ANTI-PROTOZOAL DRUGSANTI-PROTOZOAL DRUGS

ANTI-AMEBIC DRUGSANTI-AMEBIC DRUGS

Life cycle of E. histolyticaLife cycle of E. histolytica

Therapeutic Classification of Anti-Amebic DrugsTherapeutic Classification of Anti-Amebic Drugs

I.I. Luminal Amebicides Luminal Amebicides (Drugs effective in Luminal Infection only) (Drugs effective in Luminal Infection only)

1.1. DichloroacetamidesDichloroacetamides Diloxanide FuroateDiloxanide Furoate2.2. Halogenated HydroxyquinolinesHalogenated Hydroxyquinolines Idoquinol (Diiodohydroxyquine)Idoquinol (Diiodohydroxyquine)

3.3. Antibiotics: Antibiotics: Tetracyclines, ParomomycinTetracyclines, Paromomycin 4.4. Oral Bismuth Salt : Oral Bismuth Salt : Emetine Bismuth IodideEmetine Bismuth Iodide

II. Extra-Luminal AmebicidesII. Extra-Luminal AmebicidesA: Systemic or Tissue Amebicides A: Systemic or Tissue Amebicides 1. Chloroquine1. Chloroquine2. Emetines : Emetine, Dehydroemetine2. Emetines : Emetine, DehydroemetineB: Mixed Amebicides /Drugs effective in systemic & Intestinal B: Mixed Amebicides /Drugs effective in systemic & Intestinal

Amebiasis . (Amebiasis . (Not reliably effective against luminal infections as Not reliably effective against luminal infections as luminal concentrations are too low for single drug treatment)luminal concentrations are too low for single drug treatment) NitroimidazolesNitroimidazoles

MetronidazoleMetronidazole Tinidazole Tinidazole

Secnidazole.Secnidazole.

Metronidazole (Flagyl)Metronidazole (Flagyl)

Most commonly usedMost commonly used

Mixed tissue amebicide (Intestinal & extra Intestinal) not reliably Mixed tissue amebicide (Intestinal & extra Intestinal) not reliably effective against amebae in the lumen as luminal concentrations are effective against amebae in the lumen as luminal concentrations are too low for single drug treatment.too low for single drug treatment.

Kills only trophozoits in intestinal wall but not the cysts of E. Kills only trophozoits in intestinal wall but not the cysts of E. histolytica.histolytica.

Chemically --- NitroimidazoleChemically --- Nitroimidazole

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.

MOAMOA

Metronidazole kills protozoa & is bactericidal for anaerobic bacteria.Metronidazole kills protozoa & is bactericidal for anaerobic bacteria.• Metronidazole is a pro drug.Metronidazole is a pro drug. It requires reductive activation of theIt requires reductive activation of the NITRO group.NITRO group.• This occurs inThis occurs in sensitive anaerobic protozoa & anaerobic sensitive anaerobic protozoa & anaerobic bacteria by bacteria by Ferredoxins; Ferredoxins; which are electron transport which are electron transport proteins.proteins.• These proteins can donate electrons to Metronidazole ,which serves These proteins can donate electrons to Metronidazole ,which serves

as electron acceptor.as electron acceptor.• The reduced product is cytotoxic, it targets DNA & other The reduced product is cytotoxic, it targets DNA & other

biomolecules / proteins, resulting in cell death. biomolecules / proteins, resulting in cell death. Hence it kills the micro-organisms .Hence it kills the micro-organisms .

Resistance:Resistance:

Not a therapeutic problem.Not a therapeutic problem.

Some strains of T. vaginalis are becoming resistance. Some strains of T. vaginalis are becoming resistance.

Antimicrobial SpectrumAntimicrobial Spectrum

Kills anaerobic protozoa & bacteriaKills anaerobic protozoa & bacteria• Entameba Histolytica (Trophozoits only)Entameba Histolytica (Trophozoits only)

Trichomona VaginalisTrichomona Vaginalis

Giardia LambliaGiardia Lamblia

Clostridia – C . difficileClostridia – C . difficile

B. fragilisB. fragilis

Helicobacter pylori. Helicobacter pylori.

Also toxic to hypoxic / anoxic cellsAlso toxic to hypoxic / anoxic cells

Therapeutic UsesTherapeutic Uses

Versatile drugVersatile drug

1.1. Amebiasis Amebiasis: DOC in all tissue infections: DOC in all tissue infections• Acute intestinal Amebiasis / Amebic colitis with Acute intestinal Amebiasis / Amebic colitis with

dysentery. dysentery. 10 d course with a luminal amebicide10 d course with a luminal amebicide

Not reliably effective against parasites in lumen,Not reliably effective against parasites in lumen,• Hepatic AmebiasisHepatic Amebiasis :10 d course cures 95 % cases :10 d course cures 95 % cases

For cases in which initial therapy fails – For cases in which initial therapy fails –

Aspiration of abscess & addition of Chloroquine / Aspiration of abscess & addition of Chloroquine / Dehydroemetine or Emetine--- toxic Dehydroemetine or Emetine--- toxic

2. Trichomoniasis :2. Trichomoniasis : Treatment of choice single dose of 2g. Treatment of choice single dose of 2g.

Vaginal & urethral Trichomoniasis. Can be used topically.Vaginal & urethral Trichomoniasis. Can be used topically.

3.3. Giardiasis Giardiasis Treatment of choice--- single dose 90 % efficacy. Treatment of choice--- single dose 90 % efficacy.

4.4. Bacterial vaginosis: Can be used topically as a gel.Bacterial vaginosis: Can be used topically as a gel.

5.5. Eradication of H. Pylori in Peptic ulcer--a component of 14 Eradication of H. Pylori in Peptic ulcer--a component of 14 days triple therapy regimen. Metronidazole 500mg BD along days triple therapy regimen. Metronidazole 500mg BD along with a proton pump inhibitor BD, Clarithromycin 500mg BDwith a proton pump inhibitor BD, Clarithromycin 500mg BD

6.6. Pseudomembranous enterocolitis by Clostridium difficile. Pseudomembranous enterocolitis by Clostridium difficile. DOC. (Vancomycin is the drug of second choice)DOC. (Vancomycin is the drug of second choice)

5.5. Anaerobic/ mixed intra abdominal infections.Anaerobic/ mixed intra abdominal infections.6.6. Component of prophylaxis specially for colorectal Component of prophylaxis specially for colorectal

surgery. surgery. 7.7. Brain abscess. Brain abscess. 8.8. Acute Ulcerative Gingivitis.Acute Ulcerative Gingivitis.9.9. Facilitates extraction of adult guinea worm in Facilitates extraction of adult guinea worm in

DranculosisDranculosis10.10. Acne rosacae.Acne rosacae.

Adverse EffectsAdverse Effects GIT:GIT:

Dry mouth, metallic taste --- most common.Dry mouth, metallic taste --- most common. Nausea, vomiting, abdominal cramps , Diarrhea.Nausea, vomiting, abdominal cramps , Diarrhea. Oral thrush--stomatitisOral thrush--stomatitisRarelyRarely Pancreatitis. Pancreatitis.Neurotoxicity:Neurotoxicity: Headache, Insomnia, numbness or paraesthesias, Headache, Insomnia, numbness or paraesthesias,

weakness , dizziness.weakness , dizziness.Rarely Rarely Ataxia, encephalopathy & seizures.Ataxia, encephalopathy & seizures.

III. OTHER A/E: III. OTHER A/E: 1.1. Disulfiram like action with alcohol.Disulfiram like action with alcohol.2.2. Dysuria ,Dark urine.Dysuria ,Dark urine.3.3. Mutagenic in bacteria. Mutagenic in bacteria. 4.4. Carcinogenic in Rodents.Carcinogenic in Rodents.5.5. Hypersensitivity reactions--- rash, neutropeniaHypersensitivity reactions--- rash, neutropeniaIV. Drug interactionsIV. Drug interactions

- Potentiate Anticoagulant effect of Warfarin.- Potentiate Anticoagulant effect of Warfarin.

- Metabolism of Metronidazole induced by Phenytoin & - Metabolism of Metronidazole induced by Phenytoin & Phenobarbitone & Cimetidine may inhibit it.Phenobarbitone & Cimetidine may inhibit it.

- Metronidazole increases Lithium toxicity.- Metronidazole increases Lithium toxicity.

ContraindicationsContraindications

Patient with active disease of the CNS.Patient with active disease of the CNS.

Hepatic Disease/Renal disease, dose adjustment should Hepatic Disease/Renal disease, dose adjustment should be done.be done.

Pregnancy/ Nursing Mothers. Pregnancy/ Nursing Mothers.

Tinidazole Tinidazole : : • It is a second- generation Nitroimidazole.It is a second- generation Nitroimidazole.• Congener of MetronidazoleCongener of Metronidazole• It is similar to Metronidazole in spectrum of activity, MOA , It is similar to Metronidazole in spectrum of activity, MOA ,

absorption , A/E & D/I.absorption , A/E & D/I.• It is also effective against cysts of E.histolytica.It is also effective against cysts of E.histolytica.• It is longer acting –once daily dose.It is longer acting –once daily dose.• Short course– 2gm daily, single dose-- for 3 days. Short course– 2gm daily, single dose-- for 3 days. Secnidazole:Secnidazole: Longer acting Longer acting Single 2gm dose is given Single 2gm dose is given

EmetinesEmetines

Source:Source: Emetine --- Alkaloid of Ipecacuanna (Ipecac) Emetine --- Alkaloid of Ipecacuanna (Ipecac)

Dehydroemetine---Synthetic analogDehydroemetine---Synthetic analog

Effective against the trophozoits of Entameba histolytica.Effective against the trophozoits of Entameba histolytica.

Therapeutic UsesTherapeutic Uses :Limited use: Only w :Limited use: Only when Metronidazole can not be hen Metronidazole can not be used in :used in :

Severe Amoebic dysentrySevere Amoebic dysentry

Hepatic AmebiasisHepatic Amebiasis

Dehydroemetine is preferrd– better toxic profileDehydroemetine is preferrd– better toxic profile

Drug should be used S/C or I/M injection in a supervised setting Drug should be used S/C or I/M injection in a supervised setting

Never given I/V Never given I/V

Used only for minimum period to relieve severe symptoms. Usually 3-5 Used only for minimum period to relieve severe symptoms. Usually 3-5 days. days.

Adverse EffectsAdverse EffectsMild when used for 3-5 days, increase with time Mild when used for 3-5 days, increase with time

Diarrhea .Diarrhea .

Central nausea & vomitingCentral nausea & vomiting

Pain & tenderness at site of injection/ sterile abscess.Pain & tenderness at site of injection/ sterile abscess.

Muscle weakness & discomfort.Muscle weakness & discomfort.

Minor ECG changesMinor ECG changes

Serious toxicity:Serious toxicity:

Hypotension, Cardiac arrhythmias, Cardiac failure.Hypotension, Cardiac arrhythmias, Cardiac failure.

Contraindications:Contraindications:

Cardiac /renal disease Cardiac /renal disease

Young children , pregnancy.Young children , pregnancy.

ChloroquineChloroquine

Antimalarial drug –already discussed.Antimalarial drug –already discussed.

Tissue Amebicide specially against Amoebic Hepatitis & Tissue Amebicide specially against Amoebic Hepatitis & Liver Abscess.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 Dichloroacetamide derivative

Pharmacokinetics: Pharmacokinetics: Given orally, in gut splits into Diloxanoid Given orally, in gut splits into Diloxanoid & furoic acid. 90% Diloxanoid is absorbed & conjugated & furoic acid. 90% Diloxanoid is absorbed & conjugated to form glucuronide -- excreted in urine to form glucuronide -- excreted in urine

MOA:MOA: Not understood. Not understood.

Unabsorbed Diloxanoid is directly amebicidalUnabsorbed Diloxanoid is directly amebicidal

against amebea in lumen but not those in intestinal wall.against amebea in lumen but not those in intestinal wall.

Therapeutic uses:Therapeutic uses:

Drug of choice for Asymptomatic Luminal Amoebiasis Drug of choice for Asymptomatic Luminal Amoebiasis (cyst passers)(cyst passers)

Alongwith tissue amebicide in severe intestinal & extra Alongwith tissue amebicide in severe intestinal & extra

intestinal amebiasisintestinal amebiasis..Adverse effectsAdverse effects

FlatulenceFlatulence

Nausea, abdominal crampsNausea, abdominal cramps

Skin rashes rarely.Skin rashes rarely.

Precautions:Precautions: Pregnancy Pregnancy

IODOQUINOLIODOQUINOL

Iodoquinol (Diiodohydroxyquine) is a halogenated hydroxyquinoline. Iodoquinol (Diiodohydroxyquine) is a halogenated hydroxyquinoline.

An effective luminal amobecide used with metronidazole to treat An effective luminal amobecide used with metronidazole to treat amebic infections.amebic infections.

Only effective against trophozoits in lumen.Only effective against trophozoits in lumen.

Pharmacokinetics :-Pharmacokinetics :-Poorly understoodPoorly understood

90% unabsorbed 90% unabsorbed → amebicide.→ amebicide.

110% absorbed 0% absorbed →Metabolized to Glucronides ,excreted in urine. Half →Metabolized to Glucronides ,excreted in urine. Half life 11-14 hrs.life 11-14 hrs.

ADVERSE EFFECTSADVERSE EFFECTS

Diarrhoea, anorexia, nausea, vomiting, abdominal pain.Diarrhoea, anorexia, nausea, vomiting, abdominal pain.

Headache Headache

IodismIodism:: Dermatitis, urticaria , pruritis ,fever. Dermatitis, urticaria , pruritis ,fever.

Increased in protein bound iodine --- decreased Increased in protein bound iodine --- decreased 131131I measurement.I measurement.

Some idoquinol can produce severe neurotoxicity on prolonged use Some idoquinol can produce severe neurotoxicity on prolonged use & high doses--- so used with caution & high doses--- so used with caution

CAUTIONSCAUTIONS

Taken with meals.Taken with meals.

With caution in: optic neuropathy , Non-amebic Hepatic disease , With caution in: optic neuropathy , Non-amebic Hepatic disease , Renal or Thyroid disease.Renal or Thyroid disease.

C/I in intolerance to Iodine.C/I in intolerance to Iodine.

ANTIBIOTICSANTIBIOTICS

..

ParomomycinParomomycin

Tetracyclines Tetracyclines

Uses: Uses: Luminal amebicides Luminal amebicides

1.1. Asymptomatic infection (Carriers).Asymptomatic infection (Carriers).

2.2. Along with extra luminal amebicides in serious Along with extra luminal amebicides in serious infections.infections.

Paromomycin sulphate:Paromomycin sulphate:An aminoglycoside antibiotic.An aminoglycoside antibiotic.Not significantly absorbed from the gut.Not significantly absorbed from the gut.

Used as Luminal amebicideUsed as Luminal amebicide..Less toxic than other agents.Less toxic than other agents.Superior to Diloxanide furoate in clearing asyptomatic Superior to Diloxanide furoate in clearing asyptomatic infections.infections.No effect on extra-intestinal amebic infections.No effect on extra-intestinal amebic infections.Also used in visceral leishmeniasis paenterally.Also used in visceral leishmeniasis paenterally.

A/E: Abd. Distress & diarrhea.A/E: Abd. Distress & diarrhea.

Tetracyclines:Tetracyclines:Used as Luminal amebicide.Used as Luminal amebicide.

Does not kill bacteria directly but disturbs the symbiosis Does not kill bacteria directly but disturbs the symbiosis between normal intestinal flora & E .histolytica . Thebetween normal intestinal flora & E .histolytica . The

amebae grow at expense of normal intestinal flora .amebae grow at expense of normal intestinal flora .

Tetracyclines are broad spectrum antibiotics & kill these Tetracyclines are broad spectrum antibiotics & kill these flora leading to death of E .histolytica also.flora leading to death of E .histolytica also.

Used in resistant cases.Used in resistant cases.

Treatment of specific forms of Amebiasis:Treatment of specific forms of Amebiasis:

Asymptomatic intestinal infection.Asymptomatic intestinal infection.

Generally not treated in endemic area.Generally not treated in endemic area.

In non-endemic area treated with luminal amebicide. In non-endemic area treated with luminal amebicide. – Dolixanide furoateDolixanide furoate– IodoquinolIodoquinol– Paromomycin. Paromomycin.

May be combined with tetracyclines.May be combined with tetracyclines.

Amebic Colitis with dysentery:Amebic Colitis with dysentery:Mild to moderate intestinal infection:Mild to moderate intestinal infection:DOC ---- Metronidazole & Luminal agent.DOC ---- Metronidazole & Luminal agent.Alternative ---- Alternative ---- Dolixanide furoate, Iodoquinol, Dolixanide furoate, Iodoquinol,

Paromomycin + Tetracycline / Erythromycin. Paromomycin + Tetracycline / Erythromycin. Severe intestinal infectionSevere intestinal infectionDOC ---- Metronidazole & Luminal agentDOC ---- Metronidazole & Luminal agentAlternative ---- Alternative ---- Dolixanide furoate, Iodoquinol, Dolixanide furoate, Iodoquinol,

Paromomycin + Tetracycline / dehydroemetine or Paromomycin + Tetracycline / dehydroemetine or emetine.emetine.

Hepatic abscess, ameboma & other Extra intestinal Hepatic abscess, ameboma & other Extra intestinal Infections:Infections:

DOC ---- Metronidazole & luminal agent.DOC ---- Metronidazole & luminal agent.

For unusual cases--- not responding to Metronidazole For unusual cases--- not responding to Metronidazole – Chloroquine + Luminal agent.Chloroquine + Luminal agent.– Dehydroemetine or emetine.Dehydroemetine or emetine.