Anti-protozoal drug
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INTRODUCTION:
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Humans host a wide variety of protozoal
parasites that can be transmitted by insect
vectors, directly from other mammalian
reservoirs or from one person to another.
Because protozoa multiply rapidly in their hosts
and effective vaccines are unavailable,
chemotherapy has been the only practical way
to both treat infected individuals and reduce
transmission.
Protozoa:
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Basic Properties of Protozoa
– Eukaryotic microorganisms
– No cell walls
– Most have heterotrophic
metabolisms
– A few protozoa (eg Euglena) are
photosynthetic.
– Many are free-living in soil or
aquatic environments; a few are
parasitic.
– Single-celled or simple colonial
organization
– Classification based
predominately on the
mechanism of motility
Cont..
Basic properties of protozoa
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“Trophozoite” and “Cyst”
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Some protozoa go through different stages in
their life cycle.
This is especially true of certain parasitic
protozoa.
Trophozoite: Actively growing and reproducing
stage
Cyst: A dormant stage, enclosed in a resistant
cyst coat
Classification of protozoa
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1)Class- Sarcodina
 Motile by
pseudopodia &
amoeboid movement
 Examples:
– Amoeba
– Entamoeba
histolytica
– Naegleria fowleri
3)Class - Ciliophora
 Motile by cilia
 Examples:
– Paramecium
– Balantidium coli
2) Class- Mastigophora
 Motile by flagella
 Examples:
– Euglena
– Giardia lamblia
4)Class -Sporozoa
 Most have complex life
cycles with both sexual
& asexual stages
 Adult
forms
are
nonmotile
 Examples:
– Plasmodium
– Toxoplasma gondii
Protozoan Diseases
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B.
C.
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E.
F.
G.
H.
I.
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Amebiasis
Giardiasis
Leishmeniasis:
Primary Amoebic Meningoencephalitis
Trichomoniasis
Balantidiasis
Malaria
Pneumocystosis
Toxoplasmosis
Amoebiasis:
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Two morphologically identical but
genetically
distinct
species
of
Entamoeba (i.e., E. histolytica and E.
dispar) have been isolated from infected
persons.
At the present time ,Entamoeba
histolytica, is the causative agent of
amebic dysentery and amebic liver
abscess.
Entamoeba
dispar
morphologically
similar to E. histolytica is considered
non-pathogenic at this time.
Entamoeba Life Cycle
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Entamoeba species exist in only
two forms.
The non-infective trophozoite
stage and the ineffective cyst
stage.
Ineffective cysts are ingested by
man.
Some time after passing through
the stomach and small bowel they
excyst to form motile trophozoites.
these
trophozoites
of
E.
histolytica that can penetrate,
invade and colonize intestinal
mucosa.
As the trophozoite travels down
the large bowel at some point
when conditions are right , it
encysts into the ineffective cyst
stage and is excreted with the
feces.
www.practicalscience.com/introentamoeba.html
PATHOLOGY:
Flask-shaped ulcers:
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E. histolytica invades mucosal
cells of colonic epithelium,
producing the classic flaskshaped ulcer in the submucosa.
If the trophozoite gets into the
portal circulation, it will be
carried to the liver, where it
produces abscess and periportal
fibrosis.
Amoebic ulcerations can affect
the perineum and genitalia, and
abscess may occur in the lung
and brain.
Manifestations:
Intestinal Disease:
 Abdominal discomfort, severe abdominal cramps,
flatulence, bloody diarrhea with mucus.
Amoebic Liver Abscess:
 High fever, significant leukocytosis with left shift,
elevated alkaline phosphatase.
 Hepatomegaly, and liver tenderness, with referred
pain to the left or right shoulder
 Erosion of liver abscesses also present as
peritonitis.
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Antiamebic drugs:
Tissue amoebicides:
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FOR BOTH INTESTINAL AND EXTRA INTESTINAL AMEBIASIS:
Nitroimidzoles: Metronidazole, Tinidazole, Secnidazole,Ornidazole,
Satranadazole
Alkaloids: Emetine, Dehydroemetine
FOR EXTRAINTESTINAL AMOEBIASIS ONLY:
Chloroquine
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Luminal amoebicides:
AMIDE: Diloxanide furote
8-HYDROXYQUINOLINES:Quiniodochlor (Iodochlorohydroxyquin,Clioquine),
Diiodohydroxyquin (Idoquinol)
ANTIBIOTICS: Tetracyclines, paromomycine sulfate.
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Mechanisms
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Inhibiting peptidyl-tRNA transposition → inhibiting
elongation of peptide chain → inhibiting protein
synthesis → interfering cleavage and breeding of
trophozoites
Treatment of Specific Forms of Amebiasis
A. ASYMPTOMATIC INTESTINAL INFECTION:
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Asymptomatic carriers generally are not treated in
endemic areas but in nonendemic areas they are
treated with a luminal amebicide.
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A tissue amebicidal drug is unnecessary.
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Standard luminal amebicides are diloxanide
furoate, iodoquinol, and paromomycin.
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Each drug eradicates carriage in about 80-90% of
patients with a single course of treatment.
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Therapy with a luminal amebicide is also required
in the treatment of all other forms of amebiasis.
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Cont..
B. AMOEBIC COLITIS
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Metronidazole + luminal amebicide is the
treatment of choice for colitis and dysentery.
Tetracyclines
and
erythromycin
are
alternative drugs for moderate colitis but are
not effective against extraintestinal disease.
Dehydroemetine or emetine can also be
used, but are best avoided because of
toxicity.
Cont..
C. EXTRAINTESTINAL INFECTIONS
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The treatment of choice is metronidazole plus a
luminal amebicide.
A 10-day course of metronidazole cures over 95%
of uncomplicated liver abscesses.
For unusual cases in which initial therapy with
metronidazole has failed, aspiration of the abscess
and the addition of chloroquine to a repeat course
of metronidazole should be considered.
Dehydroemetine and emetine are toxic alternative
drugs.
Metronidazole:
Metronidazole
is
selectively
toxic
to
anaerobic
microorganisms.
Mechanism of action:
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Metronidazole is a prodrug; it requires reductive activation of
the nitro group by susceptible organisms.
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These anaerobic organisms contain electron transport
components such as ferredoxins, small Fe-S proteins that
have a sufficiently negative redox potential to donate
electrons to metronidazole.
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The single electron transfer forms a highly reactive nitro
radical anion that kills susceptible organisms by radicalmediated mechanisms that target DNA and possibly other
vital biomolecules.
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Cont..
Pharmacokinetics:
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Metronidazole is almost completely
absorbed from the small intestine: little
unabsorbed drug reaches the colon.
It is metabolized in liver primarily by
oxidation and glucuronide conjugation and
excreted in urine.
Plasma t1/2 is 8 hrs.
Unwanted effects & contraindication
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GI-anorexia, diahorrea , headache ,abdominal cramp,
unpleasant metallic taste , furry tongue.
Hematological –leucopenia
Renal-darkened urin,dysuria,cystitis
Cardiac-t-wave flattening
Hypersensitivity reaction- urticaria, erythematous rash, dry
mouth
Contraindicated in pregnancy
Disulfiram like effect with alcohol
Increase the action of warfarin
Cont….
USES:
Amoebiasis:
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Metronidazole is first line drug for all forms of amoebic infection.
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It is less effective than many luminal amebiasis in eradicating amoebic cysts
from the colon.
Giardiasis:
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It is highly effective.
Trichomonas vaginitis;
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It is the drug of choice; 400mg TDS for 7 days achives nearly 100% cure.
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Additional intravaginal treatment has been given but only in refractory cases.
Anaerobic bacterial infection:
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Metronidazole is generally used with gentamicin and cephalosporins.
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Pseudomembranous enterocolitis
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Ulcerative gingivitis
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H. pylori gastritis
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Tinidazole:
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It is similar to metronidazole in its
mechanism of action and unwanted effects,
but is eliminated more slowly, having a halflife of 12-14 hours.
Emetine:
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It is an alkaloid from cephalis ipecacunha.
Emetine is a potent and directly acting
amoebicide-kills tropozoites but has no
effects on cysts.
It acts by inhibiting protein synthesis in
amoebae by arresting intra-rebosomal
translocation of tRNA –amino acid complex.
Cont…
Toxicity:
Pain and tenderness in the area of injection are frequent, and
sterile abscesses may develop.
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Diarrhea is common.
Other adverse effects are:
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Nausea, vomiting, muscle weakness and discomfort, and
minor electrocardiographic changes
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Serious toxicities include:
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cardiac arrhythmias, heart failure, and hypotension.
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The drugs should not be used in patients with cardiac or renal
disease, in young children, or in pregnancy unless absolutely
necessary.
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Cont…
Use:
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Because of toxicity, emetine is now seldom
used as a reserve drug in severe intestinal
or extra intestinal amoebiasis.
It is also used for patients not responding to
or not tolerating metronidazole.
Dehydroemetine:
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Semisynthetic derivative of emetine.
Equally effective but less cumulative and less
toxic to heart.
Thus, it is preferred over emetine.
Chloroquine:
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Chloroquine reaches high liver
concentrations → treatment of amoebic liver
abscess.
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Amoebae do not develop resistance to
chloroquine.
Not effective in the treatment of intestinal or
other extrahepatic amoebiasis.
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DILOXANIDE FUROATE:
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It is an effective luminal amebicide but is not active
against tissue trophozoites.
The mechanism of action of diloxanide furoate is
unknown.
Diloxanide furoate does not produce serious adverse
effects.
Flatulence is common, but nausea and abdominal
cramps are infrequent and rashes are rare.
The drug is not recommended in pregnancy.
It is the drug of choice for mild intestinal/
asymptomatic amoebiasis.
8-HYDROXYQUINOLINES:
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They are active against Entamoeba, Giardia, Trichomonas.
They kill the cyst forming tropozoites in the intestine, but do not
have tissue amoebicidal action.
They are not very effective in acute amoebic desentry but afford
relief in chronic intestinal amoebiasis.
They are totally valueless in extraintestnal Amoebiasis.
They are widely used for the prophylaxis and treatment of
nonspecific diarrheas, traveler's diarrheas.
PAROMOMYCIN SULFATE:
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Paromomycin sulfate is an amino glycoside antibiotic.
Paromomycin is an effective luminal amebic idée that appears to have
similar efficacy and probably less toxicity than other agents; in a recent
study, it was superior to diloxanide furcated in clearing asymptomatic
infections.
Paromomycin shares the same mechanism of action as neomycin and
kanamycin (binding to the 30S ribosomal subunit) and has the same
spectrum of antibacterial activity.
Paromomycin has become the drug of choice for treating
intestinal colonization with E. histolytic.
It is used in combination with metronidazole to treat amebic colitis and
amebic liver abscess and can be used as a single agent for
asymptomatic individuals found to have E. histolytica intestinal
colonization.
References:
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Tripathi K D., Essential of medical pharmacology,
2003; 5: 749-758
Rang H P., Dale M M., Ritter JM., flower RJ.,
Pharmacology, 2007; 6: 698-711
Brunton L L., Lazo J S., Parker K L., Goodman &
Gilman's the pharmacological basis of therapeutics,
2006; 11: 1097-1120
Katzung B G., Basic and clinical pharmacology,
2007; 9: 1207-1237
Seth S D.,Seth Vimlesh.,pharmacology,2009;3:xi.20xi32
Thank
you
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