Antiamoebic Drugs

• Amebiasis affects about 10% of the world'spopulation, causing invasive disease in about 50million people and death in about 100,000 ofthese annually.

• Amoebiasis is an acute or chronic infection withEntamoeba histolytica produced by ingestion ofcysts of this organism.

• The parasite exist in two form:

-Trophozoites or active form- does not persist outside the body.

– Cyst or inactive form: can survive outside the body, & labile.

• The outcome infection is variable.

• Asymptomatic but excrete the infectious cyst form,making them a source for further infections.

• Amebic dysentery : Trophozoites invade into thecolonic mucosa with resulting colitis and bloodydiarrhea .

• Amebic liver abscess: Trophozoites invade throughthe colonic mucosa, reach the portal circulation, andtravel to the liver and cause liver abscess.

• Choice of drug depends upon:– Clinical presentation– Desired site of action

• Asymptomatic carriers generally are not treated in endemic areas but in nonendemic areas they are treated with a luminal amebicide.

• Luminal agents used to treat asymptomatic individuals found to be infected with E. histolytica.

- Diloxanide furoate- The nonabsorbed aminoglycoside

paromomycin & the 8-hydroxyquinoline compound iodoquinol

• Metronidazole and Tinidazole are the only

nitroimidazoles are the drugs of choice for the

treatment of amebic colitis, amebic liver abscess,

and any other extraintestinal form of amebiasis.

• Metronidazole is so well absorbed in the gut, levels

may not be therapeutic in the colonic lumen, and it

is less effective against cysts.

• Patients with amebiasis (amebic colitis or amebic

liver abscess) also should receive a luminal agent to

eradicate any E. histolytica trophozoites residing

within the gut lumen.

• Nitatzoxanide an oral synthetic broad-spectrum antiparasitic agent , effective against a number of intestinal helminths and protozoans.

• Other agents, dehydroemetine and chloroquine, rarely used in Rx of amebic colitis or amebic liver abscess and are reserved for only very unusual cases where metronidazole is contraindicated.

• Tetracyclines and erythromycin are alternative drugs for moderate colitis but are not effective against extraintestinal disease.

Con’d

Metronidazole

• Metronidazole is a nitroimidazole antiprotozoal

drug, Kills the E. histolytica trophozoites.

• Has antibacterial activity against anaerobes,

including bacteroides & clostridium species.

• It is the drug of choice for the

pseudomembranous colitis caused by the

anaerobic, gram-positive bacillus cl difficile & is

also effective in the treatment of brain abscess

caused by these organisms

• Antiparasitic & antimicrobial spectrum

– Obligate anaerobic bacteria

– Helicobacter pylori

– Bacteroids

– Clostridia

– -E histolytica

– Giardia lumblia

– -Trichomona vaginalis

• P/K:

– Well absorbed after oral & rectal administration

– Distributed in sufficient concentration in the liver, gut, pelvic tissues, CNS, lungs & other tissues like bone tissue. Reaches high concentration in body fluids including CSF

– Metabolized by oxiadation & glucoronide conjugation in the liver

– It is eliminated mainly by the kidney (urine) in unchanged & some as metabolized from

– Plasma protein binding low (<20%)

– t½ 8 hours

Mechanism of action

– Metronidazole is a prodrug.

– Susceptible microorganisms including

anaerobic bacteria & certain protozoa reduce

the nitro group of metronidazole by a

nitroreductase & convert it to a cytotoxic

derivative.

– Aerobic bacteria lacks this nitroreductase &

are therefore not susceptible to metronidazole

• Metronidazole diffused into anaerobic bacterial or sensitive protozoal cells

↓

In electron transport chain, the nitro group of metronidazole is reduced by ferridoxine (by accepting electron from transport protein)

↓

The reduced product appear to be responsible for killing the organism probably reacting with cellular macromolecules such as DNA, protein & membrane .

↓

Inactivation of DNA

↓

Death of protozoa & susceptable bacteria.

Indications:

– All symptomatic forms of amoebiasis

– Giardiasis

– Trichomoniasis of urogenital tract in both sex

– Anaerobic infection (clostridial)

– Prophylaxis of post-surgical abdominal & pelvic infection

– Helicobacter pylori

– Acute ulcerative gingivitis

– Acute dental infection

– Balantidiasis

– Osteomylitis

– Abscess of brain & lungs

– Pseudomembranous colitis

– Prophylaxis of endocarditis by bacillus fragilis

– Treatment of sepsis: post surgical infection,

intraabdominal infection & septicemia

• Toxicities:

– Common: headache, nausea, dry mouth, metallic taste

– Occasional: vomiting, diarrhea, abdominal distress

– Serious warrant discontinuation: Dizziness, vertigo, Encephalopathy, Convulsion, Incoordination, Ataxia

– Rare are: Urticaria, Flushing, Pruritus, Cystitis

– Disulfiram like reaction: Severe nausea & vomiting ,Due to inhibition of Acetyldehydedehydrogenase enzyme.

Disulfirum:

– In alcoholic patient

– Severe Hangover: Due to ↑Acetyldehydedehydrogenase.

– Symptom: Flushing of the skin, Accelerated HR, shortness of breath, nausea,vomiting, throbbing headache, visual disturbance, circulatory collupse. Should not take 12 hours after alcohol consume.

• Disulfiraum is used in cocaine dependence as it inhibit Dopa decarboxylase → Prevent

breakdown of dopamine. ( A NT whose release is stimulated by cocaine)

• The excess dopamine results in increase anxiety, high BP, restlessness.

• Contraindication:

– Active disease of CNS

– Evidence of blood dyscariasis

– 1st trimester of pregnancy

– Any type of carcinoma

Tinidazole

• A nitroimidazole, appears to have similar activity and a better toxicity profile than metronidazole

• Has a longer half-life of 13 hours.

• Excreted in urine in unchanged (mainly) form

• Indication:

– Anaerobic and protozoal infections:

– Very effective in case of – Giardiasis, trichomoniasis, ulcerative gingivitis

– Helicobacter pylori eradication

Secnidazole

• Indication: It is used in the treatment of amoebiasis,

& has also been tried in giardiasis, & trichomoniasis

• Dose:

– Given in giardiasis by mouth, usually as a single

dose of 2 gm in adult; for child, the dose is 30

mg/kg

– In invasive hepatic amoebiasis a dose of 1.5 g/ day

is given single or in divided doses for 5 days

• Trade name: Secnid Susp. 500 mg, Tab. 1 gm;

Secnidal, Sezol DS.

• Emetine, an alkaloid derived from ipecac

• Dehydroemetine, a synthetic analog

• Both are effective against tissue trophozoites of E histolytica, but because of major toxicity concerns they have been almost completely replaced by metronidazole.

• use is limited to unusual circumstances in which severe amebiasis warrants effective therapy and metronidazole cannot be used.

• Dehydroemetine is preferred because of its somewhat better toxicity profile. Should be used for the minimum period needed to relieve severe symptoms (usually 3–5 days).

Emetin & Dehydroemetine

• Routes of administration:

SC or IM in a supervised setting.

• Adverse effect:

Pain and tenderness in the area of injection are

frequent, and sterile abscesses may develop.

Diarrhea is common.

nausea, vomiting, muscle weakness and

discomfort

• Serious toxicities include cardiac arrhythmias,

heart failure, and hypotension

Iodoquinol

• Effective luminal amoebicide that is commonly used with metronidazole to treat amebic infections

• Pharmacokinetics:

– Poorly understood

– 90% of the drug is retained in the intestine & excreted in the feces. The remainder enters the circulation, has a t½ of 11-14 hours, & is excreted in the urine as glucoronides

• Mechanism of action:

– unknown. It is effective against organisms in the bowel lumen but not against trophozoites in the intestinal wall or extraintestinal tissue

• Adverse effects:

– anorexia, nausea, vomiting, abdominal pain, headache, rash, & pruritus

• The drug may increase protein-bound serum iodine, leading to a decrease in measured 131I uptake that persist for months

• Should be taken with meal to limit GI toxicity

• Should be taken with caution in patient with optic neuropathy, renal or thyroid disease. Di-iodo chlorhydroxyquinoline causes subacutemyelo optic neuropathy, so it is not used now

• The drug should be discontinued if it produces persistent diarrhea or signs of iodine toxicity (dermatitis, urticaria, pruritus, fever)

• It is contraindicated in patients with intolerance to iodine

Diloxanide furoate

•A dichloroacetamide derivative.

• It is an effective luminal amebicide but is not active against tissue trophozoites.

• In the gut, diloxanide furoate is split into diloxanide and furoic acid

•About 90% of the diloxanide is rapidly absorbed and then conjugated to form the glucuronide, which is promptly excreted in the urine.The unabsorbed diloxanide is the active antiamebic substance.

• The mechanism of action of diloxanide furoate is unknown.

• Diloxanide furoate is the drug of choice for asymptomatic luminal infections.

• It is used with a tissue amebicide, usually metronidazole, to treat serious intestinal and extraintestinal infections.

• Diloxanide furoate does not produce serious adverse effects. Flatulence is common, but nausea and abdominal cramps are infrequent and rashes are rare.

• The drug is not recommended in pregnancy.

Paromomycin sulfate

• It is an aminoglycoside antibiotic that is not significantly absorbed from the GIT

• It is used only as a luminal amebicide & has no effect against extraintestinal amebic infections

• The drug may accumulate with renal insufficiency & contribute to renal toxicity

• Have similar efficacy & probably less toxicity than other agents; in a recent study, it was superior to diloxanide furoate in clearing asymptomatic infections

• Adverse effects:– Occasional abdominal distress & diarrhea

• Should be avoided in patients with significant renal disease & GI ulceration.

Nitazoxanide

• An oral synthetic broad-spectrum

antiprotozoal agent

• It was found initially to have activity against

a number of intestinal helminths &

protozoans

• Spectrum of activity:

– Cryptosporidium parvum; G.lumblia;

– E.histolytica

– A lumbricoides; Fasciola hepatica

– H. pylori

• Nitazoxanide appears to have activity against metronidazole-resistant protozoal strains & is well tolerated

• M/A:

Nitazoxanide is a nitrothiazolyl-salicylamide prodrug.

It is rapidly absorbed & converted to active metabolite tizoxanide which inhibits the pyruvate:ferredoxinoxidoreductase (PFOR) enzyme-dependent electron-transfer reaction.

This reaction is essential in anaerobic glucose energy metabolism.This results in cell swelling, mem. Damage causing dysfunction of parasite.

• Therapeutic uses:

• Treatment of G. intestinalis infection & treatment of diarrhea caused by cryptosporidia

• Dose:

– Children between 12 & 47 months

• 100 mg 12 hourly for 3 days

– Children between 4-12 years

• 200 mg 12 hourly for 3 days

– Children over 12 years & adults

• 500 mg 12 hourly for 3 days

• Adverse effects:

– Rare. Abdominal pain, diarrhea, vomiting & headache have been reported. A greenish tint to the urine is seen in most individuals taking nitazoxanide

• Nitazoxanide is considered a category B agent for use in pregnancy based on animal teratogenicity & fertility studies, but there is no clinical experience with its use in pregnant women or nursing mothers