Antiamoebic Drugs

ANTI-PROTOZOAL DRUGS: 

ANTI-PROTOZOAL DRUGS

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ANTI-AMEBIC DRUGS

Life cycle of E. histolytica: 

Life cycle of E. histolytica

Therapeutic Classification of Anti-Amebic Drugs: 

Therapeutic Classification of Anti-Amebic Drugs I. Luminal Amebicides (Drugs effective in Luminal Infection only) 1. Dichloroacetamides Diloxanide Furoate 2. Halogenated Hydroxyquinolines Idoquinol ( Diiodohydroxyquine ) 3. Antibiotics: Tetracyclines , Paromomycin 4. Oral Bismuth Salt : Emetine Bismuth Iodide

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II. Extra-Luminal Amebicides A: Systemic or Tissue Amebicides 1. Chloroquine 2. Emetines : Emetine, Dehydroemetine B: 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): 

Metronidazole (Flagyl) Most commonly used Mixed tissue amebicide (Intestinal & extra Intestinal) not reliably effective against amebae in the lumen as luminal concentrations are too low for single drug treatment. Kills only trophozoits in intestinal wall but not the cysts of E. histolytica .

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Chemically --- Nitroimidazole

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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.

MOA: 

MOA Metronidazole 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 .

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Resistance: Not a therapeutic problem. Some strains of T. vaginalis are becoming resistance.

Antimicrobial Spectrum: 

Antimicrobial Spectrum Kills 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: 

Therapeutic Uses Versatile drug 1. 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

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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. Bacterial vaginosis : Can be used topically as a gel. 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 BD Pseudomembranous enterocolitis by Clostridium difficile . DOC. ( Vancomycin is the drug of second choice)

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Anaerobic/ mixed intra abdominal infections. Component of prophylaxis specially for colorectal surgery. Brain abscess. Acute Ulcerative Gingivitis. Facilitates extraction of adult guinea worm in Dranculosis Acne rosacae .

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Adverse Effects GIT: Dry mouth, metallic taste --- most common. Nausea, vomiting, abdominal cramps , Diarrhea. Oral thrush-- stomatitis Rarely Pancreatitis. Neurotoxicity: Headache, Insomnia, numbness or paraesthesias , weakness , dizziness. Rarely Ataxia, encephalopathy & seizures.

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III. OTHER A/E: Disulfiram like action with alcohol. Dysuria ,Dark urine. Mutagenic in bacteria. Carcinogenic in Rodents. Hypersensitivity reactions--- rash, neutropenia IV. Drug interactions - Potentiate Anticoagulant effect of Warfarin . - Metabolism of Metronidazole induced by Phenytoin & Phenobarbitone & Cimetidine may inhibit it. - Metronidazole increases Lithium toxicity.

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Contraindications Patient with active disease of the CNS. Hepatic Disease/Renal disease, dose adjustment should be done. Pregnancy/ Nursing Mothers.

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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

Emetines: 

Emetines Source: Emetine --- Alkaloid of Ipecacuanna (Ipecac) Dehydroemetine---Synthetic analog Effective against the trophozoits of Entameba histolytica.

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Therapeutic Uses :Limited use: Only w hen Metronidazole can not be used in : Severe Amoebic dysentry Hepatic Amebiasis Dehydroemetine is preferrd – better toxic profile Drug should be used S/C or I/M injection in a supervised setting Never given I/V Used only for minimum period to relieve severe symptoms. Usually 3-5 days.

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Adverse Effects Mild 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 changes Serious toxicity: Hypotension, Cardiac arrhythmias, Cardiac failure. Contraindications: Cardiac /renal disease Young children , pregnancy.

Chloroquine: 

Chloroquine Antimalarial 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): 

Diloxanide Furoate (Luminal amebicide) Dichloroacetamide derivative Pharmacokinetics: Given orally, in gut splits into Diloxanoid & furoic acid. 90% Diloxanoid is absorbed & conjugated to form glucuronide -- excreted in urine MOA: Not understood. Unabsorbed Diloxanoid is directly amebicidal against amebea in lumen but not those in intestinal wall.

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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 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 . 1 0% absorbed →Metabolized to Glucronides ,excreted in urine. Half life 11-14 hrs.

ADVERSE EFFECTS: 

ADVERSE EFFECTS Diarrhoea , anorexia, nausea, vomiting, abdominal pain. Headache Iodism : Dermatitis, urticaria , pruritis ,fever. Increased in protein bound iodine --- decreased 131 I measurement. Some idoquinol can produce severe neurotoxicity on prolonged use & high doses--- so used with caution CAUTIONS Taken with meals. With caution in: optic neuropathy , Non-amebic Hepatic disease , Renal or Thyroid disease. C/I in intolerance to Iodine.

ANTIBIOTICS: 

ANTIBIOTICS . Paromomycin Tetracyclines Uses: Luminal amebicides Asymptomatic infection (Carriers). Along with extra luminal amebicides in serious infections.

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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.

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Tetracyclines: Used as Luminal amebicide. Does not kill bacteria directly but disturbs the symbiosis between normal intestinal flora & E .histolytica . The amebae 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.

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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.

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Amebic Colitis with dysentery: Mild to moderate intestinal infection: DOC ---- Metronidazole & Luminal agent. Alternative ---- Dolixanide furoate, Iodoquinol, Paromomycin + Tetracycline / Erythromycin. Severe intestinal infection DOC ---- Metronidazole & Luminal agent Alternative ---- Dolixanide furoate, Iodoquinol, Paromomycin + Tetracycline / dehydroemetine or emetine.

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Hepatic abscess, ameboma & other Extra intestinal Infections: DOC ---- Metronidazole & luminal agent. For unusual cases--- not responding to Metronidazole Chloroquine + Luminal agent. Dehydroemetine or emetine.