Amoebiasis. A protozoan infection of intestinal tract that occurs due to
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2 Amoebiasis A protozoan infection of intestinal tract that occurs due to ingestion of food or water contaminated with mature cysts of E. Histolytica which passes into colon, where they divide into trophozoites; that either enter the tissues or reform cysts. This agent can cause a symptomatic intestinal infection, colitis, dysentery (severe intestinal infection), liver abscess and extra intestinal infection (liver, lung, or the brain).
3 Life cycle of E. Histolytica 3
4 1-Bowel Lumen (luminal) Amebiasis: 90 % of cases Is asymptomatic (subclinical) (carriers), the motile trophozoites (non infective) & cysts (infective) are passed in the feces transmission of infection Drug of choice (luminal amebicide) is diloxanide furoate (furazole ); iodoquinol or paromomycin as alternative drugs Symptoms can range from mild diarrhea to severe dysentery with blood and mucus Incubation period takes about 2-4 weeks then pt develops symptoms 2- Tissue Invading Amebiasis: 10% of cases It causes dysentery, hepatic amebiasis and liver abscess. Drug treatments include: metronidazole, tinidazole (systemic amebicides; kill ameba in intestinal wall and liver), these drugs are also available in parenteral form for pts who are too ill to take drugs by mouth. In severe cases of amoebic dysentery, tetracycline or emetine or dehydroemetine can be used in addition to the systemic amebicide to avoid perforation and peritonitis 4
5 Mechanism of action: 1-Metronidazole (Flagyl, Amrizole ) Nitro group of metronidazole is chemically reduced by ferridoxine oxidoreductas (In protozoa & anaerobic bacteria) FRs and cytotoxic compounds Disrupt DNA, inhibit nucleic acid synthesis Inhibition of enzymes important for energy production These enzymes are located in bacterial cytoplasm but protected by mitochondria in mammalian cell Clinical uses: kills trophozoites but not cysts of E histolytica. 1-Antiprotozoal: Metronidazole is the first drug of choice in: Amebiasis (intestinal (Amoebic dysentery) & hepatic) Giardiasis (infection of small intestine by giardia lamblia flagellated protozoan ) Metronidazole plus albendazole work synergistically for giardiasis Trichomoniasis (vaginitis) 2- Antimicrobial: - Colitis (inflammation of large intestine) & Brain abscess - Peptic ulcer - Dental infections 5
6 Adverse effects of metronidazole: Nausea, vomiting, (metallic taste) headache, dry mouth, insomnia, weakness, dizziness, rash, dark urine, vertigo, neutropenia and ototoxicity (high dose, systemic treatment). Metronidazole alone rarely causes Stevens Johnson syndrome, but is reported to occur at high rates when combined with mebendazole Disulfiram-like effect [N, V, flushing, tachycardia] if taken with ethanol As Metronidazole inhibit dehydrogenase so inhibit metabolism of alcohol. So alcohol consumption should be avoided during Metronidazole therapy or at least 24 hrs after completion of treatment It potentiates the effect of anticoagulant (coumarin)..it decrease its breakdown Phenytoin and phenobarbital increase metabolism of metronidazole, while cimetidine decreases its plasma clearance. 6
7 2-Tinidazole (Fasigyn ) It is a long acting (half-life 14 hours) amoebicidal drug It has less adverse effects than metronidazole It is given as a single daily dose for only 3-5 days It is more expensive than metronidazole. NB: CONAZ (norfolxacin400mg+ tinidazole 600mg) treat diarrhea, dysentery of bacterial, amoebic or mixed origin. 3- Secnidazole (Fladazole, Secinda-Misr ) A new second-generation 5-nitroimidazole derivative with a broad spectrum of activity against anaerobic bacteria. It is used for amoebiasis, trichomoniasis and giardiasis It has longer half-life (20 hrs) than metronidazole, making it suitable for single-dose (2 gm) therapy, therefore potentially offers an advantage over multiple-dose metronidazole regimens. Side effects: Nausea, mouth ulcer and stomach pain. 8
8 4-Diloxanide (Damizol, Furamibe ) It is highly effective luminal amoebicide directly kill trophozoites It exerts no antibacterial action. Mech is Unkn may, it may inhibit protein synthesis. It is less effective in invasive amoebic dysentery, probably because of a poor tissue amoebicidal action 5- Dehydroemetine (Mebadin ) It is a synthetic analog of emetine used as a trophozoticidal agent I.M. Injection is the preferred route cause vomiting if taken orally. It inhibits protein synthesis by blocking chain elongation It is only used in severe intestinal amebiasis It may induce HF or arrhythmia in susceptible pts It should not be taken for more than 5 days (cardiotoxicity). 9
9 6-Iodoquinol Metro trophozoite only a halogenated hydroxyquinoline, the drug of choice for treating asymptomatic or moderate forms of amebiasis. Unkn mechanism It is effective against the luminal trophozoite & cyst forms of E. histolytica About 90% of the drug is retained in the intestine (as it is poorly absorbed from GIT so its amoebicidal effect produced at the site of infection) and excreted in the feces. The t 1/2 is hrs and excreted in the urine as glucuronides. It should be taken with meals to minimize GIT toxicity. Side effects: Stomach cramps, Anorexia, vomiting, abdominal pain, headache, rash, thyroid enlargement. On long period treatment it may cause blindness (optic neuritis). 10
10 7- Paromomycin It is an aminoglycoside antibiotic, only effective against the intestinal (luminal) forms of E. histolytica because it is not significantly absorbed from GIT. It works by stopping the growth of parasites in the intestine. via inhibition of protein synthesis by binding to 16 S ribosomal RNA. 11
11 is an oral nitrofuran antibiotic Nifuroxazide (Antinal, Diax ) and used to treat colitis and diarrhoea in humans and non-humans it control diarrhea with in 24 hrs of intake. Broad spectrum intestinal anti-infective agent which covers most enteropathogenic microbacterials, Shigella, E-coli, salmonella, staphylococcus Mechanism of action It inhibit bacterial growth by acting on nucleic acid and energy metabolism of pathogen Dose: duration of treatment 5-7 days Adult..200 mg 4 times daily 2-18 years..200 mg 3 times daily Less than 2 years it is not recommended, also in pregnancy & breastfeeding Side effects: urticaria, anaphylactic shock NB:-Not teratogenic in animals, there is no studies on human but should not administered 12
12 Anthelmintic drugs 13
13 Types of helminthes:- 1. Nematodes (Roundworms): Intestinal e.g. Up to 45 cm Ascaris Ascaris lumbricoides largest nematodes, causes abdominal pain, intestinal obstruction Ankylostoma duodenale (Hookworms) intestinal blood loss Iron deficiency anemia. Enterobius vermicularis (Pinworms) (also known as enterobiasis or oxyuriasis) Pain, itching in anal area irritability and difficulty of sleep, these symptoms are caused by the female pinworm during laying its eggs. Measures should be taken during treatment of enterobiasis: 1-simultaneously treat all family from E. Vermicularis 2-Prescribe drug at least 3 times at 2 weeks interval. 3-Personal & group hygiene must improve. Ankylostoma pinworms 4-discourage children from sucking fingers. 14
14 2. Trematodes (Flukes or flat worms): Blood-dwelling flukes e.g. Schistosoma haematobium, S.mansoni & S. japonicum 3. Cestodes (Tapeworms): Taenia saginata (Beef tapeworms), Taenia solium (Pork tapeworms) 15
15 1. Drugs for the treatment of nematodes 1-Albendazole (Bendax, Vermizole, Antizole ) Broad spectrum oral anthelmintic Its absorption is increased with fatty meal. Mechanism of action 1. It selectively binds to nematode ß-tubulin, inhibiting its polymerization preventing the formation of microtubules stopping cell division. 2. Impaired glucose uptake by the parasite depletion of glycogen stores and ATP stores immobilization and death of the parasite. It is C.I. in pregnancy (category C.), liver cirrhosis and in children under the age of 2 in some countries. 16
16 Clinical uses: 1. Ascariasis, hook worm and pinworms adult or child > 2 years: 400 mg single dose repeated after 7 days. Child up to 20 kilos: 200 mg, (10 ml of suspension) repeated after 7 days. Side effects: alopecia, elevation of liver enzymes, nausea, headache, diarrhea, dizziness, insomnia, fever, fatigue. 17
17 2. Mebendazole (Antiver, Mebamox, Vermox ) Mechanism of action It Inhibits microtubule synthesis and glucose uptake leading to depletion of ATP stores immobilization and death of the parasite. Absorption is increased with fatty meal Therapeutic uses: It is effective in Ascariasis, hookworm and pinworm infections dose: adult, children > 2 years: 100 mg single oral dose, repeated after 2 wks if necessary). It is C.I. in pregnancy (category C, fetotoxic in animal) 3. Flubendazole (Fluvermal ) Fluoro-analogue of mebendazole Inhibits glucose uptake & affects microtubule formation Contraindicated in pregnancy 18
18 4. Thiabendazole ( Mintezol ) Mechanism of action: It may inhibit mitochondrial enzyme fumarate reductase of worms thus decreasing the formation of ATP Uses: for the treatment of trichinosis (due to consumption of larvae of Trichinella spiralis in undercooked meat, especially pork). 5. Pyrantel pamoate (Combantrin ) Mechanism of action - it is a depolarizing neuromuscular blockers, causing persistent activation of parasite's nicotinic receptors -It Increases release of acetylcholine & also inhibits acetylcholinesterase spastic paralysis of worm Uses: it is the drug of choice in Ascariasis also highly effective against Ancylostoma & Enterobius infections 19
19 6. Levamisole (Ketrax ) Depolarizing neuromuscular blocker & also has anticholinesterase effect Used in roundworm infections & is also immunostimulant Used now in colon cancer 7- Diethylcarbamazine (Hetrazan ) Used in the treatment of filariasis because of its ability to immobilize worms and render them susceptible to host defense mechanisms Filariasis (elephantiasis): Arms, legs or genitals are filled with fluid due to Wuchereria bancrofti (round worms) that destroy the lymph channels so disrupt the flow of the lymph causing lymphoedema. NB: bite of infected mosquito release microflariae into human blood that migrate and mature into adult worm in lymphatic system leading to its blockade varices 20
20 B- Drugs for the treatment of trematodes (flat worms): Mechanism of action 1- Praziquantel ( Distocide, Biltricide ) Increases cell permeability to Ca ++ resulting in contraction & spastic paralysis of worm Therapeutic uses: Drug of choice in all species of schistosoma Adverse effects: Abdominal pain, headache, dizziness, fever & rash Contraindicated in first trimester of pregnancy 2. Oxamniquine (Vansil ) The drug is activated inside the parasite and binds to DNA and inhibit synthesis of nucleic acid Effective only against S. mansoni Not used in pregnancy & epilepsy 21
21 3- Metrifonate ( Bilarcil ) Acts by inhibiting cholinesterase enzyme thus paralyzing the worm Effective only against S. haematobium Contraindicated in pregnancy C- Drugs for the treatment of Cestodes (tape worms) Niclosamide (Yomesan ) Blocks glucose uptake & damages the scolex (attachment end) of tapeworms Purgatives can be used to expel the dead worm segments Drug of choice in T saginata & T solium 22
22 Case study Mona is 7 years old girl who travelled to Alex with her mother to visit her grandmother. Upon getting there, her grandmother took her out to eat at a local restaurant. Two weeks later after returning home Mona began feeling ill with stomach cramping and loose stools. Her symptoms became worse and she developed a fever, bloody stools, felt weak, and she complained of severe stomach pain and perianal itching at night. Her mother took her to get examined by the family physician who ran several tests including a complete blood count which showed she was anemic and microscopic stool studies that revealed E. Histolytica trophozoites and some eggs of Enterobius vermicularis (pinworms). The family physician prescribed metronidazole 500mg TID for amoebiasis and mebendazole for enterobiasis. 23
23 1-Does the treatment(s) afforded for Mona be used simultaneously to cure her infections? If NO, Justify? 2-Describe the mechanisms by which metronidazole and mebendazole act to cure Mona s infections? 3- What measures would you recommend the patient to prevent reinfection with enterobiasis? 4-Mention the dose regimen of mebendazole that prescribed for Mona to treat her pinworm infection? 24
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