AMOEBIASISVipul Agarwal

M.Pharm I Year

BBAU

Lucknow

AMOEBIASIS

Amoebiasis is caused by E. histolytica, a protozoa parasite

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

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LIFE CYCLE

Entamoeba histolytica exists in two forms:

Cysts (infective):• can survive outside the human body.• transform to trophozoites. Trophozoites (non-infective; invasive):

• Can reproduce • They may feed on intestinal bacteria

or invade and ulcerate wall of large intestine, and may migrate to liver or other tissues.

• transform to cysts which are excreted in feces.

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LIFE CYCLE

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DIGNOSIS

Diagnosis of E. histolytica has historically relied on Microscopic examination of protozoan morphology

LIMTATIONo Difficult though, to detect morphological

differences in protozoao Sensitivity o Specificity

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NEWER DIAGNOSTIC TECHNIQUE

DNA based methods:

The ability of Polymerase Chain Reaction (PCR) to specifically amplify minute amounts of pathogen DNA has revolutionized the diagnosis of amoebiasis

Most, but not all, rely on amplifying unique regions of the SSUrRNA

Coupled with antigen detection PCR, may offer the best way to diagnose patients

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NEWER DIAGNOSTIC TECHNIQUE-CONTD

ELISA

Becoming increasingly popular in diagnoses symptomatic patients are thought to have

high levels of specific antibodies, serum anti-lectin immunoglobulin G (IgG), associated with the E. histolytica infection within one week of symptoms,

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AVAILABLE DRUGS

1. Tissue amoebicides: Intestinal and extra-intestinal:

Nitroimidazoles – Metronidazole, Tinidazole, Secnidazole, Ornidazole, Satranidazole

Alkaloides – Emetine and Dihydroemetine Extra-intestinal –Chloroquine

2. Luminal amoebicides: Amides – Diloxonide furoate, Nitazoxamide 8-Hydroxyquinolines – Quinodochlor, Antibiotics - Tetracycline

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METRONIDAZOLE – PROTOTYPE

Belongs to Nitroimiidazole CLass Mixed Amoebicide Originally discovered and used for

Trichomoniasis in 1959 Broad spectrum cidal activity against ---

Protozoa Acts on trophozoites. Has no effect on cysts.

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Infected cell

Reduced to highly reactive nitro

radicals

Ferredoxin

MOA

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Competes with biological electron

acceptor

Acts as electron sink –electrons by

PFOR p/w

Energy metabolism disrupted

Reduced to highly reactive nitro

radicals

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METRONIDAZOLE – CONTD. Pharmacokinetics: Well absorbed from the small intestine Metabolized in liver by oxidation and

glucoronidation Half life – 8 Hrs

ADRs: Most common - Nausea, Vomiting, abdominal

cramps and metallic taste Less frequent – headache,rashes and dryness of

mouth Seizures at high dose

Interactions:– Disulfiram-like intolerance with alcohol.

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METRONIDAZOLE - USES

1. 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

2. Giardiasis3. Anaerobic infections4. Pseudo-membranous enterocolitis5. Helicobacter pylori

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OTHER NITROIMIDAZOLES

• 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 hr

• Satranidazole: 14 hrs half life – better tolerated plus no nausea, vomiting and metallic taste - no disulfiram like reaction and neurological symptoms

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EMETINE Emetine, alkaloid derived from Cephaelis ipecacuanha

and dehydroemetine, a synthetic analog, are effective against tissue trophozoites of E histolytica

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. NO

ORAL because oral preparations are absorbed erratically and vomiting

MOA inhibits protein synthesis……arrest intraribosomal translocation of t RNA-AA complex

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

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EMETINE - ADRS Pain and tenderness in the area of injection Gastrointestinal tract discomfort Cardiac toxicity: arrhythmias, congestive

heart failure, hypotension, ECG changes.

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CHLOROQUINE

Kills trophozoites of E. histolytica Concentrates in liver – used in liver

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

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CHLOROQUINE 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 buildup of free heme.

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DILOXANIDE FUROATE (DF) Highly effective luminal amoebicide Chemistry Ester of diloxanide + furoic acid . Kills trophozoites responsible for production of cyst – however

no antibacterial action MOA

Oral DF

Furoic hydrolyzed and Diloxanide is freed

90% Diloxanide is absorbed

Remaining 10% reaches Large intestine

Kills the trophozoites Absorbed D – low serum level – no therapeutic effects

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DILOXANIDE FUROATE – CONTD

ADRs: Well tolerated, only falatulence, nausea, itching and rarely urticaria

For eradication of infection given along with all forms of amebiasis.

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NITAZOXANIDE

Salicylamide congener of Niclosamide Also effective in E. Histolytica, T. Vaginalis, H.

Pylori etc. Converted to Tizoxanide after absorption MOA: Inhibition of PFOR enzyme,an esential

pathway of electron transport energy metabolism

Uses: Giardiasis, aboebiasis as luminal amebicide,diarrhoea

Dose: 500 mg BD for 3 days20

8-HYDROXYQUINOLINES Drugs – Iodoquinol, Clioquinol and Iodochlorohydroxyquin Luminal amoebicidal but no tissue action Effective 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 and fungal and bacterial infections. 250 to 500 mg tds

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TETRACYCLINES

Luminal amoebicide Disturbs the symbiosis between normal

intestinal flora & E .histolytica -----------amoebae grow at expense of normal intestinal flora .

Tetracyclines are broad spectrum antibiotics & kill these flora leading to death of E .histolytica also.

Used in resistant and chronic cases.

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Infected cell

increased expression of iron-containing superoxide dismutase (Fe-SOD) and

peroxiredoxin

Ferredoxin

RESISTANCE Increased Antioxident enzyme activity so less radicle formation

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RECENT DRUGS

Paromycin Auranofin Pyrimidine Analouges Etophamide

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PAROMOMYCIN Aminoglycoside antibiotic. Not significantly absorbed Less toxic Superior to Diloxanide furoate in clearing

asyptomatic infections. No effect on extra-intestinal amoebic

infections.MOA Direct amebicidal action (causes leakage by its action on

cell membrane of parasite). Indirect killing of bacterial flora essential for

proliferation of pathogenic amoebae. S/E: Abdominal Distress & diarrhea.

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AURANOFIN A gold-containing drug approved arthritis

drug In Phase IIa Identification by High-Throughput Screen

(HTS) Less Costly Effective against amoebas in lab and animal

studies Orphan Drug Status Ten times more potent than the current

treatment 26

AURANOFIN MOA

Targets the Thioredoxin reductase

No reduction of thioredoxin

Enhancing sensitivity of trophozoites to reactive oxygen-mediated killing

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Etophamide

Dose of 1 g per day, for three consecutive days

Tolerance of a new antiamebic drug was excellent

Cure rate obtained 92% Used for treatment of chronic intestinal

amebiasis. MOA is Unkown

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PYRIMIDINE ANALOUGES Pyrazolo[3,4-d]pyrimidine analogues Active against HM1:IMSS strain of Entamoeba

histolytica Comparable to MTZ Low Side effect

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CHOICES OF DRUGS

Asymptomatic cysts carriers

Iodoquinol or ParomomycinOr 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 30

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