Outline

I. IntroductionII. Classification of Amebicidal Drugs

i. Tissue Amebicides1. Nitromidazole

a. Metronidazoleb. Secnidazolec. Ornidazoled. Tinidazole

2. Dehydroemetine

3. Chloroquine

ii. Luminal Amebicides1. Paromomycin2. Erythromycin3. Tetracycline4. Iodoquinol5. Dioloxanide furoate

1. Infection by Entamoeba histolytica occurs by ingestion of mature cysts in fecally contaminated food, water, or hands.

2. Excystation occurs in the small intestine and release trophozoites which migrate to the large intestine.

3. The trophozoites multiply and produce both cysts and trophozoites

♦ In many cases, the trophozoites remain confined to the intestinal lumen (noninvasive infection) - asymptomatic carriers that continuously pass cysts in their stool.

♦ In some patients the trophozoites invade the intestinal mucosa (intestinal disease), or go to extraintestinal sites such as the liver, brain, and lungs (extraintestinal disease) through the bloodstream, with resultant pathologic manifestations. Both cysts and trophozoites are passed in the feces.

♦ Trophozoites passed in the stool are rapidly destroyed once outside the body. If ingested, would not survive exposure to the gastric environment.

♦ Cysts are typically found in formed stool, whereas trophozoites are typically found in diarrheic stool. The cysts can survive days to weeks in the external environment because of the protection conferred

Subject: PharmacologyTopic: Amoebicidal DrugsLecturer: Dr. Dela CruzDate of Lecture: Nov. 9, 2011Transcriptionist: Pinay Pages: 8

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by their walls, and are responsible for transmission. They are resistant to gastric acid and become the source of infection.

Classification of Amebicidal Drugs

I. Tissue Amebicides- Drugs that act primarily in the bowel wall, liver and other extraintestinal

tissues

1. Nitroimidazole- with nitro group

Metronidazole- prototype drug

Ornidazole

Secnidazole

Tinidazole

2. Dehydroemetine

3. Chloroquine

II. Luminal Amebicides- Drugs that act in the bowel lumen- Do not invade the intestinal wall

1. Paromomycin2. Erythromycin3. Tetracycline4. Iodoquinol5. Diloxanide furoate- removed from the market

Metronidazole

“Flask-shaped” ulcer of invasive intestinal amebiasis Note that the apex of the ulcer at the bowel lumen is narrower than the base, accounting for the flask shape. This is formed as trophozoites invade through the mucosa and move laterally into the submucosa (direction of ulcer expansion is marked by arrows). Microscopically, trophozoites are localized to the advancing edges of the submucosal ulcer.

Mode and Spectrum of action: (-cidal)

♦ Amebicidal for E. histolytica

♦ Bactericidal for Anaerobic bacteria: Bacteroides, Clostridium species

♦ also -cidal for the protozoans Trichomonas vaginalis and Giardia lamblia

Pharmacokinetics:

♦ oral forms (tablet and suspension) are rapidly and completely absorbed from the GIT (almost 100% oral bioavailability)

♦ also available for intravenous injection, intravaginal (for trichomoniasis) and topical formulations

♦ absorption of topical preparation are less complete and more prolonged

♦ distributes well to all body tissues and fluids (therapeutic levels in vaginal and seminal fluids, saliva, breast milk and CSF)

♦ peak plasma concentration is reached in 1-3 hours

♦ Intracellular concentrations rapidly approximates extracellular levels (intracellularly located can penetrate the cells of microorganisms)

♦ low plasma protein binding (<20%)

♦ half-life of 8 hours

♦ Metabolized by hepatic oxidation of the side chain by CYP450 (Phase I) and subsequently glucuronylated (Phase II)

Metronidazole is activated by the reduction of the nitro group (arrow) leading to the generation of a reactive radical. Reactive reduction products appear to be responsible for antimicrobial activity

The nitro group of Metronidazole is chemically reduced in anaerobic bacteria and sensitive protozoans. It binds to the DNA and proteins of these organisms which causes cell death.

Mechanism of Action:

Nitro group of the drug serve as an electron acceptor forming reduced cytotoxic cpds that binds to proteins and DNA resulting in cell death.

Anaerobic and protozoal parasites possess ferredoxin-like, low-redox potential, electron-transport proteins that participate in metabolic electron removal reactions

♦ drug and its metabolites are excreted in the urine (only ~ 10% excreted unchanged)

Clinical Indications:

1. Anaerobic infection- serious infection

♦ Intra-abdominal infection

♦ Brain abscess

♦ Peritonsillar abscess

♦ primary therapy for infection with Clostridium difficile (pseudomembranous colitis)

2. Amebiasis

♦ Drug of choice for treatment of all symptomatic forms of amebiasis, including amebic colitis and amebic liver abscess (extra-intestinal infection)

♦ Both tissue and luminal amebicide (extra- and intra-intestinal infection)

3. Giardiasis

4. Genital infection with Trichomonas vaginalis in both female (carrier of organism) and male (transmits organism). (2 g single dose)

5. H. pylori infection- Peptic Ulcer Disease

♦ In combination with other antimicrobials and proton pump inhibitors

♦ Clarithromycin + Amoxicillin

6. Rosacea – topical lotion

Adverse Effects:

1. GIT

♦ dry mouth, nausea, vomiting

♦ epigastric distress, abdominal cramps

♦ unpleasant metallic taste in the mouth

♦ diarrhea

♦ furry tongue, glossitis, and stomatitis

2. CNS- neurotoxic

♦ headache, dizziness , vertigo

♦ insomnia

♦ numbness or paresthesias in the extremities

♦ encephalopathy, convulsions, incoordination, and ataxia (especially when given to Px with renal/liver dysfunction)

3. Darkening of the urine (reddish brown urine discoloration)- d/t reduction of nitro group production of pigments

4. Disulfiram-like effect when taken with Alcohol (during and within 3 days of therapy)

♦ Disulfiram acts by inhibiting the enzyme Aldehyde dehydrogenase

♦ Disulfiram is used to treat alcoholism

♦ produce accumulation of acetaldehyde

♦ When a patient takes alcohol in the presence of Disulfiram, acetaldehyde accumulates producing an unpleasant reaction such as facial flushing, nausea, vomiting, dizziness and headache so Px would stop taking alcohol

5. Hypersensitivity reactions

♦ skin rashes, urticaria

♦ flushing, pruritus

♦ Stevens Johnson Syndrome

Emetine / Dehydroemetine

♦ Emetine hydrochloride is a plant alkaloid derived from Ipecac

♦ Dehydroemetine is a synthetic analogue (less toxic)

♦ Dehydroemetine is only available under compassionate investigational new drug protocol through the Center for Disease Control and Prevention (last resort if all the other drugs are used and still has no effect)

♦ alternative drugs for treatment of extra-intestinal amebiasis

Mechanism of action:

♦ Irreversible inhibition of protein synthesis by blocking chain elongation

♦ acts on trophozoites

Pharmacokinetics:

♦ erratic oral absorption

♦ preferably given by subcutaneous or intramuscular injection

♦ should never be given intravenously!

♦ concentrated in the liver, lungs, spleen, kidneys, myocardium, intestinal wall (persist for a month after a single dose)

♦ slowly metabolized and excreted

♦ trace amounts could be detected in urine 1- 2 months after last dose

♦ should not be used for more than 10 days (usually 3-5 days)

♦ half-life 5 days

♦ use is limited by toxicity

♦ close clinical observation is necessary when drug is administered

Adverse effects:

1. Cardiotoxicity (depression of cardiac conduction and contraction)

♦ Arrhythmia

♦ Congestive heart failure

♦ Death

2. Antiadrenergic action

♦ Hypotension

♦ Dizziness

3. Nausea and vomiting

♦ central origin

4. Decrease serum potassium

5. Pain at site of injection

6. Neuromuscular weakness

Iodoquinol

• a halogenated 8-hydroxyquinoline

• exact MOA unknown

• amebicidal vs E. histolytica

• effective against trophozoites and cyst forms in the intestinal lumen

• not for trophozoites in the bowel wall

Pharmacokinetics:

♦ oral preparation (tablet)

♦ poor absorption from the GIT

♦ metabolized by glucuronidation

♦ 10% of the drug enters the circulation and excreted as glucuronide metabolite in the urine

♦ half life is 11-14 hrs

♦ primarily excreted in the feces

Adverse effects:

♦ fever and chills, rash

♦ GIT – nausea, vomiting, diarrhea

♦ thyroid gland enlargement & abnormalities in the thyroid function test (d/t Iodine present in the structure)

♦ dose related peripheral neuropathy (e.g. optic neuritis)

Paromomycin

♦ an aminoglycoside antibiotic

♦ same antibacterial action as other Aminoglycosides

♦ Oral (capsule), topical and parenteral formulations

♦ Effective against intestinal forms of E. histolytica

Mechanism of Amebicidal action:

♦ Direct action - causes leakage of intracellular components by its action on cell membrane of parasite (direct action on the cyst)

♦ Indirect action – reduces population of intestinal flora destroy the source of nutrients

Pharmacokinetics:

♦ oral formulation (capsule)

♦ negligible absorption from the GIT

♦ 100% of the drug is recovered in the feces

♦ small amount absorbed is excreted unchanged in the urine (may accumulate with renal insufficiency)

Therapeutic Uses:

1. Amebiasis

♦ asymptomatic cysts passers- they can still transmit the infection

♦ as adjunct in the treatment of amebic and amebic liver abscess

2. Adjunct treatment of Hepatic coma

3. Cutaneous and visceral Leishmaniasis

4. Giardiasis

Adverse Effects:

♦ abdominal pain and cramping

♦ nausea and vomiting

♦ steatorrhea

♦ diarrhea

♦ skin rashes

♦ Headache

Chloroquine

♦ used in combination with Metronidazole and Diloxanide furoate (luminal amebicide) in the prevention and treatment of amebic liver abscess

♦ eliminates trophozoites in extraintestinal sites

♦ not useful in eradicating cysts in the bowel lumen it has luminal effect but is not significant to remove the cyst

♦ also effective in the treatment of malaria

Classification of Amebiasis and Treatment

Asymptomatic Intestinal Infection

- asymptomatic carriers generally are not treated in endemic areas- in non-endemic areas they are treated with a luminal amebicide (diloxanide

furoate, iodoquinol, paromomycin). Each drug eradicates carriage in about 80-90% of Px with a single course of treatment.

- a tissue amebicidal drug is unnecessary

Amebic colitis & dysentery

- Metronidazole + luminal amebicide- Tetracycline and Erythromycin for moderate colitis; not effective against

extra-intestinal disease- Dehydroemetine and Emetine can also be used, but are best avoided because

of toxicity

Extraintestinal Infection

- Metronidazole + Luminal amebicide- 10-day course of treatment cures 95% of uncomplicated liver abscesses.- Addition of Chloroquine + aspiration of abscess if initial therapy of

metronidazole has failed- Dehydroemetine and Emetine can also be used, but are best avoided because

of toxicity

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