1.amebic & other protozoals and drugs for leishmaniasis

drugs for protozoa

1. PROTOZOA
•Primary unicellular eukaryotes,
often also called protists
•Many important human and
veterinary pathogens
•vast variety of morphological and
biochemical adaptations to almost
any ecological environment

2. Entamoeba histolytica
•Fedor Alexandrewitch
Lösch describes amoebae
associated with severe
dysentery in a patient in
1873
•He transferred amoebae to a
dog by rectal injection,
which became ill and
showed ulceration of colon
•Patient who died from
infection showed similar
ulcers upon autopsy

3. Trophozoites and cysts

5. Entamoeba cysts (light microscopy)
E. coli E. histolytica

6. Human infection
•Major sources for human infection are contamination
of drinking water and vegetables
•Patients without any symptoms might shed large
amounts of cysts
•cysts can stay infectious for up to a month
•Cysts are fairly resistant to chlorination of drinking
water (10 mg/l versus 0.1 -1.0 mg/l for enteric
bacteria)

7. Colitis is the most common form of disease
associated with amoebae
•Gradual onset of
abdominal pain, watery
stools containing mucus
and blood
•Some patients have only
intermittent diarrhea
alternating with
constipation
•Fever is uncommon
•Formation of ulcers

8. Colitis is the most common form of disease
associated with amoebae
•Amoeba invade mucosa and erode
through laminia propria causing
characterisitic flask shaped ulcers
contained by muscularis

9. Extraintestinal amebiasis

10. CLASSIFICATION
•TISSUE
AMOEBICIDE
1.Intestinal &
extraintestinal
Metronidazole, tinidazole,
ornidazole, secnidazole,
satranidazole
Emetine, dehydroemetine
2. Extraintestinal
Chloroquine (4 OH)
•LUMINAL
AMOEBICIDE
i.Diloxanide furoate
(amides)
ii.Diiodohydroxyquin &
quinidochlor (8 OH
quinolines)
iii.Tetracyclines &
paramomycin (antibiotics)

11. Metabolism of Amoebae
•Entamoeba lacks a functional
Krebs cycle and oxidative
phosphorylation
•Final endproducts of
E. histolytica fermentation are
CO
2, acetate, ethanol

12. Tissue amoebicides -metronidazole
•Metronidazole is the drug of
choice for invasive amoebiasis
( combined with a lumen acting
drug as it is not effective on
luminal stages)
Metronidazole is a prodrug
which is activated by an
enzyme involved in the
microaerobic fermentation
metabolism of E. histolytica

13. Pharmacokinetics
•Usually given orally
•Rapidly, completely absorbed from small intestine
•Peak plasma concentration 1-3 hrs
•Half-life 7 hrs
•Distributed rapidly through the tissues reaching
high concentrations in the body fluids and CSF
•Metabolized by glucuronidation and excreted in
urine

14. Metronidazole is activated by PFOR
acetate
CO
2
ADP
ATP
•Entamoeba uses a pyruvate
ferredoxin oxidoreductase (PFOR) to
break down pyruvate
•This enzyme system is limited to
anaerobic bacteria and some
protozoa and humans lack this
enzyme
•PFOR and ferredoxin can transfer an
electron to metronidazole producing
a highly toxic nitroradical

15. Clinical uses
1.Drug of choice in extra luminal amoebisasis. No
action on cysts.
Dose 400mg tds for 7 days..800 mg tds incase of
liver abscess
2.Giardiasis –200mg tds for 7 days
3.Trichomonas –400 mg tds for 7 days
4.After colorectal surgery or appendicectomy 7.5
mg i.v 6
th
hourly followed by 400 mg tds for 7
days

16. 4. Clostridium difficile –500mg
5. Ulcerative gingivitis and stomatitis –used
with tetracycline
6. Dracunculiasis
7. In H.pylori regimen

17. Unwanted effects
•Metallic taste in the mouth
•Minor gastrointestinal disturbances
•Dizziness, headache, sensory neuropathies
•Drug interferes with alcohol metabolism
` ( disulfiram like reaction )
•Warfarin & lithium toxicity

18. Tinidazole
•Similar to metronidazole
•Eliminated more slowly
•Half-life 12-14 hrs
•Lesser nausea, epigastric distress & metallic
taste
•Dosage -Amoebiasis –600mg b.d 7 days
Trichomoniasis & giardiasis –600mg 7
days

19. •Ornidazole–slowly metabolised
•Satranidazole-more potent,no neurological
toxicity, no disulfiram like reaction,
•Dose-Amoebiasis -300 mg bd 5days
• Giardiasis & trichomoniasis 600mg od

20. •Secnidazole-longer t1/2(20hrs)
•Dose-Amoebiasis,giardiasis,trichomoniasis
2g single dose
•Benznidazole-additional use in chagas
disease
•Nimorazole-similar to metronidazole
•Dose-amoebiasis, giardiasis 1g bd for `
5days

21. Emetine & dehydroemetine
•Emetine alkaloid –from cephalis
ipecacuanha
•No effects on cyst
•Parenteral, s/c , im
•Adverse effects –cardio toxic, nausea
vomiting, hypotension, cramps, muscle
weakness

22. Extra intestinal amoebicide
•Chloroquine-highly concentrated in liver
•To treat hepatic abscess, amoeboma (500mg
bd for 2 days followed by 500mg od for 21
days )

23. Diloxanide(luminal amoebicide)
•Effective against the non-invasive intestinal
parasite
•Drugs have a direct amoebicidal action
affecting the amoebae before encystment
•Given orally 500mg tds for 10 days
•No serious adverse effects

24. 8 HYDROXY QUINOLINES
•Iodoquinol (diiodohydroxyquin) &
clioquinol (quinidochlor)
•10-30% absorbed
•t1\2-12hrs
•Amoebiasis –Iodoquinol 600mg tds,
Clioquinol 250-500mg tds
•Giardiasis, trichomoniasis
•Adverse effects-goiter, iodism ,SMON

25. ANTIBIOTICS
Tetracycline, doxycycline,erythromycin
&paromomycin
Paromomycin has direct amoebicidal action
others inhibit intestinal flora & choke amoeba

26. LEISHMANIASIS :
Transmitted by the bite of sandflies
•Cutaneous –Oriental sore(L.tropica)
•Mucocutaneous(L.braziliensis)
•Visceral ( Liver and Spleen) -Kala
Azar(L.donovani)
Delhiboil Espundia

27. Leshmaniasis :
•Antimonials -Sodium stibogluconate
•Diamidine derivative-Pentamidine
•Amphotericin, ketoconazole
•Miltefosine
•Allopurinol
•Aminocidin (paramomycin)

28. Pentavalent antimonials
Sodium stibogluconate :
•It acts by inhibiting glycolysis and fatty
acid oxidation –ATP / GTP
•It is administered i.m or i.v
•Cardiac arrhythmia, delirium, hematuria
and metallic taste are adverse effects.

29. Diamidine derivatives
Pentamidine
•Active against trypanosoma and
leshmaniasis and fungus -pneumocystis
jiroveci
•Pentamidine binds mitochondrial DNA of
trypanosomes (kDNA) & inhibits
topoisimerase II
•Administered IV or aerosol
•ADR: Histamine release, kidney and
liver damage, IDDM

30. MILTEFOSINE:
•Visceral leishmaniasis
•MOA: not clear, interferes with signalling
pathways
•Orally
•ADR: Hepatic, renal and GI Toxicity
ALLOPURINOL:
•Incorporated into RNA and halts protein synthesis

31. TRYPANOSOMIASIS
Caused by Trypanosoma
•African sleeping sickness
Tryp brucei gambiense-tse tse fly -slow to enter CNS
Tryp brucei rhodiense –open woodland flies -
invade CNS early.

32. African sleeping sickness
Suramin
•Used in the early treatment and prophylaxis
of African trypanosomiasis.
•It acts by inhibiting enzymes of energy
metabolism including glycerol phosphate
dehydrogenase –for trypanocidal activity
•Does not cross BBB
•ADR: photophobia, paresthesia, cylindruria,
nephrotoxicity

33. Melarsoprol :
•Trivalent arsenical
•Mainly used to treat trypanosoma infections
with CNS involvement.
•The drug acts by reacting with SH groups of
various enzymes
•IV
•ADR: colic, proteinuria, neuritis, blood
dyscrasias, arsenical encephalopathy

34. Pentamidine
•Active against trypanosomaand
leshmaniasisand fungus -pneumocystis
jiroveci
•Pentamidineinterfere with synthesis of
RNA, DNA and proteins.
•Administered IV or aerosol
•Nephrotoxicityis the limitation.

35. Eflornithine:
•Gambian trypanosomiasis
•IV
•MOA: inhibits polyamine synthesis
•ADR: alopecia, diarrhoea,
thrombocytopenia, convulsions, hearing
loss

36. American sleeping sickness
(Chagasdisease)
•Trypcruzi–reduviidbug –mega colon,
cardiomyopathy

37. American sleeping sickness
Nifurtimox : Chagas disease
•It acts by generating superoxide and
hydrogen peroxide radicals –toxic as
they lack catalase.
•Orally well absorbed
•ADR: arthralgia, weight loss, insomnia,
neuropathy

38. Protozoal diseases Drugs
Trpanosomiasis
Chagas disease
Nifurtimox
T.gambiense
African Sleeping sickness
Suramin & Pentamidine
T.Rhodesiense -CNS
African Sleeping sickness
Melarsoprol
Leishmaniasis Stibogluconate
Trichomoniasis,
Giardiasis
Metronidazole
Toxoplasmosis Pyrimethamineand
Sulfadiazine