Amebicidal Drugs

Subject: Pharmacology Topic: Amoebicidal Drugs Lecturer: Dr. Dela Cruz Date of Lecture: Nov. 9, 2011 Transcriptionist: Pinay  Pages: 8

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Outline

ii.

Luminal Amebicides

I.

Introduction

1.

Paromomycin

II.

Classification of Amebicidal Drugs i.

2.

Erythromycin

Tissue Amebicides

3.

Tetracycline

1.

4.

Iodoquinol

5.

Dioloxanide furoate

Nitromidazole a.

Metronidazole

b.

Secnidazole

c.

Ornidazole

d.

Tinidazole

2.

Dehydroemetine

3.

Chloroquine

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)

bloodstream,

with

resultant

through

the

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

1

“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.

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. Paromomycin 2. Erythromycin 3. Tetracycline 4. Iodoquinol 5. Diloxanide furoate- removed from the market

Metronidazole

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 re sponsible for antimicrobial activity

2

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, electrontransport

proteins

that

participate

in

metabolic electron removal reactions

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 approximates extracellular levels (intracellularly (intracellularly located located  can

penetrate the cells of microorganisms) ♦

low plasma protein binding (