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Antiamoebic drugs
This document discusses various antiamoebic drugs used to treat protozoal infections caused by Entamoeba histolytica, the parasite that causes amebiasis. It describes the life cycle of E. histolytica and clinical manifestations of amebiasis. Several classes of antiamoebic drugs are outlined, including their mechanisms of action, pharmacokinetics, clinical uses, and adverse effects. The main drugs discussed are metronidazole, tinidazole, diloxanide furoate, iodoquinol, emetine/dehydroemetine, paromomycin, and tetracyclines. Metronidazole is highlighted as the drug of choice for
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Antiamoebic drugs
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- 2. Introduction • Protozoal infectionsare common among people in underdeveloped tropical and subtropical countries, where sanitary conditions, hygienic practices, and control of the vectors of transmission are inadequate. • However, with increased world travel, protozoal diseases, such as amebiasis, giardiasis, trichomoniasis, malaria, leishmaniasis, trypanosomiasis, are no longer confined to specific geographic locales.
- 3. Cont’d • Protozoa areeukaryotes, the unicellular protozoal cells have metabolic processes closer to those of the human host than to prokaryotic bacterial pathogens. • Protozoal diseases are thus less easily treated than bacterial infections, and many of the antiprotozoal drugs cause serious toxic effects in the host, particularly on cells showing high metabolic activity, such as neuronal, renal tubular, intestinal, and bone marrow stem cells.
- 4. • Amebiasis: (Itis also called amoebic dysentery) is an infection of the intestinal tract caused by Entameba histolytica. • The disease can be acute or chronic, with patients showing varying degrees of illness, from no symptoms to mild diarrhoea to fulminating dysentery. • The diagnosis is established by isolating E. histolytica from fresh feces.
- 5. Life cycle ofE. histolytica
- 6. Cont’d • Entameba histolyticaexists in two forms: cysts that can survive outside the body, and labile but invasive trophozoites that do not persist outside the body. • Cysts, ingested through feces contaminated food or water, pass into the lumen of the intestine, where the trophozoites are liberated. The trophozoites multiply, and they either invade and ulcerate the mucosa of the large intestine or simply feed on intestinal bacteria.
- 7. Cont’d • One strategyfor treating luminal amebiasis is to add antibiotics, such as tetracyclines to the treatment regimen, resulting in a reduction in intestinal flora – the ameba’s major food source. • The trophozoites within the intestine are slowly carried toward the rectum, where they return to the cyst form and are excreted in feces.
- 8. Cont’d • Large numbersof trophozoites within the colon wall can also lead to systemic invasion. • Amebiasis is infection with Entameba histolytica. This organism can cause; 1. Asymptomatic intestinal infection 2. Mild to moderate colitis 3. Severe intestinal infection (dysentery) 4. Ameboma 5. Liver abscess 6. Other intestinal infections
- 10. Antiamebic Drugs Antiamebic drugs MetronidazoleTinidazole Diloxanide furoate Iodoquinol Emetine and dehydroemetine Paromomycin Chloroquine Most antiprotozoal agents have not proved to be safe for pregnant women.
- 11. Classification of AntiamebicDrugs: systemic • Tinidazole • metronidazole • Chloroquine • Emetine • Dehydroemetine • They are effective against amebas in the intestinal wall and liver. Luminal • Diloxanide furoate • Iodoquinol • Paromomycin • They act on the parasites in the lumen of the bowel only Mixed • luminal and systemic Systemic antiamebic against trophozoites Luminal antiamebic against cyst
- 13. Metronidazole • A nitroimidazole,is the drug of choice in the treatment of extra luminal amebiasis. • It kills trophozoites but not cysts of E.histolytica and effectively eradicates intestinal and extra intestinal tissue infections.
- 14. PK of metronidazole •Route of administration: oral and I.V. • Oral metronidazole is readily absorbed and permeates all tissues by simple diffusion. • Intracellular concentration rapidly approaches extracellular levels. • Peak plasma concentration is reached in 1- 3 hours. • Therapeutic levels can be found in vaginal and seminal fluids, saliva, breast milk, and cerebrospinal fluid (CSF).
- 15. Cont’d • Protein bindingis low (10-20%) • Metabolism of the drug depends on hepatic oxidation followed by glucuronylation • The half life of the drug is 7.5 hours for metronidazole • Metronidazole and its metabolites are excreted mainly in the urine.
- 17. MOA 1. Some parasites(including amebas) possess ferrodoxin-like, low-redox-potential, electron-transport proteins 2. these proteins remove electrons. 3. The nitro group of metronidazole accepts the electron from reduced ferrodoxin 4. Then metronidazole become reduced cytotoxic compounds that bind to proteins and DNA, resulting in cell death.
- 18. Uses • Amebiasis: Metronidazoleis the drug of choice in the treatment of all tissue infections with E. histolytica. • It is not reliably effective against luminal parasites and must be used with a luminal amebicide
- 19. Cont’d • Giardiasis: -Treatment ofchoice -The dosage for giardiasis is much lower and the drug is thus better tolerated than that for amebiasis. • Trichomoniasis: treatment of choice
- 20. • Anaerobic Bacterialinfections: -for example, Bacteroids fragilis, Fusobacterium, and Clostridium perfringens. • Dracunculosis: infection caused by guinea worm.
- 21. Adverse effects • Drymouth • Metallic taste in the mouth and, • Nausea • Headache • Vomiting, Diarrhea, insomnia, weakness, dizziness, thrush, dysuria, dark urine, paraesthesias, and neutropenia are infrequently encountered. • Pancreatitis along with CNS symptoms eg. ataxia, encephalopathy, and seizures are rarely seen. Commonly occurs
- 22. • I.V. infusionrarely causes seizures or peripheral neuropathy. • Precautions 1. The drug should be used with caution in patients with CNS diseases. 2. Avoided in pregnancy due to the possible risk of teratogenicity just like any other azole. 3. Dose adjustment in renal or live impairment
- 23. DRUG INTERACTION • Metronidazolehas a disulfiram like effect when taken with alcohol. • It potentiates the anticoagulant effect of coumarin (warfarin) type of anticoagulants. • Phenytoin & phenobarbitone may increase the elimination of the drug, while cimetidine decreases plasma clearance by manipulating with the hepatic cytochrome enzymes. • Lithium + metronidazole lithium toxicity
- 24. Tinidazole • Tinidazole, anitroimidazole, is similar to metronidazole • has a better toxicity profile. • It offers simpler dosing regimens. • Tinidazole is as effective as metronidazole, with a shorter course of treatment, yet it is more expensive. Pharmacokinetics: The half life of Tinidazole is 12-14 hours
- 25. Clinical uses • Trichomoniasis:It may be effective against some of these resistant organisms • Adverse effects: toxicity profile is similar to metronidazole, but it is better tolerated.
- 26. Diloxanide furoate • Diloxanidefuroate is a dichloroacetamide derivative. • It is an effective luminal amebicide but is not active against tissue trophozoites. PK: • After oral administration diloxanide furoate is split in the gut into diloxanide and furoic acid • 90% of the drug is rapidly absorbed then conjugated via glucuronidation to be promptly excreted in the urine.
- 27. Cont’d • The unabsorbedportion (10%) is the active antiamebic substance. • MOA: Unknown Clinical uses: • It is considered the drug of choice for asymptomatic luminal infections • It is used with a tissue amebicide, usually metronidazole to treat serious intestinal and extra intestinal infections. • Adverse effects: flatulence is common, nausea, abdominal cramps and rashes might also occur • Not recommended in pregnancy
- 28. Iodoquinol • Iodoquinol (diiodohydroxyquin)is a halogenated hydroxyquinoline. PK: • 90% of the drug is retained in the intestine and excreted in feces. • The remainder enters the circulation, and is excreted in the urine as glucuronidated metabolites. • Half life= 11 hours • MOA: Unknown
- 29. Cont’d • It iseffective against organisms in the bowel lumen but not against trophozoites in the intestinal wall or extra intestinal tissues. • Adverse effects: Diarrhea, anorexia, nausea, vomiting, abdominal pain • Headache, rash, pruritus • Neurotoxicity with prolonged use and high dosage.
- 30. • Precautions: 1. Iodoquinolshould be taken with meals to limit GI toxicity 2. It should be used with caution in patients with optic neuropathy, renal or thyroid disease, or non amebic hepatic disease. 3. The drug may increase protein-bound serum iodine, leading to a decrease in measured 131I uptake that persist for months. 4. It should be discontinued if it produces persistent diarrhea or signs of iodine toxicity eg, dermatitis, urticaria, pruritus, or fever. 5. It is contraindicated in patients with intolerance to iodine.
- 31. Emetine and Dehydroemetine •Emetine, an alkaloid • are effective against tissue trophozoites of E. histolytica, but because of major toxicity concerns they have been almost completely replaced by metronidazole. • Both act by inhibiting protein synthesis in amoeba. Route of administration: • Subcutaneous (preferred) or I.M. Never IV
- 32. CLINICAL USES • Theiruse is limited to unusual circumstances: 1- severe amebiasis warrants effective therapy 2- metronidazole can not be used. Dehydroemetine is preferred because it has a better toxicity profile. It should be only used for the minimum period of 3- 5 days. Adverse effects: • Diarrhea is common • Nausea, vomiting, muscle weakness • Cardiac arrhythmias, heart failure, hypotension (serious toxicity)
- 33. Cont’d • Precautions: 1. Thedrug should not be used in patients with cardiac or renal disease, 2. Young children, or 3. In pregnancy.
- 34. Paromomycin • Paromomycin isan aminoglycoside antibiotic. • It is not significantly absorbed from the GIT. • Small amount is absorbed. And it is slowly excreted unchanged, mainly by glomerular filtration. • MOA: It inhibits protein synthesis by binding to the A-site of 16s rRNA and induces misreading of mRNA • Clinical uses: -It is used only as a luminal amebicide. -Paromomycin has similar efficacy and less toxicity than other agents.
- 35. Cont’d • Parenteral (IV)paromomycin is now used for the treatment of visceral leishmaniasis. • Adverse effects: 1. Abdominal distress, diarrhea. • Precautions: It should be avoided in patients with significant renal disease and cautiously used with GI ulceration
- 36. Tetracyclines: • They areactive against many gram-positive and gram-negative bacteria and against some protozoa, for example, amebas.
- 37. MOA • Tetracyclines entermicroorganisms by 1- passive diffusion 2- active transport. • tetracyclines bind reversibly to the 30S subunit of the bacterial ribosomes, blocking the binding of aminoacyl-tRNA to the acceptor site on the mRNA- ribosome complex. • This prevents the addition of amino acids to the growing peptide chain .
- 38. Adverse effects: Previously mentionedin the antibiotics lecture Erythromycin Erythromycin inhibits protein synthesis via binding to the 50S ribosomal RNA, which blocks the aminoacyl translocation reaction and formation of initiation complexes.
- 39. Chloroquine • It isused in combination with metronidazole and diloxanide furoate to treat and prevent amoebic liver abscesses. • It eliminates trophozoites in liver abscesses, but it is not useful in treating luminal amebiasis • MOA: Chloroquine probably acts by concentrating in parasitic food vacuoles, preventing the polymerization of the hemoglobin breakdown product, heme into hemozoin, and thus eliciting parasite toxicity due to the building up of free heme.
- 40. Adverse effects: 1. Pruritusis common, 2. Nausea, vomiting, abdominal pain, anorexia. 3. Headache, blurring of vision uncommon. 4. Hemolysis in G6PD deficient patients, impaired hearing, agranulocytosis, alopecia, hypotension.
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