Antiamoebic drugs 10 marks

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Antiamoebic Drugs

Introduction

Amoebiasis is caused by Entamoeba histolytica, transmitted via the fecal-oral route. It affects approximately 10% of the world's population, producing invasive disease in about 50 million people annually. The parasite can cause asymptomatic cyst carriage, amebic colitis (bloody dysentery), or extraintestinal disease (most commonly amebic liver abscess). Antiamoebic drugs are classified by their site of action into tissue amoebicides, luminal amoebicides, and drugs active at both sites.

Classification of Antiamoebic Drugs

Category	Drugs	Site of Action
Tissue amoebicides	Metronidazole, Tinidazole	Gut wall, liver, systemic
Luminal amoebicides	Diloxanide furoate, Paromomycin, Iodoquinol	Intestinal lumen
Both tissue + luminal	Metronidazole (partial luminal activity)	Both
Hepatic amoebicides	Chloroquine	Liver only
Alkaloids (obsolete)	Emetine, Dehydroemetine	Tissue

1. Metronidazole (Drug of Choice)

Class: Nitroimidazole

Mechanism of Action: Metronidazole undergoes reductive activation by low-redox-potential electron carriers (ferredoxin or pyruvate-ferredoxin oxidoreductase, PFOR) in anaerobic/microaerophilic organisms. The reduced nitro radical intermediate damages DNA by strand breaks, halting nucleic acid synthesis and causing cell death. Aerobic host cells do not reduce the drug, providing selective toxicity.

Pharmacokinetics:

Oral bioavailability: nearly 100%; absorbed completely and promptly
Plasma protein binding: < 20%
Volume of distribution: approximates total body water
Half-life: ~8 hours
Penetrates all body tissues and fluids including CSF, saliva, breast milk, and vaginal secretions (exception: placenta is less well penetrated)
Metabolized in liver by oxidation; > 75% excreted in urine (partly as metabolites); urine may appear reddish-brown

Therapeutic Uses:

Amebic colitis and amebic liver abscess (drug of choice): 500-750 mg orally three times daily for 7-10 days (adults); 35-50 mg/kg/day in three divided doses for children
Trichomoniasis: 2 g single dose
Giardiasis: 5-7 day course
Anaerobic bacterial infections (e.g., Bacteroides, Clostridium)
Helicobacter pylori (triple therapy)

Adverse Effects:

Gastrointestinal: nausea, vomiting, metallic taste, dry mouth, abdominal distress
CNS (dose-related): dizziness, vertigo, headache; rarely encephalopathy, convulsions, ataxia, peripheral neuropathy (warrants discontinuation)
Urticaria, flushing, pruritus (hypersensitivity)
Rarely: Stevens-Johnson syndrome (especially with concurrent mebendazole)
Reddish-brown discoloration of urine

Drug Interactions:

Disulfiram-like reaction with alcohol (avoid during and for 3 days after therapy): flushing, vomiting, abdominal distress
Prolongs prothrombin time with warfarin
May precipitate lithium toxicity
Metabolism induced by rifampin, phenobarbital; inhibited by cimetidine
Do not combine with disulfiram (psychotic states possible)

Contraindications/Precautions:

First trimester of pregnancy (generally avoided)
Active CNS disease (risk of neurotoxicity)
Dose reduction in severe hepatic disease

Important caveat: Because metronidazole is so well absorbed in the gut, luminal concentrations may not reach therapeutic levels. It is also less effective against cysts. Therefore, after completing metronidazole, a luminal amoebicide must always be added to eradicate intestinal cysts and trophozoites.

2. Tinidazole

Class: Second-generation nitroimidazole

Same mechanism as metronidazole
Longer half-life than metronidazole; can be used as a single dose (2 g) for amoebiasis and trichomoniasis
Better tolerated than metronidazole
Drug of choice for giardiasis (single 2 g dose, FDA-approved)
Used successfully against metronidazole-resistant T. vaginalis
Generally preferred over metronidazole when single-dose therapy is desired

3. Diloxanide Furoate

Class: Dichloroacetamide derivative; luminal amoebicide

Mechanism: Poorly absorbed; acts directly on amoebic trophozoites in the intestinal lumen by an unknown mechanism. About 90% is hydrolysed in the gut to diloxanide, which exerts the amoebicidal effect; only 10% is absorbed.

Uses:

Asymptomatic cyst passers (drug of choice for luminal eradication)
Always used after metronidazole/tinidazole to eradicate intestinal cysts
No effect against hepatic amoebiasis (not absorbed systemically)

Dose: 500 mg three times daily for 10 days

Adverse Effects: Flatulence (most common), nausea, vomiting, urticaria - generally well tolerated

4. Paromomycin

Class: Non-absorbed aminoglycoside antibiotic; luminal amoebicide

Mechanism: Acts directly in the intestinal lumen; inhibits protein synthesis (30S ribosomal subunit) in the parasite; is not significantly absorbed from the GI tract.

Uses:

Drug of choice for intestinal colonization with E. histolytica
Used in combination with metronidazole to treat amebic colitis and liver abscess (luminal phase)
Safe in pregnancy (drug of choice when metronidazole must be avoided, e.g., giardiasis or amoebiasis in pregnancy)
Alternative for metronidazole-resistant giardiasis

Dose: 25-35 mg/kg/day in three divided oral doses (adults and children)

Adverse Effects: Generally mild with oral use - abdominal cramping, epigastric pain, nausea/vomiting, steatorrhea, diarrhea; rarely rash and headache

5. Iodoquinol (Diiodohydroxyquin)

Class: 8-Hydroxyquinoline compound; luminal amoebicide

Mechanism: Chelates metal ions required by the parasite; acts only in the intestinal lumen (poorly absorbed)

Uses:

Luminal amoebiasis (asymptomatic cyst carriers)
Follow-up luminal treatment after metronidazole in invasive disease

Adverse Effects:

GI: nausea, diarrhea
Prolonged high-dose use may cause subacute myelo-optic neuropathy (SMON) - peripheral neuropathy and optic atrophy
Contains iodine - contraindicated in thyroid disease and iodine sensitivity
Interferes with thyroid function tests

6. Chloroquine

Class: 4-Aminoquinoline; hepatic amoebicide only

Mechanism: Concentrates in liver tissue; mechanism against amoebae similar to its antimalarial action (interferes with heme polymerization)

Uses:

Amebic liver abscess (third-line/alternative when metronidazole fails or is contraindicated)
Has no effect on intestinal amoebiasis
Usually combined with a luminal amoebicide

Dose: 600 mg base/day for 2 days, then 300 mg/day for 2-3 weeks

Note: Limited clinical use now due to superiority of metronidazole and tinidazole.

7. Emetine and Dehydroemetine (Historical/Obsolete)

Class: Ipecac alkaloids; tissue amoebicides

Mechanism: Inhibit protein synthesis by blocking peptide chain elongation (inhibit ribosomal translocation); kills trophozoites in tissues (gut wall and liver) but not cysts

Uses: Historically used for amebic colitis and liver abscess; now largely replaced by metronidazole due to high toxicity

Adverse Effects: Cardiotoxicity (ECG changes, arrhythmias, heart failure - most serious), myopathy (proximal muscle weakness), GI toxicity, neurotoxicity, pain at injection site. Must be given IM (not IV). ECG and bed rest mandatory during therapy. Dehydroemetine is less cardiotoxic.

8. Nitazoxanide

Class: Thiazolide antiparasitic

Mechanism: Inhibits PFOR enzyme-dependent electron transfer reactions essential to anaerobic metabolism in protozoa

Uses:

FDA-approved for cryptosporidiosis and giardiasis
Active against E. histolytica, G. intestinalis, T. vaginalis in vitro
Alternative for intestinal amoebiasis

Treatment Summary by Clinical Scenario

Clinical Presentation	First-line Treatment	Luminal Agent
Asymptomatic cyst passer	Diloxanide furoate or Paromomycin	Same drug
Amebic colitis	Metronidazole (7-10 days)	+ Diloxanide furoate or Paromomycin
Amebic liver abscess	Metronidazole or Tinidazole	+ Diloxanide furoate
Pregnancy	Paromomycin (luminal)	-

Key principle: Tissue amoebicides (metronidazole/tinidazole) must always be followed by a luminal amoebicide to prevent relapse, since metronidazole is poorly active in the gut lumen and does not eliminate cysts. Follow-up stool examination and treatment of household contacts are also recommended.

Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics (antiamoebic drug profiles, pharmacokinetics, and therapeutic uses); Maingot's Abdominal Operations; Bailey and Love's Short Practice of Surgery 28th ed.

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