.Unabsorbed Diloxanoid is directly amebicidal against amebea in lumen but not those in intestinal wall.
24. Therapeutic uses: Drug of choice for Asymptomatic Luminal Amoebiasis (cyst passers) Alongwith tissue amebicide in severe intestinal & extra intestinal amebiasis. Adverse effects Flatulence Nausea, abdominal cramps Skin rashes rarely.Precautions: Pregnancy
25. IODOQUINOL Iodoquinol (Diiodohydroxyquine) is a halogenated hydroxyquinoline. An effective luminal amobecide used with metronidazole to treat amebic infections. Only effective against trophozoits in lumen.Pharmacokinetics :-Poorly understood 90% unabsorbed → amebicide. 10% absorbed →Metabolized to Glucronides ,excreted in urine. Half life 11-14 hrs.
26. ADVERSE EFFECTS Diarrhoea, anorexia, nausea, vomiting, abdominal pain. Headache Iodism: Dermatitis, urticaria , pruritis ,fever. Increased in protein bound iodine --- decreased 131I measurement. Some idoquinol can produce severe neurotoxicity on prolonged use & high doses--- so used with cautionCAUTIONS Taken with meals. With caution in: optic neuropathy , Non-amebic Hepatic disease , Renal or Thyroid disease. C/I in intolerance to Iodine.
27. ANTIBIOTICS. Paromomycin TetracyclinesUses: Luminal amebicides5. Asymptomatic infection (Carriers).6. Along with extra luminal amebicides in serious infections.
28. Paromomycin sulphate: An aminoglycoside antibiotic. Not significantly absorbed from the gut. Used as Luminal amebicide. Less toxic than other agents. Superior to Diloxanide furoate in clearing asyptomatic infections. No effect on extra-intestinal amebic infections. Also used in visceral leishmeniasis paenterally.A/E: Abd. Distress & diarrhea.
29. Tetracyclines: Used as Luminal amebicide. Does not kill bacteria directly but disturbs the symbiosis between normal intestinal flora & E .histolytica . Theamebae grow at expense of normal intestinal flora .Tetracyclines are broad spectrum antibiotics & kill these flora leading to death of E .histolytica also.Used in resistant cases.
30. Treatment of specific forms of Amebiasis:Asymptomatic intestinal infection. Generally not treated in endemic area. In non-endemic area treated with luminal amebicide. – Dolixanide furoate – Iodoquinol – Paromomycin. May be combined with tetracyclines.