Antiamoebic and Antiprotozoal Drugs


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Antiamoebic and Antiprotozoal Drugs:

Antiamoebic and Antiprotozoal Drugs Dr. D. K. Brahma Associate Professor Department of Pharmacology NEIGRIHMS, Shillong

PowerPoint Presentation:

Section – 1 Antiamoebic Drugs Drugs useful in infections caused by the protozoa Entamoeba histolytica (E. histolytica)

Amoebiasis - Epidemiology:

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:

E. Histolytica – Pathogenesis It is a water-borne pathogen transmitted by the fecal-oral route Exists in 2 (two) forms: 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 reaches colon transform to trophozoites May live as commensals Form cysts that pass on to stool Form amoebic ulcers (acute dysentery) - galactose/N- acetyl-galactosamine (Gal/GalNAc) lectin Chronic amoebic dysentery (vague symptoms, amoeboma)

Pathogenesis of E. Histolytica – contd.:

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:

Available Drugs Tissue amoebicides: 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; 8-Hydroxyquinolines – Quinodochlor, Diiodohydroxyquin; Antibiotics - Tetracycline

Metronidazole – Prototype:

Metronidazole – Prototype Originally 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 G. lamblia T. vaginalis

Metronidazole – MOA:

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. :

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. :

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:

Metronidazole - uses Ameobiasis – K ills 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:

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 and D ehydroemetine Emetine, alkaloid derived from Cephaelis ipecacuanha and dehydroemetine , a synthetic analog, are effective against tissue trophozoites of E histolytica MOA: Inhibiting intraribosomal translocation of tRNA-amono 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:

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):

Diloxanide furoate (DF) Highly effective luminal amoebicide Kills trophozoites responsible for production of cyst – however no antibacterial action MOA: Oral DF F is 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 :

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:

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:

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.

PowerPoint Presentation:

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:

Available Drugs Antimonial – Sodium stibogluconate (SSG) Diamide – Pentamidine Antifungal – Amphotericin B (AMB), Ketoconazole (KTZ) Others – Mifepristone, Paromomycin and Allopurinol

Sodium stibogluconate (SSG):

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:

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. ?:

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:

Thank you