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Antiamoebic and antiprotozoal drugs - drdhriti
 

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A Power point presentation on "Antiamoebic and antiprotozoal drugs" suitable for UG MBBS level students

A Power point presentation on "Antiamoebic and antiprotozoal drugs" suitable for UG MBBS level students

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    Antiamoebic and antiprotozoal drugs - drdhriti Antiamoebic and antiprotozoal drugs - drdhriti Presentation Transcript

    • ANTIAMOEBIC AND ANTIPROTOZOAL DRUGS Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong
    • Section – 1 Antiamoebic Drugs Drugs useful in infections caused by the protozoa Entamoeba histolytica (E. histolytica)
    • AMOEBIASIS - EPIDEMIOLOGY E. histolytica, a protozoa parasite is the causative agent of amoebiasis  Approximately 48 million individuals suffer from amoebiasis throughout the world  At least 40 thousand deaths are attributable to amoebiasis  Ranks third among parasitic causes of deaths, behind only malaria and schistosomiasis 
    • E. HISTOLYTICA – PATHOGENESIS • • It is a water-borne pathogen transmitted by the fecal-oral route Exists in 2 (two) forms: 1. 2. • Cyst or the dormant form – can survive outside the body Trophozoite or the dividing form - Non-infective and do not persists outside the body but invasive Two stages of development: Ingested cyst trophozoites May live as commensals reaches colon Form cysts that pass on to stool transform to 1. Form amoebic ulcers (acute dysentery) - galactose/Nacetyl-galactosamine (Gal/GalNAc) lectin 2. Chronic amoebic dysentery (vague symptoms, amoeboma)
    • PATHOGENESIS OF E. HISTOLYTICA – CONTD. Trophozoites can also enter the blood stream and travel to other parts— commonly the liver, but sometimes the lungs or brain and can cause abscesses. • Remember - In tissues, only trophozoites are present •
    • AVAILABLE DRUGS 1. Tissue amoebicides: a) b) 2. Intestinal and extra-intestinal: Nitroimidazoles – Metronidazole, Tinidazole, Secnidazole, Ornidazole, Satranidazole and Alkaloides – Emetine and Dihydroemetine Extra-intestinal – Only Chloroquine Luminal amoebicides: Amides – Diloxonide furoate, Nitazoxamide; 8Hydroxyquinolines – Quinodochlor, Diiodohydroxyquin; Antibiotics Tetracycline
    • METRONIDAZOLE – PROTOTYPE G. lamblia  Originally T. vaginalis discovered and used for Trichomoniasis in 1959  Broad spectrum cidal activity against --Protozoa – E. histolytica, T. vaginalis, G. lamblia  Anaerobic bacteria – B.fragilis, C.perfringes, H.pylori, Cl. difficile  Resistance – no significant resistance for E. histolytica till now, but developed for T. vaginalis
    • METRONIDAZOLE – MOA • • • Selective Toxicity to anerobic microorganisms A system unique to anaerobics - Pyruvate:ferredoxin oxidoreductase pathway (PFOR) normally generates ATP via oxidative decarboxylation of pyruvate Metronidazole: Entry into the microorganism by diffusion (LMW) ---- Reduced to nitro radical by certain redox proteins in the mitochondria to nitro group --- nitro radicals act as an electron sink --- competes with Biological acceptor sites of anaerobic organisms for the electrons generated PFOR pathway of pyruvate reduction – Reduction of metronidazole creates a concentration gradient that drives uptake of more drug, and promotes formation of intermediate compounds and free radicals – Cytotoxic intermediate particles interact with host cell DNA, resulting in DNA strand breakage and fatal destabilization of the DNA helix
    • METRONIDAZOLE – CONTD.  Pharmacokinetics: Well absorbed from the small intestine  Widely distributed in the body secretions – vaginal secretions, semen, saliva and CSF  Metabolized in liver by oxidation and glucoronidation  Half life – 8 Hrs   ADRs: Most common - Nausea, Vomiting, abdominal cramps and metallic taste  Less frequent – headache, glossitis, rashes and dryness of mouth  Prolonged administration – Peripheral neuropathy and CNS effects  Seizures at high dose 
    • METRONIDAZOLE – CONTD. • Contraindications: – – – • First trimester of pregnancy Neurological diseases and Blood dyscrasias Chronic alcoholism Interactions: – – Disulfiram-like intolerance: Symptoms: flushing, burning sensation, throbbing headache, perspiration, dizziness, vomiting, visual disturbance, mental confusion, fainting and circulatory collapse Enzyme inducers like Phenobarbitone and Rifampicin (reduced therapeutic effect)
    • METRONIDAZOLE - USES 1. 2. 3. 4. 5. 6. 7. Ameobiasis – Kills E. histolytic trophozoites but not cysts. Treatment of all tissue infections with E histolytic. No effects against luminal parasites and so must be used with a luminal amebicide – for eradication Giardiasis Trichomonas vaginalis – additional intravaginal treatment and both partners !! Anaerobic infections Pseudo-membranous enterocolitis Ulcerative gingivitis Helicobacter pylori
    • OTHER NITROIMIDAZOLES • • Tinidazole, Secnidazole, Ornidazole, Satranidazole Tinidazole: – – – • • • Slower metabolism, duration of action longer (t1/2 12 hrs) – single dose Higher cure rates (!) Better tolerated – lesser incidence of side effects Secnidazole: Rapid absorption, but slower metabolism – half life 17-29 hrs Ornidazole: 12 -24 Satranidazole: 14 hrs half life – better tolerated plus no nausea, vomiting and metallic taste - no disulfiram like reaction and neurological symptoms
    • EMETINE AND DEHYDROEMETINE  • •   Emetine, alkaloid derived from Cephaelis ipecacuanha and dehydroemetine, a synthetic analog, are effective against tissue trophozoites of E histolytica MOA: Inhibiting intraribosomal translocation of tRNAamono acid complex → inhibiting elongation of peptide chain → inhibiting protein synthesis Action: Effects on trophozoites but not on cysts. Potent and rapid action – symptomatic relief in 1-3 days, but not curative Administered subcutaneously (preferred) or i.m. (but never i.v.) because oral preparations are absorbed erratically and vomiting Uses: Seldom used now. Reserve drug for severe intestinal and extraintestinal amoebiasis or for patients not responding to metronidazole. Luminal amoebicide needed to be added
    • EMETINE - ADRS      Local stimulation: pain and tenderness in the area of injection Gastrointestinal tract discomfort: nausea, vomiting, diarrhoea and abdominal cramps Neuromuscular blockade: muscle weakness and discomfort Cardiac toxicity: arrhythmias, congestive heart failure, hypotension, ECG changes Not be used in patients with cardiac or renal disease, in young children, or in pregnancy
    • CHLOROQUINE  Kills trophozoites of E. histolytica  Concentrates in liver – used in hepatic amoebiasis  Completely absorbed from upper intestine – not effective in invasive or luminal dysentery  Efficacy in amoebic liver is equal to emetine, but longer treatment and relapse  Used after a course of Metronidazole – but a luminal amoebicide must be added  Dose - 600mg stat and next day &300mg for 2-3 days
    • DILOXANIDE FUROATE (DF) Highly effective luminal amoebicide  Kills trophozoites responsible for production of cyst – however no antibacterial action  MOA: Oral DF F hydrolyzed and D is freed 90% D is absorbed remaining 10% reaches Large intestine and exerts effects   Absorbed D – low serum level – no therapeutic effects Uses: Mild tissue amoebiasis/asymptomatic cyst passers, Tissue amoebiasis and liver abscess with Metronidazole  ADRs: Well tolerated, only falatulence, nausea, itching and rarely urticaria 
    • NITAZOXANIDE Newer Drug for Giardiasis  Also effective in E. Histolytica, T. Vaginalis, H. Pylori etc.  Converted to Tizoxanide after absorption  MOA: Inhibition of PFOR  Uses: Giardiasis, aboebiasis as luminal amebicide  Dose: 500 mg BD for 3 days 
    • 8-HYDROXYQUINOLINES     Drugs – Iodoquinol, Clioquinol and Iodochlorohydroxyquin Act against Entamoeba, Giardia, Trichomanas, some fungi and Bacteria Luminal amoebicidal but no tissue action – not effective in acute dysentery but in chronic intestinal amebiasis (but lesser than DF) Absorbed very less amount (10-30%) - therapeutic conc. Is not attained      conjugated and excreted in urine Once a popular drug – but less now because of ADRs ADRs – well tolerated – only nausea, green stools pruritus etc. plus Iodism But Subacute myelo-optic neuropathy (SMON) - the inflammation of the optic nerve causing a complete or partial loss of vision and also peripheral neuropathy Uses: Alternative to DF in amoebiasis, Giardia, local treatment of vaginal Trichomous and fungal and bacterial infections. 250 to 500 mg tds
    • CHOICES OF DRUGS Asymptomatic cysts carriers Iodoquinol or Paromomycin Or Diloxanide furoate Diarrhea / Dysentery Metronidazole + Iodoquinol or Diloxanide or Paramomycin Amebic liver abscess Chloroquine + Metronidazole + DF Giardiasis (Giardia labmlia) Metronidazole or Nitazoxamide or Iodoquinol or Furazolidone
    • TRICHOMONAS VAGINITIS TREATMENT  Metronidazole – 400 mg tds for 7 days or 2 gm single dose, or  Tinidazole 600 mg BD for 7 days or 2 gm single dose  Repeat after 6 weeks  Additional intravaginal treatment for refractory cases  Resistance have been reported  Both partners should be treated  Local application drugs: Quinodochlor, ClotrimazoleNatamycin, Povidone Iodine etc.
    • • Section – 2 • Drugs for Leishmaniasis • • • Visceral leishmaniasis or kala-azar caused by Leishmania donovani Transmitted by bite of female sand fly of genus phlebotomus Amastigote and Promastigote
    • AVAILABLE DRUGS Antimonial – Sodium stibogluconate (SSG)  Diamide – Pentamidine  Antifungal – Amphotericin B (AMB), Ketoconazole (KTZ)  Others – Mifepristone, Paromomycin and Allopurinol 
    • SODIUM STIBOGLUCONATE (SSG)    The drug of choice in Leishmaniasis – some resistance Water soluble pentavalent antimonial compound – 1/3 rd antimony by weight MOA: Not clear -SH dependent enzymes are inhibited – bioenergetics of the parasite  Blocks glycolytic and fatty acid oxidation pathways  Enzyme in leishmania converts SSG to trivalent compound – causes efflux of glutathione and thiols – oxidative damage    Not metabolized – excreted unchanged in urine after IM injection Dose: 20-30 mg/kg deep IM daily in buttock for 20-30 days or more – depends on response – also IV   Response in Bone marrow and splenic aspirates Should be give on alternate days I poor health patients
    • SSG - ADRS All antimonials are toxic  Pentavalent compounds are less toxic and better tolerated  Nausea, vomiting, metallic taste, cough and pain abdomen  Stiffness and abscess in injected muscles  Pancreatitis, liver and kidney damage etc.  Rarely shock and death 
    • PENTAMIDINE • • • • MOA: Not clear, inhibits Topoisomerase II or interferes with aerobic glycolysis Dose: 4 mg/kg IM or slow IV for 1 Hr on alternate days for 5-15 weeks Not metabolized but stored in kidneys and liver – slowly released Toxicity: Histamine release – acute reactions – – – Sharp fall in BP, dyspnoea, palpitation, fainting, vomiting and rigor etc. – supine position Other reactions - rashes, mental confusion, kidney and liver damage Cytolysis of pancreatioc beta cells – initially insulin release – hypoglycaemia, but later IDDM
    • PENTAMIDINE – USES SSG failure cases as salvage therapy - AMB is preferred now  Leishmaniasis with Tuberculosis  Pneumocystis jiroveci pneumonia in AIDS patients  Other drugs AMB and Paromomycin etc. – shall be discussed elsewhere!
    • DID YOU SLEEP DURING LAST 45 MIN. ? If yes, no problem – just have to go and read Metronidazole and SSG If No, enjoy today - for knowing Metronidazole and SSG
    • THANK YOU