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• 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.
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