This document discusses anti-amoebic agents used to treat protozoal infections like amebiasis. It covers several classes of drugs: 1. Nitroimidazole derivatives like metronidazole are the drugs of choice for treating amebiasis. They kill both the trophozoite and cyst forms. 2. Luminal amebicides like diloxanide furoate and iodoquinol act directly on the trophozoite and cyst forms in the intestines. 3. Systemic amebicides like emetine and dehydroemetine inhibit protein synthesis and are used for invasive amebiasis in tissues. However, they have

1. ANTI-AMOEBIC AGENTS

2. Protozoal Infection
 Protozoal diseases are less easily treated than bacterial
infections:
Unicellular protozoal cells have metabolic processes closer to
human cells than bacteria.
Many of antiprotozoal drugs cause serious toxic effects and most of
them are not safe I n pregnancy.
Protozoal diseases, such as:
 Malaria
 Amebiasis
Leishmaniasis
Trypanosomiasis
Trichomoniasis
Giardiasis

3. Amoeba
• Dientamoeba fragilis-causes Dientamoebiasis
• Entamoeba dispar
• Entamoeba hartmanni
• Entamoeba coli
• Entamoeba moshkovskii
• Endolimax nana
• Iodamoeba butschii

4. 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

6. Clinical Classification Antiamoebic
Drugs
Mixed amebicides : both systemic and luminal
 Metronidazole
 Tinidazole
Luminal amebicides
– treatment of the asymptomatic colonization state.
 Iodoquinol,
 Paromomycin
 diloxanide furoate
systemic amebicides
– These drugs are useful for treating liver abscesses and intestinal wall
infections caused by amebas
 Chloroquine
 Emetine
 Dehydroemetine

7. Another Classification of Antiamoebics
I. Tissue Amoebicide
A. Intestinal as well as extra intestinal amoebicide
i) Nitroimidazole derivatigves: Metronidazole,
Ornidazole, Secnidazole, Tinidazole
ii) Alkaloid: Emetine and Dehydroemetine
B. Extra intestinal/hepatic amoebicide
Chloroquine
II. Luminal Amoebicide
a. Amide Derivatives: Diloxanide Furoate
b. 8-Hyroxyquinolines: Iodoquinol, clioquinol
c. Antibiotic : Tetracycline, Pramomycin

8. Chemical Classification
1. Nitroimidazole derivatives: Metronidazole, Tinidazole , Ornidazole ,
Secnidazole
2. Dichloroacetamides: Diloxanide Furoate, Etofamide, Clefamide, Teclozan
3. Emetines: Emetine, Dehydroemetine
4. Halogenated 8 Hydroxyquinolines: Clioquinol Iodoquinol
5. 4-amino quinoline derivatives: Chloroquine
6. Antibiotics: Paromomycin, Tetracycline
7. Nitrothiazolidines: Nitazoxanide

9. Life cycle of Entameaba histolytica and the sites of action of
amebicidal drugs

10. 1. Nitroimidazole derivatives:
Metronidazole, Tinidazole , Ornidazole ,
Secnidazole

11. Nitroimidazoles
 Metronidazole
 MOA: Releases in the parasites toxic superoxide
or hydroxyl radical forming reduced cytotoxic
compounds that bind to proteins and DNA,
resulting in cell death.
 Metronidazole is Drug of choice (DOC) for
amebic infection and for infections caused by:
 Giardia lamblia
 Trichomonas vaginalis
 Anaerobic cocci, gram+ve bacilli and “C.difficile” that
cause Pseudomemberanous colitis

12. Metronidazole (cont.)
 It kills the trophozoites and less effective
against the cyst
 Most effective against the invasive amebae
 Less effective against the luminal amebae
SO
• it is usually administered with a luminal amebicide,
such as iodoquinol or paromomycin

14. Metabolism of Metronidazole

16. Tinidazole
• Tinidazole is an anti-parasitic drug used gainst protozoan infections. It is
widely known throughout Europe and the developing world as a
treatment for a variety of amoebic and parasitic infections. It was
developed in 1972 and is a prominent member of he nitroimidazole use
of tinidazole for infections from amoebae, giardia, and trichomonas, just
like metronidazole.
• Tinidazole may be a therapeutic alternative in the setting of
metronidazole tolerance. Tinidazole may also be used to treat a variety of
other bacterial infections (e.g., as part of combination therapy
for Helicobacter pylori eradication protocols).
• Elimination half-life is 13.2 ± 1.4 hours. Plasma half-life is 12 to 14 hours
• Drinking alcohol while taking tinidazole causes an unpleasant disulfiram-
like reaction, which includes nausea, vomiting, headache, increased blood
pressure, flushing, and shortness of breath.

17. Ornidazole
• Ornidazole is a antibiotic used to treat
some protozoan infections. It has also been investigated
for use in Crohn's disease after bowel resection.
• After passive absorption into bacterium cell, the nitro
group of ornidazole is reduced to an amine group
by ferrodoxin-type redox systems. The formation of redox
intermediate intracellular metabolites is believed to be the
key component responsible for killing microorganisms. The
drug is active against anaerobic bacteria
including Peptostreptococcus, Clostridium, Bacteroides
fragilis, Prevotella, Porphyromonas gingivalis,
and Fusobacterium as well
as protozoa including Entamoeba histolytica, Trichomonas
vaginalis, and Giardia lamblia

18. MOA of Ornidazole

19. Secnidazole
• Secnidazole is structurally related to the commonly
used 5-nitroimidazoles metronidazole and tinidazole.
These drugs share a common spectrum of activity
against anaerobic micro-organisms and they appear
particularly effective in the treatment of amoebiasis,
giardiasis, trichomoniasis and bacterial vaginosis.

20. 2. Dichloroacetamides: Diloxanide Furoate,
Etofamide, Teclozan

21. Luminal Amebicides
Iodoquinol *Paromomycin *diloxanide furoate
• They have a direct amebicidal effect to the
trophozoites and cyst forms.
• Used in: asymptomatic cyst carriers and in intestinal
amebiasis.
• Amebae feed on intestinal Flora so tetracycline is
added to luminal amebicides to decrease major food
source.
• Side effects
• iodoquinol include rash, diarrhea, and dose-related
peripheral neuropathy, including a rare optic neuritis.

22. Diloxanide
furoate
• Diloxanide is a medication used to treat amoeba
infections. It is a second line treatment
after paromomycin when no symptoms are present in
places where infections are not common. For people
who are symptomatic, it is used after treatment
with metronidazole or tinidazole. It is taken by mouth.
• Diloxanide generally has mild side effects. Side effects
may include flatulence, vomiting, and
itchiness. During pregnancy it is recommended that it
be taken after the first trimester. It is a luminal
amebicide meaning that it only works on infections
within the intestines.

23. • Dloxanide furoate works only in the digestive
tract and is a lumenal amebicide. It is considered
second line treatment for infection with
amoebas when no symptoms are present but the
person is passing cysts, in places where
infections are not common. Paromomycin is
considered the first line treatment for these
cases.
• For people who are symptomatic, it is used after
treatment with ambecides that can penetrate
tissue, like metronidazole or tinidazole.
Diloxanide is considered second-line, while
paromomycin is considered first line for this use
as well.

24. MOA of Diloxanide
• Diloxanide furoate destroys trophozoites of E.
histolytica and prevents amoebic cyst formation. The
exact mechanism of diloxanide is unknown.
• Diloxanide is structurally related to chloramphenicol
and may act in a similar fashion by blocking protein
synthesis.
• The prodrug, diloxanide furoate, is metabolized in the
gastrointestinal tract to release the active drug,
diloxanide.
• 90% of each dose is excreted in the urine and the other
10% is excreted in the feces
• Diloxanide 500 mg tid x 10d

25. Etofamide
• Etofamide is an antiprotozoal drug used in the
treatment of amoebiasis.
• 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

26. Teclozan
Acetamide, N,N'-[1,4-phenylenebis(metylene)]bis[2,2-dichloro-N-(2-etoxyetyl)-

27. 3. Emetines: Emetine, Dehydroementine

29. Systemic Amebicides
Emetine and Dihydroemetine
• They inhibit protein synthesis
• Direct amebicidal on invasive amebae in tissue.
• Given IM.
• Its half-life in plasma is 5 days
• They should not be taken for more than 5 days
• ADRs:
– GIT upset very common (N&V).
– Cardiotoxicity: arrhythmia and CHF
– Neuromuscular weakness ,dizziness and skin rash.

30. Dehydroemetine
Dehydroemetine is a synthetically produced antiprotozoal agent similar to emetine
in its anti-amoebic properties and structure (they differ only in a double bond next
to the ethyl group), but it produces fewer side effects.
Emetine
Dehydroemetine and Emetine

31. SAR of Emetine
• Emetine posesses a skeleton with two
tetrahydroisquinoline ring systems and a terpenoidal
portion.
• Psychotrine is a phenolic. It gives Ementine on
reduction followed by methylation.
• Emetine is non phenolic alkaloid.
• Emetine induces broad range of cellular effects,
including an increase in alternative splicing of the gene
and antagonism of α2 adrenergic receptors.
• Emetine showed that n-2’, N-5 and C-9 are critical
positions that are essentially required for biological
activities.

32. MOA of Ementine and
Dehydroemetine
• They completely block the inhibition of DNA synthesis ,
mitosis and inhibiting the translocation of peptidyl –E-
RNA in ribosomes resulting in the inhibition of
polypeptide chain elongation and may leads to protein
synthesis inhbition and cell death.
• Ementine acts by blocking early S-Phase of DNA
replication
• Used in combination with either tetracycline or
chloroquine while dehydroementine used for rapid
releif of sympatoms in patients with sevre amoebic
dysentry

33. 4. Halogenated 8 Hydroxyquinolines:
Clioquinol & Iodoquinol

34. Clioquinol
• It is 8-hydroxyquinoline derivative.
• MOA: It inhibits certain enzymes related to DNA replication.
Clioquinol is antifungal and antiprotozoal drug.
• Clioquinol's use as an antiprotozoal drug has been restricted
or discontinued in some countries due to an event in Japan
where over 10,000 people developed subacute myelo-optic
neuropathy (SMON) between 1957 and 1970. The drug was
used widely in many countries before and after the SMON
event without similar reportse drug is neurotoxic in large
doses.
• Recent animal studies have shown that clioquinol can reverse
the progression of Alzheimer's, Parkinson's and Huntington's
diseases

35. Iodoquinol
• Iodoquinol is an amebocide used against Entamoeba
histolytica, and it is active against both cyst and
trophozoites that are localized in the lumen of the
intestine. It is considered the drug of choice for
treating asymptomatic or moderate forms of
amebiasis. The mechanism of action is unknown.
Iodoquinol is used for diseases caused by moderate
intestinal amebiasis.
• Iodoquinol 650 mg tid x 21d

36. 5. 4-amino quinoline derivatives: Chloroquine

37. Systemic Amebicides
• Chloroquine :useful for treating liver abscesses,
and intestinal wall trophozoites
Usually used with metronidazole and diloxanide
furoate to treat and prevent liver abscess –
orally for 25 days
Other uses: Antimalaial and anti-inflammatory in
arthritis.

38. Choloroquine
• In treatment of amoebic liver abscess,
chloroquine may be used instead of or in
addition to other medications in the event of
failure of improvement with metronidazole or
another nitroimidazole within 5 days or
intolerance to metronidazole or a
nitroimidazole.

39. 6. Antibiotics: Paromomycin, Tetracycline

40. Paromomycin
• Aminoglycoside antibiotic. It is an antibiotic used to treat intestinal
infections such as cryptosporidiosis and amoebiasis, and other
diseases such as leishmaniasis. Paromomycin was demonstrated to
be effective against cutaneous leishmaniasis in clinical studies in
the USSR in the 1960s, and in trials with visceral leishmaniasis in the
early 1990s.
• The route of administration is intramuscular injection and capsule.
Paromomycin topical cream with or without gentamicin is an
effective treatment for ulcerative cutaneous leishmaniasis,
• 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

41. Tetracyclines

42. 7. Nitrothiazolidines: Nitazoxanide

43. Nitazoxanide
Chemically, nitazoxanide is the prototype member of
the thiazolides, a class of drugs which are synthetic nitrothiazolyl-
salicylamide derivatives with antiparasitic and antiviral
activity. Tizoxanide, an active metabolite of nitazoxanide in humans,
is also an antiparasitic drug of the thiazolide class.
Nitazoxanide is a broad-spectrum antiparasitic and broad-spectrum
antiviral drug that is used in medicine for the treatment of
various helminthic, protozoal, and viral infections. It is indicated for
the treatment of infection by Cryptosporidium parvum and Giardia
lamblia in immunocompetent individuals and has
been repurposed for the treatment of influenza

44. Nitazoxanide
• Nitazoxanide is an effective first-line treatment
for infection by Blastocystis species and is
indicated for the treatment of infection
by Cryptosporidium parvum or Giardia lamblia in
immunocompetent adults and children.
• It is also an effective treatment option for
infections caused by other protozoa and
helminths (e.g., Entamoeba
histolytica, Hymenolepis nana, Ascaris
lumbricoides, and Cyclospora cayetanensis

45. Nitazoxanide
• The anti-protozoal activity of nitazoxanide is believed
to be due to interference with the pyruvate:ferredoxin
oxidoreductase (PFOR) enzyme-dependent electron
transfer reaction which is essential to anaerobic energy
metabolism.
• It has also been shown to have activity
against influenza A virus in vitro. The mechanism
appears to be by selectively blocking the maturation of
the viral hemagglutinin at a stage preceding resistance
to endoglycosidase H digestion. This impairs
hemagglutinin intracellular trafficking and insertion of
the protein into the host plasma membrane.

46. Metabolism of Nitazonaxide

47. Metabolism of Nitazoxanide
• Following oral administration, nitazoxanide is rapidly hydrolyzed to the
pharmacologically active metabolite, tizoxanide, which is 99% protein
bound.
• Tizoxanide is then glucuronide conjugated into the active
metabolite, tizoxanide glucuronide. Peak plasma concentrations of the
metabolites tizoxanide and tizoxanide glucuronide are observed 1–4 hours
after oral administration of nitazoxanide, whereas nitazoxanide itself is not
detected in blood plasma.
• Roughly ​2⁄3 of an oral dose of nitazoxanide is excreted as its metabolites in
feces, while the remainder of the dose excreted in urine. Tizoxanide is
excreted in the urine, bile and feces. Tizoxanide glucuronide is excreted in
urine and bile
• Nitazoxanide is currently available in two oral dosage forms: a tablet
(500 mg) and an oral suspension (100 mg per 5 ml when reconstituted)

48. Nitazoxanide
• The anti-protozoal activity of nitazoxanide is believed
to be due to interference with the pyruvate:ferredoxin
oxidoreductase (PFOR) enzyme-dependent electron
transfer reaction which is essential to anaerobic energy
metabolism.
• It has also been shown to have activity
against influenza A virus in vitro. The mechanism
appears to be by selectively blocking the maturation of
the viral hemagglutinin at a stage preceding resistance
to endoglycosidase H digestion. This impairs
hemagglutinin intracellular trafficking and insertion of
the protein into the host plasma membrane.

49. Other compounds
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

51. Summary

52. Asymptomatic Intestinal Infection
Diloxanide 500 mg tid x 10d
or-
Iodoquinol 650 mg tid x 21d
or-
Paromomyin 10 mg/kg tid x 7d

53. Mild to Moderate Intestinal Infection
Metronidazole 750mg tid x 10d
or-
Tinidazole 2g od x 3d
Plus-
Luminal agent

54. Severe Intestinal Infection
• Metronidazole 750mg tid (500mg IV every 6 h)
or
Tinidazole plus Luminal agent
Alternative:
Luminal agent plus either
Tetracycline or Dehydroemetine 1mg /kg SC/IM x 3-
5d

55. Hepatic / Extra intestinal
• Same as above
Alternative:
Dehydroemetine 1mg /kg S.C/IM x 3-5d
Followed by (liver abscess only) Chloroquine
500mg bd x 2d, then 500mg od x21d
Plus
Luminal agent

56. Synthesis of Ornidazole

57. Synthesis of Tinidazole

58. Synthesis of Metronidazole

59. For your patience and attention…….