> » oa a\ ew NN bed Yo A AS SW stevacsMeldeWst-yenstiks) 9 Anti-amoebic Drugs Click here to JOWNLOAD wy Zp Download “GDC CLASSES” App From Play Store for FREE Pharma Study Material & MCQs1. INTRODUCTION 2. CLASSIFICATION OF ANTI- AMOEBIC DRUGS 3. MOA,PHARMACOKINETICS ,ADR,USES OF DIFFERENT CLASS OF DRUGS 4. TREATMENT OF ANTI- AMOEBIC DRUGS O INTRODUCTION * Amoebiasis caused by the protozoan Entamoeba Histolytica. It spreads by faecal contamination of food and water. Though it primarily affects colon, other organs like liver, lungs and brain are the secondary sites. Acute amoebiasis is characterised by bloody mucoid stools and abdominal pain. Infective stage :- Trophozoite Chronic amoebiasis manifests as anorexia, abdominal pain, intermittent diarrhoea and constipation. Ca Download “GDC CLASSES” APP > Goosie Py pyaRMA EXAM PREPARATION SIMPLIFIED“+ Life cycle of Entamoeba histolytica > Entamoeba histolytica exists in two forms: 1. Cysts form (That can survive out side the body). 2. Trophozoites form (That are labile and don't persist outside the body). Y Life cycle consists of following steps: 1, Ingestion of cysts :- Cysts are ingested through feces, contaminated food or water. 2. Formation of trophozoites:- Cysts are passed into the lumen of intestine, where the trophozoites are liberated. ——» FAECES (Cyst passer) INTESTINAL LUMEN a Luminal cycle REAM f= (Dysentery) (Liver abscess) Stee MPU Rave CUBA S(O BLEUE TNC Lhe T-trophozoite , C-cyst Sern ee a ee me TST eT as3. Penetration and multiplication of trophozoites * Trophozoites are penetrated in intestinal wall and multiply within colon wall. * They either invade and ulcerate the mucosa of large intestine or simply feed on intestinal bacteria. 4. Systemic invasion + Large numbers of trophozoites within the colon wall can also lead to systemic invasion and caused liver abscess. 5. Cysts discarded * The trophozoites within the intestine are slowly carried toward the rectum, where they return to cyst form and are excreted in feces » Classification of amoebicidal drugs According to the site where the drug is effective the amoebicidal drugs are classified as: i. Luminal amoebicides (Act on parasite in the lumen of bowel) ii. Systemic amoebicides (Against amebas in intestinal wall & liver) iii. Mixed amoebicides (Against both the luminal and systemic form of diseases) Extra intestinal ——> Chloroquine. ———>| Sites. only eat - Emetine and dehydroemetine Luminat = Diloxanide turoate luminal D ledoquinot 6 ( amebicides J: totracycines —b& (Intestine () 2 Paromomyein es of action of antiamoebic drugs a) Tori) a Google Py PHARMA EXAM PREPARATION SIMPLIFIEDUO CLASSIFICATIO ANTIAMOEBIC DRUGS Tissue For intestinal+ | Nitroimidazole Metronidazole, amoebicid | extra intestinal Tinidazole, es Amoebiasis Secnidazole Ornidazole Satrinidazole Alkaloids Emetin, Dehydroemetin Amoebiasis only Lminat [Amides amoebicid | | Nitazoxanide es b | 8- hydroxyquinolines -Quiniodochlor Diiodohydroxyquin Antibiotics Tetracyclines Paromomycin 3) pri Tica ae CEST ETC tae}I. TISSUE AMOEBICIDES a. Nitroimidazole:- Metronidazole, Tinidazole, Secnidazole, Ornidazole, Satrinidazole i. Metronidazole It is the prototype Nitroimidazole introduced in 1959 for trichomoniasis. It has broad-spectrum cidal activity against anaerobic protozoa, including Giardia lamblia, E. histolytica, Trichomonas vaginalis It helps in the extraction of guinea worm (Dracunculus medinensis) Mechanism of action Metronidazole Nitroreductase Active metabolite (cytotoxic) Binds to DNA Inhibits protein synthesis Ween nce ease mu Cinco CcrAuta ha Me ee COMET ST UES UT Ns)Metronidazole is a prodrug. Microorganisms including anaerobic bacteria and certain protozoa reduce the nitro group of metronidazole by a nitroreductase and convert it to a cytotoxic derivative. This derivative binds to DNA and inhibits protein synthesis. Aerobic bacteria lack this nitroreductase and are, therefore, not susceptible to metronidazole. Pharmacokinetics * Metronidazole is well-absorbed, is widely distributed, penetrates all tissues and reaches adequate concentrations in the CSF. * Ithasa plasma t'% of 8 hr. * It is metabolised in the liver by oxidation and glucuronide conjugation. Adverse effect * Anorexia, abdominal crams, alcohol intolerance Glossitis & giddiness Taste - Metallic, thrombophlebitis Headache, stomatitis, furry tongue; dizziness ,steven -Johnson syndrome Insomnia, ataxia, vertigo, carcinogenic, mutagenic. Reddish brown colour urine «> Drug interactions * Metronidazole potentiates the anticoagulant effect of warfarin and other oral coumarins by inhibiting their metabolism. There is prolongation of prothrombin time; hence, reduction of warfarin dose may be needed. Metronidazole may potentiate lithium toxicity by decreasing the renal clearance of lithium. he “ v7 i ha Me ee COMET ST UES UT Ns)“ Uses i. Metronidazole is used in the treatment of alveolar abscess, pericoronitis, periodontitis, etc ii. Amoebiasis iii. Giardiasis iv. Trichomonas vaginitis v. Anaerobic bacterial infections Anaerobic vi. Acute necrotizing ulcerative gingivitis (ANUG) vii. Pseudomembranous enterocolitis ii. Tinidazole Tinidazole is a second-generation nitroimidazole that is similar to metronidazole in spectrum of activity, absorption, adverse effects and drug interactions. * Metabolism is slower; t14 is ~12 hr. * Duration of action is longer; dosage schedules are simpler. ¢ Thus, it is more suited for single dose or once daily therapy. *~ Side effects :- metallic taste (2%), nausea (1%), rash (0.2%). iii. Secnidazole Metronidazole, secnidazole is a Nitroimidazole derivative. Plasma tz of 17-29 hours The spectrum, side effects and mechanism of action of secnidazole are similar to metronidazole. Secnidazole is longer-acting and can be given as a single 2 g dose for most indications of metronidazole iv. Ornidazole + Ithas activity similar to metronidazole, but it is slowly metabolized— has longer t% (12-14 hr). aml mc eee Google Play PHARMA EXAM PREPARATION SIMPLIFIED* Dose and duration of regimens for amoebiasis, giardiasis, trichomoniasis, anaerobic infections and bacterial vaginosis resemble those for tinidazole. * Inchronic intestinal amoebiasis and asymptomatic cyst passers 0.5 twice daily for 5 to 7 days used. v. Satrinidazole + Satranidazole is more potent than tinidazole and also does not cause disulfiram-like antabuse reactions. “ Side effect :- nausea, metallic taste and peripheral neuropathy. I(b) Alkaloids bi loids :- Emetine, Dehydroemetin i, Emetine * Itis an alkaloid from Cephaelis ipecacuanha. * Emetine is a potent and directly acting amoebicide—kills trophozoites but has no effect on cysts. “ Mechanism of action * It acts by inhibiting protein synthesis in amoebae by arresting intraribosomal translocation of t(RNA-amino acid complex. “ Pharmacokinetics « Emetine cannot be given orally because it will be vomited out. + Itis administered by S.C. or LM. injection. *» Adverse effect * Nausea, vomiting (due to CTZ stimulation and gastric irritation) = , = ; UC sag CW USC e CTU eon cls)Abdominal cramps, diarrhoea, weakness, stiffness of muscles, myositis Hypotension , ECG changes and myocarditis. Cardiotoxicity including arrhythmias, hypotension and cardiac failure can occur. Uses + Emetine is used for acute amoebic dysentery or for amoebic liver abscess. * Aluminal amoebicide must always follow emetine to eradicate the cyst forming trophozoites. + It is also effective in liver fluke infestation ii, Dehydroemetin + Itis equally effective but less cumulative and less toxic to the heart Thus, it is usually preferred over emetine. * Similar to emetine. 2. For extra intestinal Amoebiasis only _ ae 4-aminoquinoline :- Chloroquine i. Chloroquine * Chloroquine attains high concentration in the liver, is directly toxic against trophozoites gu * Itis useful in hepatic amoebiasis. + Itkills trophozoites of E. histolytica * Pharmacokinetics * chloroquine is completely absorbed from the small intestines, it is not effective against amoebae in the colon. * It is used (300 mg base/day for 21 days) as an alternative to metronidazole in hepatic amoebiasis. he “ v7 i ha Me ee COMET ST UES UT Ns)II. LUMINAL AMOEBICIDES | 1. Amides :- Nitazoxanide , Diloxanide furoate i. Nitazoxanide * Salicylamide congener of the anthelmintic niclosamide. * Introduced for the treatment of giardiasis and cryptosporidiosis is also active against many other protozoa including e. Histolytica, T. Vaginalis, and helminths , ascaris, H. Nana, etc. “+ Mechanism of action -- It is a prodrug which on absorption is converted to the active form tizoxanide, an inhibitor of PFOR enzyme that is an essential pathway of electron transport energy metabolism in anaerobic organisms. “+ Pharmacokinetics * Tizoxanide generated from nitazoxanide is glucuronide conjugated and excreted in urine as well as bile . Metabolized in liver “+ Adverse effect + Abdominal pain * Vomiting * Headache * Greenish tint to the urine “ Uses * Itis also indicated in giardiasis, and may be used as an alternative luminal amoebicide in amoebic dysentery. * Nitazoxanide is the most effective drug for Cryptosporidium parvum infection “> Contraindication :- should be avoided in pregnancy. Set ee ee me TESTU TU etaii. Diloxanide furoate It is a highly effective luminal amoebicide which directly kills trophozoites responsible for production of cysts. “+ Mechanism of action * Diloxanide furoate is directly amoebicidal. + Itis split in the intestines to diloxanide and furoic acid. * [tacts on the parasite in the intestines but not in the tissues. nide furoate oI evr Gels Furoic acid (Gelatin lkuasi)) (Unabsorbed) > SOME LE LC) ribet * Itis primarily metabolized by glucuronidation * Pharmacokinetics * Excreted in urine. “* Side effects :- Flatulence, occasional nausea, itching and rarely urticaria “ Uses * Diloxanide is used along with a nitroimidazole for the cure of amoebiasis, as diloxanide eradicates cysts It can be used alone in asymptomatic cyst passers, mild intestinal amoebiasis. Te Ce ke Ce mT ST ety urn cl)quinoline: uiniodochlor , Diiodohydroxyquin i. Quiniodochlor & Diiodohydroxyquin 8-hydroxyquinolines including Quiniodochlor and Iodoquinol. They are active against Entamoeba Giardia, Trichomonas. Giardia, Trichomonas, some fungi (dermatophytes, Candida) * They kill the cyst forming amoebic trophozoites in the intestine, but do not have tissue amoebicidal action. * Pharmacokinetics The absorbed fraction is conjugated in liver with glucuronic acid and sulfate Excreted in urine; t% is ~12 hours. “% Side effects i, Nausea ii. loose and green stools iii. pruritus “+ Uses Used for the prophylaxis and treatment of nonspecific diarrhoeas, traveller’s diarrhoea, dietary indiscretion, etc Other uses are—giardiasis , local treatment of monilial and trichomonas vaginitis, fungal and bacterial skin infections. es ,Paromomycin i. Tetracyclines Tetracyclines have modest direct inhibitory action on Entamoeba. Tetracyclines are incompletely absorbed in the small intestine, reach the colon in large amounts and inhibit the bacterial flora with which entamoebae live symbiotically Ca ecu a1 Google Py PHARMA EXAM PREPARATION SIMPLIFIED+ The luminal cycle with little mucosal invasion. ii. Paromomycin * Paromomycin is active against many protozoa like emtamoeba, giardia, cryptosporidium, trichomonas, leishmania and some tape worms, in addition to having antibacterial spectrum like neomycin. In the 1960s an oral formulation of paromomycin was introduced as a luminal amoebicide. Paromomycin is being used in resistant kalaazar . Orally administered paromomycin acts only in the gut lumen. It is neither absorbed nor degraded in the intestines. Eliminated unchanged in the faeces. Paromomycin is an efficacious luminal amoebicide, Paromomycin is an alternative drug for giardiasis, especially during 1st trimester of pregnancy when metronidazole and other drugs are contraindicated. % Side effects * Nausea, vomiting, Abdominal cramps, diarrhoea; rarely rashes, renal impairment O) TREATMENT OF AMOEBIASIS Acute intestinal amoebiasis: One of the following can be given. ¥ Metronidazole 400-800 mg TDS for 5-7 days or 2.4 g OD for 3 days ¥ Tinidazole 2 g OD for 3 days ¥ Secnidazole 2 g single dose Alternatively ornidazole/satranidazole/ benznidazole may be used. diloxanide furoate 500 mg TDS for 10 days to eradicate the cysts. Ca ecu a1 Google Py PHARMA EXAM PREPARATION SIMPLIFIED2. Chronic amoebiasis and asymptomatic cyst passers Y Diloxanide furoate 500 mg TDS for 10 days or tetracycline 250 mg QID for10 days. v The alternatives are iodoquinol (650 mg TDS for 21 days) or paromomycin (10 mg/kg TDS for 7 days). 3. Hepatic amoebiasis * Acourse of metronidazole 600- 800 mg TDS for 10 days or tinidazole are the first-line drugs. * Acourse of diloxanide furoate 500 mg TDS for 10 days should follow in order to eradicate the cysts. Many drugs useful in amoebiasis are also effective in giardiasis lazole g TDS (children 15 mg/kg/day) for 5+ ays or2 g daily for 3 days, or Tinidazole 0.6 g daily for 7 days or 2 g single dose, or fe Metronidazole Tablets |.P. Flagyl’ 400 ae 14115 Tobe Secnidazole 2 g single dose These may be considered as the drugs of choice, but ~ 10% patients may not be cured, and a second course or alternative drug may 4 be needed. = A 5 Te Ce ke Ce mT ST ety urn cl)2. Nitazoxanide * This prodrug of the PFOR enzyme inhibitor tizoxanide has become available for the treatment of diarrhoea and dysentery caused by Cryptosporidium parvum , Giardia lamblia and E. histolytica. The dosage schedule is convenient—500 mg (children 7.5 mg/kg) twice daily for 3 days. Efficacy (~80% cure) approaches that of metronidazole. 3. Quiniodochlor 250 mg TDS for 7 days 4, Furazolidone * Jt is a nitrofuran compound active against many gram-negative bacilli including salmonella and shigella, also giardia and trichomonas. For giardiasis 100 mg TDS for 5-7 days has been used, but is inferior to metronidazole or tinidazole. It has also been used in bacterial enteritis, but is not a first line treatment. Furazolidone is partly absorbed from intestines and excreted in urine which turns orange . 3 Side effects - Nausea, Headache, Dizziness 1. Drugs used orally Metronidazole 400 mg TDS for 7 days or 2 g single dose, or Tinidazole 600 mg daily for 7 days or 2 g single dose or Secnidazole 2 g single dose, are the drugs of choice. aml mc ae Ca come PWR B ass eRe al =8)2. Drugs used intra vaginally i. Diiodohydroxyquin 200 mg inserted intra-vaginally at bed time for 1 2weeks FLORAQUIN 100 mg vaginal pessaries. ii. Quiniodochlor 200 mg inserted in the vagina every night for 1-3 weeks. GYNOSAN 200 mg vaginal tab. iii. Povidone-iodine 400 mg inserted in the vagina daily at night for weeks. BETADINE VAGINAL 200 mg Leishmaniasis is caused by protozoa of the genus leishmania. Kala-azar or visceral leishmaniasis is caused by leishmania donovan. Oriental sore by |. Tropica and mucocutaneous leishmaniasis by L. Braziliensis. Antimonials ‘Sod. Stibogluconate, Meglumine antimonate Diamidine Pentamidine Others Amphotericin B, Ketoconazole, Allopurinol, Miltefosine, Paramomycin = Fi rs oH ha Me ee COMET ST UES UT Ns)i. Sodium stibogluconate * Itis a pentavalent antimonial is the most effective drug in kala-azar. * Itis also effective in mucocutaneous and cutaneous leishmaniasis. * It is given as a 4% solution in the dose of 10-20 mg/kg IM (gluteal region) or IV for 20 days. ¢ Adverse effects Metallic taste in the mouth Nausea Vomiting, diarrhoea , headache Myalgia, arthralgia, pain at the injection site, bradycardia, skin rashes Haematuria and jaundice. ii. Meglumine antimonate and ethyl] stibamine can also be used in all forms of leishmaniasis. iii. Pentamidine is an aromatic Diamidine effective against Leishmania donovani, trypanosomes, Pneumocystis, jiroveci and some fungi. Given intramuscularly the drug is rapidly absorbed but very little reaches the CNS. * Adverse effects * Vomiting, diarrhoea, flushing, pruritus, rashes * tachycardia and hypotension apart from pain at the injection site. Hepatotoxicity renal impairment ECG changes and in some patients diabetes mellitus May be precipitated. aml cee Ca Google Play PHARMA EXAM PREPARATION SIMPLIFIEDUses i. Leishmaniasis ii. Pneumocystis iv. Miltefosine Miltefosine is the first drug that can be used orally in leishmaniasis. It has a high efficacy against both visceral and cutaneous leishmaniasis. Itis effective also in leishmania resistant to stibogluconate. It is approved for use in India in visceral leishmaniasis—700 mg/kg/day) for 4 weeks. * tis contraindicated in pregnancy. v. Amphotericin B has been tried in leishmaniasis in the endemic areas where antimonials may be ineffective. vi. Ketoconazole inhibits ergosterol synthesis in the leishmania and is effective in cutaneous leishmaniasis. AMB is also useful in mucocutaneous and dermal leishmaniasis viii. Allopurinol * In leishmania, allopurinol is converted to a metabolite which inhibits protein synthesis. + It may be used along with antimonials. Trypanosomiasis is caused by protozoa of the genus Trypanosoma. i, Suramin sodium ii. Melarsoprol iii. Eflornithine he ry v7 cam ha Me ee COMET ST UES UT Ns)i, Suramin sodium Itis the drug of choice for early stages of trypanosomiasis. It does not cross the BBB Itis also useful for the prophylaxis but pentamidine is preferable. Suramin is given IV. It is extensively bound to plasma proteins. Suramin is also effective in eradicating adult forms of Onchocerca volvulus, “+ Adverse effect i. Vomiting, shock ii. Rash, neuropathies iii. Haemolytic anaemia iv. Agranulocytosis ii. Melarsoprol is the preferred drug in later stages of trypanosomiasis which is associated with encephalitis and meningitis. iii. Eflornithine * Itis used in CNS trypanosomiasis. * Nifurtimox and benznidazole are useful in CHAGAS’ DISEASE (American trypanosomiasis). aml mc ae Ca Google Play PHARMA EXAM PREPARATION SIMPLIFIEDQUESTIONS FROM THE ABOVE TOPIC Very Short Answer Questions (2 marks) A eeieemo re iteUMmO eto lear are Write ADR of metronidazole? Write MOA of diloxanide furoate? SCY . Pear ary Write drugs name for giardiasis? CENTER Write drugs name for Trypanosomiasis? Meee w- WD) Mmm ieL erie Lee Short Answer Questions (4 marks) Discuss the classification of anti-amoebic drugs? Write short notes about tissue amoebicides of antiamoebic Plat irg Write short notes about luminal amoebicides of antiamoebic Platt tye Me ORO L mina b A) ee ee rome Geeta cd] DCO CRMC MUO Mem itclwrta etme UP ere uses of antiamoebic drugs? Time & Download “GDC CLASSES” APP > Goose Pay _pHARMA EXAM PREPARATION SIMPLIFIEDVery useful app for pharma student. Must have this app on every pharma students mobile Join “GDC CLASSES” App Cole See) t to 8th Sem MCQ Bank & Study Material PDFs Pri rice PEG see} overview NT Rupees Only McQs x Unlimited Attempt pi oa” B.PHARMA SEMESTER MCQs (PCI SYLLABUS) “GDC CLASSES” IN PLAY STORE TO DOWNLOAD aca