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.
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.
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.
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 .
Resistance: Not a therapeutic problem. Some strains of T. vaginalis are becoming resistance.
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
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
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)
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.
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.
Contraindications Patient with active disease of the CNS. Hepatic Disease/Renal disease, dose adjustment should be done. Pregnancy/ Nursing Mothers.
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
EmetinesSource: Emetine --- Alkaloid of Ipecacuanna (Ipecac)Dehydroemetine---Synthetic analogEffective against the trophozoits of Entameba histolytica.
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.
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.
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
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.
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
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.
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.
ANTIBIOTICS. Paromomycin TetracyclinesUses: Luminal amebicides5. Asymptomatic infection (Carriers).6. Along with extra luminal amebicides in serious infections.
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.
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.
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.