Parasitic Infections, PROTOZOAL DISEASES, Amebiasis, DRUG THERAPY FOR PROTOZOAL INFECTIONS Tissue amoebicides, Luminal amoebicides

1. ANTIAMEBIC
AGENTS
DR. SHILPA SUDHAKAR HARAK
ASST. PROF., PHARM. CHEM.,
GES SIR DR. M. S. GOSAVI COLLEGE OF PHARMACEUTICAL
EDUCATION AND RESEARCH, NASHIK

2. PARASITIC INFECTIONS
• Affect huge numbers of individuals > 1 billion
• Found in developing nations
• Cost of health care is the dominant factor
• Sometimes can exceed 80% of the population
• Reduced incentive for both the study of the diseases and the development of effective
therapy
• High cost of drug discovery and Lower incidence in affluentWestern countries
• Parasitic infections -
• Protozoal - amebiasis, giardiasis, babesiosis, Chagas disease, leishmaniasis, malaria, sleeping
sickness, toxoplasmosis, trichomoniasis, and pneumocystosis.
• Others - include Helminth infections (worms), scabies, lice (pediculosis), chiggers, and
bedbugs (Cimicidae family), are also considered to be parasitic infections.

3. PROTOZOAL DISEASES
AMEBIASIS
Disease of the large intestine
• caused by Entamoeba histolytica
• The disease occurs mainly in the tropics, but it is also seen in temperate
climates.
Symptoms –
• can be without significant symptoms or
• can lead to severe, life-threatening dysentery.
The organism exists in one of two forms:
• the motile trophozoite form or
• the dormant cyst form.

4. AMOEBA
Trophozoite Form
• found in the intestine or in the wall of the colon
• Expelled from the body with the feces
Cyst Form
• Encased by a chitinous wall that protects the organism from the
environment
• the organism can be transmitted through contaminated water
and foods.
• Responsible for transmission of the disease.

5. AMOEBA
Host
• rendered susceptible to infection by preexisting
conditions viz. Protein malnutrition, Pregnancy, HIV
infection, High-carbohydrate intake.

6. PARASITE CYCLE

7. PARASITE CYCLE

8. ENTAMOEBA HISTOLYTICA
Invasion of Host
Intestinal form a. Disintegration of cyst wall in small intestine
b. Movement of trophozoites into the colon
c.Adhesion of trophozoite to cells of the host, which
involves a change in composition and production of
mucus
Extraintestinal
form
d. Penetration of intestinal lining and entrance into portal
circulation
e. Invasion of liver tissue

9. DRUGTHERAPY FOR
PROTOZOAL INFECTIONS

10. ANTIAMOEBIC DRUGS
• These are drugs useful in infection caused by the protozoa
Entamoeba histolytica.
A.Tissue amoebicides
• a) For both intestinal and extraintestinal amoebiasis:
I. Nitroimidazoles: Metronidazole,Tinidazole, Secnidazole,
Ornidazole, Satranidazole
II.Alkaloids: Emetine, Dehydroemetine
• b) For extra intestinal amoebiasis only: Chloroquine

11. ANTIAMOEBIC DRUGS
B. Luminal amoebicides
• a) Amide : Diloxanide furoate, Nitazoxanide
• b) 8-Hydroxyquinolines: Quiniodochlor
(Iodochlorohydroxyquin, Clioquinol),
Diiodohydroxyquin (Iodoquinol)
• (c) Antibiotics:Tetracyclines

12. NITROIMIDAZOLES

13. METRONIDAZOLE
• Flagyl, Metryl, Satric, Dependal, Metrogyl
• Initially introduced for the treatment of vaginal infections
caused by Trichomonas vaginalis
• But is effective against amebiasis, giardiasis, and anaerobic
bacterial infections (Clostridium difficile).

14. MOA

15. ACTIVATION OF MTZ

16. FORMATION OF ROS FROM
NITROARYL COMPOUNDS

17. ACTION OF ACTIVATED FORM

18. METABOLISM
• Liver metabolism
• to two major
metabolites:
• hydroxylation of the 2-
CH3 to 2-CH2OH
metronidazole (HM)
• its oxidation 2-CH2OH
to 2-CH2COOH
(metronidazole acetic
acid)

19. PHARMACOKINETICS
• Dosage forms - IV, oral, rectal, vaginal suppositories.
• Bioavailability ~100% orally but
• 67% to 82% rectal route
• 19% to 56% vaginal route
• Not bound to plasma protein
• Distribution - uniform throughout the body, including
mother’s milk.

20. THERAPEUTIC APPLICATION
• Drug of choice for Protozoal infections:
• Amebiasis (intestinal and extraintestinal),
• Giardiasis, and
• Trichomoniasis
• gram-positive bacilli Clostridium difficile

21. THERAPEUTIC APPLICATION
Combinations
• Helicobacter pylori infections
common side effects
• abdominal distress,
• a metallic taste
• disulfiram-like effect if taken with alcohol
• Reported to be carcinogenic in mice (acetamide metabolite)
• Restrained use during the first trimester of pregnancy

22. TINIDAZOLE
• Treatment of amebiasis, giardiasis, and trichomoniasis.
• Highly effective against Helicobacter pylori infections
(unapproved)
• Rapidly and completely orally
• Administered with food to reduce GI disturbance

23. TINIDAZOLE
Mechanism of action
• parallels to metronidazole
• Similar metabolic pathway
• Mimic the actions of metronidazole,
• Effective against some metronidazole resistant
protozoa

24. LUMINAL AMOEBICIDES
Antiamebic Agents

25. AMIDES
Luminal Amoebicides

26. NITAZOXANIDE
• NTZ – orphan drug for the treatment of diarrhea in children
(age 1 to 11 years) in giardiasis & also in cryptosporidiosis in
patients with AIDS.
• Cryptosporidiosis is a protozoal infection caused by
Cryptosporidium parvum in HIV infections.

27. NTZ MOA
• Prodrug metabolised to the deacetylated drug tizoxanide (TIZ)
• TIZ then undergoes a four-electron reduction of the 5-nitro group giving
various short-lived intermediates, which can include the hydroxylamine
derivative.
• These reduced products represent the active forms of NTZ.
• NTZ has the same mechanism of action as metronidazole, this does not
appear to be the case.
• NTZ is thought to inhibit the enzyme pyruvate: ferredoxin oxidoreductase
in Trichomonas vaginalis, Entamoeba histolytica, and Clostridium perfringens.
• The result of this inhibition is disruption of the bioenergetics of these
organisms.

28. NTZ MOA
• Unlike metronidazole and tinidazole, which fragment DNA and
are suspected mutagenic agents, NTZ and TIZ do not cause
DNA fragmentation and are not considered to be mutagenic.
• This might be associated with the higher redox potential found
for NTZ, a nitrothiazole, in comparison with very low redox
potential found for the nitroimidazoles, such as metronidazole
and tinidazole.
• Additional metabolites of TIZ include the glucuronide, which
shows some biologic activity, and small amounts of an aromatic
hydroxylation product.

29. DILOXANIDE
• Furamide, or eutamide, is the 2-furoate ester of 2,2-dichloro-4-
hydroxy-N-methylacetanilide
• Result of discovery that various a,a-dichloroacetamides
possessed amebicidal activity in vitro.
• Hydrolysis of the amide is required for the amebicidal effect.
• Nonpolar esters of diloxanide are more potent than polar ones.
• Diloxanide furoate has been used in the treatment of
asymptomatic carriers of E. histolytica.

30. DILOXANIDE
• Treatment of asymptomatic amebiasis
• Its effectiveness against acute intestinal amebiasis or hepatic
abscesses, however, has not been established.
• It is ineffective as a single agent for the extraintestinal form
of the disease.
• Administered orally and is hydrolyzed in the gut to give
diloxanide (active drug)
• Diloxanide is the only form identified in the bloodstream.
• The drug is found in the urine as the glucuronide

31. 8-HYDROXYQUINOLINES
Luminal amoebicides

32. QUINOPHENOL/ OXINE
• Also known as oxyquinoline
• It is the parent compound of antiprotozoal oxyquinolines
• The antibacterial and antifungal properties of oxine and its derivatives,
which are believed to result from the ability to chelate metal ions, are well
known.
• Aqueous solutions of acid salts of oxine, particularly the sulfate (Chinosol,
Quinosol), in concentrations of 1:3,000 to 1:1,000, have been used as
topical antiseptics.
• The substitution of an iodine atom at the 7-position of 8-
hydroxyquinolines yields compounds with broad-spectrum amebicidal
properties.

33. IODOQUINOL
• 5,7-Diiodo-8-quinolinol, 5,7-diiodo-8-hydroxyquinoline, or
diiodohydroxyquin (Yodoxin, Diodoquin, Diquinol)
• Recommended for acute and chronic intestinal amebiasis
• It is ineffective in extraintestinal disease
• High incidence of optic neuropathy has occurred with its use,
iodoquinol should not be used routinely for traveler’s diarrhea.

34. EMETINE AND DEHYDROEMETINE
• Obtained from extracts of ipecac
• They are levorotatory
• Exert a direct amebicidal action on
various forms of E. histolytica.
• They are protoplasmic poisons that
inhibit protein synthesis in protozoal
and mammalian cells by preventing
protein elongation.
• Their effect in intestinal amebiasis is
solely symptomatic
• Cure rate is only 10% to 15%, hence
used only in combination
Stereochemical variation

35. EMETINE AND DEHYDROEMETINE
• The high concentrations in liver and other tissues after i.m. have high
effectiveness against hepatic abscesses and other extraintestinal
forms of the disease.
• Toxic effects limit the usefulness of emetine.
• high frequency of GI distress (especially nausea and diarrhea),
• cardiovascular effects (hypotension and arrhythmias), and
• neuromuscular effects (pain and weakness).
• A lower incidence of cardiotoxicity has been associated with the use
of dehydroemetine (Mebadin), which is available from the CDC and
is also amebicidal.

36. PENTAMIDINE ISETHIONATE
• 4,4'-(Pentamethylenedioxy) dibenzamidine diisethionate (NebuPent, Pentam 300)
• It is a water-soluble crystalline salt that is stable to light and air.
• The principal use of pentamidine is for the treatment of pneumonia caused by the
opportunistic pathogenic protozoan P. carinii, a frequent secondary invader associated
with AIDS.
• The drug may be administered by slow intravenous infusion or by deep intra- muscular
injection for PCP.
• An aerosol form of pentamidine is used by inhalation for the prevention of PCP in high-
risk patients infected with HIV who have a previous history of PCP infection or a low
peripheral CD4+ lymphocyte count.

37. PENTAMIDINE ISETHIONATE
• Both the inhalant (aerosol) and parenteral dosage forms of pentamidine
isethionate
• Adverse reactions : cough & bronchospasm (inhalation) &
hypertension & hypoglycemia (injection).
• Used for the prophylaxis and treatment of African trypanosomiasis.
• It also has some value for treating visceral leishmaniasis.
• It rapidly disappears from the plasma after IV injection & is distributed
to the tissues, where it is stored for a long period.
• Hence can be used as a prophylactic agent.

38. ATOVAQUONE
• 3-[4-(4-Chlorophenyl)-cyclohexyl]-2-hydroxy-1,4-naphthoquinone (Mepron)
• It is a highly lipophilic, water-insoluble analog of ubiquinone , an essential component of the
mitochondrial electron transport chain in microorganisms.
• The structural similarity between atovaquone and ubiquinone suggests that the former may act as an
antimetabolite for the latter and thereby interfere with the function of electron transport enzymes.
• Atovaquone was originally developed as an antimalarial drug, but Plasmodium falciparum was found
to develop a rapid tolerance to its action.
• More recently, the effectiveness of atovaquone against P. carinii was discovered.
• Alternative to trimethoprim- sulfamethoxazole (TMP-SMX) for the treatment and prophylaxis of PCP
in patients intolerant to this combination.
• Atovaquone was also shown to be effective in eradicating T. gondii in preclinical animal studies.

39. EFLORNITHINE
• Treatment of West African sleeping sickness, caused by Trypanosoma
brucei gambiense.
• Specifically indicated for the meningoencephalitic stage of the disease.
• Is myelosuppressive drug that causes high incidences of anemia,
leukopenia, and thrombocytopenia.
• Complete blood cell counts must be monitored during the course of
therapy.
• Causes irreversible inactivation of ornithine decarboxylase
• It causes decarboxylation & release of fluoride ion from the inhibitor
• It is enzyme- catalyzed activation of the inhibitor

40. EFLORNITHINE
• Only the (-) isomer, stereochemically related to L-ornithine, is
active.
• Eflornithine is supplied as the hydrochloride salt.
• It may be administered either intravenously or orally.
• Approximately 80% of the unchanged drug is excreted in the
urine.
• Penetration of eflornithine into the CSF is facilitated by
inflammation of the meninges.

41. • ThankYou