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Amoebiasis AMEBIASIS •An infection of the intestinal tract •Occurs due to ingestion of foods or water •Contaminated with Entameba Histolytica cysts AMEBIASIS •Was first described by •A disease caused Lambl and Losch in a by a one-celled dysenteric patient parasite called (1859) •Councilman and Entamoeba lafleur in 1981 histolytica. described amoebic •More common in liver abscess. •Schauudinn (1903) people who live in tropical areas with differentiated pathogenic and poor sanitary nonpathogenic types conditions. of Amoebae AMOEBIASIS A MAJOR HEALTH PROBLEM • Estimated to cause 70,000 deaths per year world wide • Severe Amoebiasis infections (known as invasive amoebiasis). • Invasion of the intestinal lining causes amoebic dysentery or amoebic colitis. Transmitted by :• Fecal contamination of drinking water and foods • Direct contact with dirty hands or objects • By sexual contact SYMPTOMS:• Range from mild diarrhoea to dysentery with blood and mucus in the stool. • Gastrointestinal including • Diarrhoea, vomiting, abdominal pain or discomfort and fever. • Symptoms take from a few days to a few weeks to develop • Most infected people are asymptomatic but this disease has the potential to make the sufferer dangerously ill. SYMPTOMS • Gastrointestinal including • Diarrhoea, vomiting, abdominal pain or discomfort and fever. • Symptoms take from a few days to a few weeks to develop • Most infected people are asymptomatic but this disease has the potential to make the sufferer dangerously ill, especially if there is any suggestion of immunocompromised. LIFE CYCLE Entamoeba histolytica exists in two forms: 1.Cysts (infective): • Can survive outside the human body. • Transform to trophozoites. 2. Trophozoites (non-infective; invasive): •Reproduce •They may feed on intestinal bacteria or • Invade and ulcerate wall of large intestine • May migrate to liver or other tissues. •Transform to cysts which are excreted in feces. LIFE CYCLE 1. Cysts ingestion. 2. Formation of trophozoites 3. Penetration of intestinal wall 4. Multiplication of trophozoites within colon wall. 5. Systemic invasion. 6. Cyst formation in rectum and excretion in feces. EVENTS ON AMOEBIASIS LIFE CYCLE Precystic stage: • Trophozoites living in the intestine undergo binary fission • Round and 10-20µ in size Cystic stage: • Enters by forming a delicate cystwall around itself • Size is 12µ • Quadrinucleated cyst is the infective stage of the parasite • Ingested by human host pass along with food into the small intestine • Wall of cyst dissolved by trypsin • Tetranucleate emerges out from cyst into lumen of large intestine called excystment The Trophozoite Stage: • 10-40 µm, fragile. • Uninucleate • Erythrophagocytosis • Reside, feed and multiply by binary fission in lumen of colon. • May invade – Lytic & physical mechanisms and metastasize to liver and other extraintestinal sites. CLINICAL PRESENTATIONS •Asymptomatic Intestinal infection (Carriers, passing cysts) •Mild to moderate intestinal disease (Nondysenteric Colitis) •Severe Intestinal infection ( Dysentery) •Hepatic abscess, ameboma (localized granulomatous lesion of colon) and other extraintestinal disease DIAGNOSIS •Light Microscopy of Stool •Identification of trophozoites / cysts in fresh stool Serology Stool antigen-detection test •Sensitive and Specific •A sample of freshly collected Fecal specimen CLASSIFICATION LUMINAL AMEBICIDES • For treating intestinal infections. (a) Amide: Diloxanide furoate, Nitazoxanide (b) 8-Hydroxyquinolines : Quiniodochlor, Diiodohydroxyquin (c) Antibiotics : Tetracyclines TISSUE AMEBICIDES • Used to destroy amoebae that have invaded tissue, rapidly absorbed into the bloodstream and transported to the site of infection. (a) For both intestinal and extraintestinal amoebiasis: A)Nitroimidazoles: • Metronidazole, Tinidazole, Secnidazole,Ornidazole, Satranidazole B) Alkaloids: • Emetine, Dehydroemetine (b) For extraintestinal amoebiasis only: • Chloroquine METRONIDAZOLE • Mixed amoebicide • Choice for intestinal &extraintestinal amoebiasis. • Acts on trophozoites. • Has no effect on cysts. Mechanism: • Nitro group of metronidazole is reduced by protozoan. • Leading to cytotoxic reduced product • That binds to DNA and proteins • Resulting into parasite death. MECHANISM • Selectively toxic to anaerobic microorganisms. • After entering the cell by diffusion • Its nitro group is reduced by certain redox proteins (operative only in anaerobic microbes) • To highly reactive nitro radical which exerts cytotoxicity. • Acts as an electron sink • Competes with the biological electron acceptors of the anaerobic organism • For the electrons generated by the pyruvate : ferredoxin oxidoreductase (pfor) enzyme pathway of pyruvate oxidation. • The energy metabolism of anaerobes is, thus, disrupted. • Aerobic environment attenuates cytotoxicity RESISTANCE: • Develop resistance become deficient in the mechanism that generates the reactive nitro radical from it. PHARMACOKINETICS: • Given orally or IV. • Absorption is rapid and complete. ▪ Due to rapid absorption from GIT, not reliably effective against luminal parasites. • Wide distribution to all tissues and body fluids (CSF, saliva, milk). • Plasma protein binding is low ( < 20%). • Plasma half life is 8 h • Metabolized in liver • Excreted in urine ADVERSE EFFECTS • Relatively frequent and unpleasant, but mostly nonserious. • Anorexia (an emotional disorder characterized by an obsessive desire to lose weight by refusing to eat) • Nausea • Metallic taste • Abdominal cramps • Looseness of stool. Less frequent side effects are• • • • Headache, Glossitis (inflammation of the tongue) , Dryness of mouth, Dizziness(a feeling that you are about to fall), • Rashes • Neutropenia (abnormally number of neutrophils). • Prolonged administration low • Peripheral neuropathy (damage to nerves of the peripheral nervous system) and • CNS effects. • Very high doses:• Seizures (Due to the electrical discharge in the nervous system) • If the solution is not well diluted:• Thrombophlebitis of the injected vein (inflammation of the wall of a vein with associated thrombosis) occurs CLINICAL USES • Ulcerative gingivitis, • Extraluminal amoebiasis trench mouth (combined with luminal ( a severe form of gingivitis that causes amebicide). painful, infected, bleeding gums and ulcerations. ) • Giardiasis • Guinea worm infestation (Infection of the intestine with a flagellate protozoan which causes (a painful and debilitating infestation diarrhea and other symptoms.) • Trichomoniasis (An infection caused by parasitic trichomonads (genus Trichomonas), chiefly affecting the urinary tract, vagina, or digestive system.) • Broad spectrum of Anaerobic bacteria • Helicobacter pylori infection • Pseudomembranous colitis (Clostridium defficile). (is an infection of the colon.) contracted by drinking stagnant water contaminated with Guinea worm larvae that can mature inside a human's abdomen until the worm emerges through a painful blister in the person's skin ) CONTRAINDICATIONS / PRECAUTIONS • Pregnancy and nursing women. • Alcohol intake • CNS diseases • Severe hepatic disease • Severe renal disease TINIDAZOLE • Efficacious as metronidazole • Similar to it in every way except: • Metabolism is slower • T1/2 is -12 hr • Duration of action is longer • More suited for single dose or once daily therapy • better tolerated • Lower side effects SECNIDAZOLE • A congener of metronidazole • Same spectrum of activity and potency. • Oral administration • Absorption is rapid and complete • Metabolism is slower • Plasma t1/2 of 1 7-29 hours. • Side effect similar to metronidazole • USES: • • • • • Intestinal Amoebiasis Giardiasis Trichomonas Vaginitis Nonspecific Bacterial Vaginosis Hepatic Amoebiasis. ORNIDAZOLE • Activity similar to metronidazole • Slowly metabolized• Longer t1/2 -12-14 hr USES: • • • • • Amoebiasis, Giardiasis, Trichomoniasis, Anaerobic Infections Bacterial Vaginosis. • Side effect profile is also similar. SATRANIDAZOLE • Nitroimidazole • Longer t1/2 -14 hr. ADVANTAGES ARE: • Better tolerability, • No nausea, vomiting or metallic taste, • Absence of neurological and disulfiram-like reactions. USE : • Amoebiasis • Giardiasis • Trichomoniasis EMETINE AND DEHYDROEMETINE CHEMISTRY : • Emetine hydrochloride is a plant alkaloid derived from Cephaelis ipecawanha. • Dehydroemetine is a synthetic analogue PHARMACOKINETICS: • Variable oral absorption. • Given preferably S.C. but could be given by IM, NEVER I.V • Plasma half life is 5 days. • Concentrated in Liver, Lungs, Spleen, Kidney, Cardiac muscle and Intestinal wall. MECHANISM • Act on tissue trophozoites • No effect on cysts • Acts by inhibiting protein synthesis in amoebae • By arresting intraribosomal translocation of trnaamino acid complex ADVERSE EFFECTS CLINICAL USES • Amoebic liver abscess • Dehydroemetine is less toxic than • Intestinal wall infections emetine • Severe forms of amebiasis • Pain at site of injection, abcesses. • Acute amoebic Dysentery • GIT: Nausea, vomiting, diarrhoea. (dehydroemetine is preferable due to less toxicity) • Neuromuscular weakness CONTRAINDICATIONS • Serious toxicities: • Cardiotoxicity - Cardiac arrhythmias, - Hypotension - Heart failure • Heart disease • Kidney disease • Pregnancy DEHYDROEMETINE • Semisynthetic derivative of emetine • Equally effective • Less toxic to the heart. • Thus, it is preferred over emetine by most physicians. CHLOROQUINE • Antimalarial drug • Used in combination • For amebic liver Diseases • Followed by luminal amebicide. • Kills trophozoites • Highly concentrated in liver. • Therefore used in hepatic amoebiasis only. • Completely absorbed from the upper intestine and not so highly concentrated in the intestinal wall . • Amoebae do not develop resistance to chloroquine. • Because of safety of chloroquine, it may be given concurrently or immediately after a course of metronidazole • To ensure complete eradication of the trophozoites in liver. • A luminal amoebicide must always be given with or after chloroquine to abolish the luminal cycle. • It is now employed only when metronidazole is not effective or not tolerated. DILOXANIDE FUROATE CHEMISTRY • Ester of diloxanide + furoic acid PHARMACOKINETICS • Given orally. • Split in the intestine • Diloxanide is absorbed, conjugated to form a glucoronide which is excreted in urine • Diloxanide is a weaker amoebicide than its furoate ester : no systemic antiamoebic activity. PHARMACODYNAMICS • Highly effective luminal amoebicide: directly kills trophozoites responsible for production of cysts. • Diloxanide furoate exerts no antibacterial action. • Less effective in invasive amoebic dysentery, because of poor tissue amoebicidal action. • High cure rate in mild intestinal amoebiasis and in asymptomatic cyst passers. THERAPEUTIC USES • For mild intestinal/ asymptomatic intestinal infection • Given after any tissue amoebicide to eradicate cysts. • For eradication of infection given along with all forms of amebiasis. • Combined use with metronidazole/ tinidazole is quite popular. • Some chronic cases require repeat courses for eradication. ADVERSE EFFECTS • Flatulence ( the accumulation of gas in the alimentary canal) • Nausea, vomiting, abdominal cramps. • No serious adverse effects CONTRAINDICATIONS: - Pregnancy - Children (less than 2 years). • NITAZOXANIDE • Salicylamide congener • Use in treatment of giardiasis is also active against E. Histolytica, T. Vaginalis, cryptosporidium, H. Pylori, ascaris, H. Nana and some other protozoa and helminths. • It is a prodrug which on absorption is converted to the active form tizoxanide. MECHANISM OF ACTION: • An inhibitor of PFOR enzyme that is an essential pathway of electron transport energy metabolism in anaerobic organisms. • Tizoxanide produced in the body is conjugated and excreted in urine and bile. USES: • Giardiasis (infection of the intestine with a flagellate protozoan, which causes diarrhoea and other symptoms.) • Cryptosporidiasis (is a parasitic disease caused by Cryptosporidium) • Amoebic dysentery as luminal amoebicide. • Against metronidazoleresistant giardia (an intestinal infection marked by abdominal cramps, nausea and watery diarrhea) SIDE EFFECTS: • Abdominal pain • Vomiting • Headache TETRACYCLINES • Directly inhibit amoebae only at higher concentrations. • The older tetracyclines are incompletely absorbed in the small intestine, reach the colon in large amounts and inhibit the bacterial flora with which entamoebae live symbiotically. • Indirectly reduce proliferation of entamoebae in the colon • Especially valuable in chronic, difficult to treat cases with only the luminal cycle and little mucosal invasion. • Adjuvant role in conjunction with a more efficacious luminal amoebicide. • They are not good for acute dysentery and for hepatic amoebiasis. 8-HYDROXYQUINOUNES SPECTRUM: • Active against • Entamoeba, giardia, trichomonas, some fungi (dermatophytes, candida) and some bacteria. • They kill the cyst forming trophozoites in the intestine • Do not have tissue amoebicidal action • Valueless in extraintestinal amoebiasis • Intestine absorption is variable. • Therapeutic concentrations are not attained in the intestinal wall or in liver. • The unabsorbed part reaches lower bowel and acts on luminal cycle of amoebae. USES • Lumen amoebicide. • For eradication of infection given along with tissue amoebicide (metronidazole). ADVERSE EFFECTS • Peripheral neuropathy including optic neuritis • GIT: Nausea, vomiting, diarrhoea. • Enlargement of the thyroid gland. • Agranulocytosis (A deficiency of granulocytes in the blood). • Iodine sensitivity. • Drug interfere with thyroid function tests (increase proteinbound serum iodine thus decrease in measured 131I uptake). CONTRAINDICATIONS • Optic neuropathy (Disease or dysfunction of one or more peripheral nerves) • Thyroid disease • Sensitivity to iodine • Severe kidney disease • Discontinued if it produces persistent diarrhea or signs of iodine toxicity (dermatitis, urticaria (A rash of round, red welts on the skin that itch intensely), pruritus (Severe itching of the skin), fever) TREATMENT OF AMOEBIASIS 1. INVASIVE INTESTINAL AMOEBIASIS • Metronidazole/tinidazole are the drugs of choice. • Secnidazole, ornidazole, satranidazole are the alternatives. • Adjuvant measures for diarrhoea and abdominal pain may be needed. • The above treatment should be followed by a course of luminal amoebicide to eradicate E. histolytica from the colon and to prevent carrier (cyst passing) state. 2. CHRONIC INTESTINAL AMOEBIASIS/ASYMPTOMATIC CYST PASSERS • These cases are more difficult to treat, two or more repeated courses may be needed. • Diloxanide furoate produces high cure rates and is the drug of choice. • Nitazoxanide is an alternative. • A tetracycline may be given concurrently with the luminal amoebicide in cases which fail to clear completely. 3. AMOEBIC LIVER ABSCESS • A serious disease • Complete eradication of trophozoites from the liver is essential to avoid relapses. • Metronidazole/tinidazole are the first choice drugs effective in> 95% cases. • Dehydroemetine is to be used only if metronidazole cannot be given for one reason or the other, and in patients not cured by metronidazole. • A luminal amoebicide must be given later to finish the intestinal reservoir of infection. • A course of chloroquine may be administered after that to ensure that no motile forms survive in the liver. THANK YOU - PHARMA STREET