Anti-amoebic drugs, Amoebiasis(some basic concepts) ,Symptoms,Diagnosis of Amoebiasis,Treatment of Amoebiasis etc.

1. PRESENTED BY:
Tribhuwan Bahuguna
NIPER Hyderabad
2013-15 Batch
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2.  Intestinal amebiasis is caused by the protozoan Entamoeba
histolytica.
 Most infection is asymptomatic; clinical manifestations
include amebic dysentery and extra-intestinal disease,
Worldwide , approximately 40 to 50 million people develop
colitis or extra-intestinal disease annually with 40,000
deaths.
 Extra-intestinal manifestations include amebic liver abscess
and other more rare manifestations such as pulmonary,
cardiac, or brain involvement.
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3.  Amoebiasis is an infection of the intestine, liver, or other
tissues caused by a one-celled parasite called
Entamoeba histolytica.
 Amoebiasis is most prevalent in tropical and subtropical
countries.
 Poverty, ignorance, overcrowding, poor sanitation and
malnutrition favor transmission.
 It is acquired by ingesting food or water contaminated by
infected feces.
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4.  Mostly they are quite mild and can include
 Loose stools
 Stomach pain
 Abdominal cramps
 Amoebic dysentery – severe form
 Stomach pain
 Bloody stools
 Fever & jaundice
 Anorexia
 Weight loss
 Rarely the parasite invades liver and forms an abscess and
spread to other parts of the body, such as lungs or brain
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5.  Medical history, physical examination, lab tests and stool
examination.
 Blood test to reveal antibodies against the organism.
 Sigmoidoscopy(similar to colonoscopy) to evaluate the
intestinal wall.
 Radiological studies including ultrasound and CT scans
to detect liver abscesses.
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7.  Tissue amoebicides
 For both intestinal and extra intestinal amoebiasis:
▪ Nitroimidazoles: Metronidazole, Tinidazole, Secnidazole,
Ornidazole, Satranidazole.
▪ Alkaloids: Emetine, Dehydroemetine
 For extraintestinal amoebiasis only:
▪ Chloroquine
 Luminal amoebicides
 Amide: Diloxanide furoate
 8-Hydroxyquinolines: Quiniodochlor, Diiodohydroxyquin
 Antibiotics: Tetracycline
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10.  Prototype Nitromidazole(1959)
 Highly active amoebicide.
 Broad spectrum cidal activity against protozoa.
 It is selectively toxic to anaerobic microorganism.
 For optimum anti-amoebic activity, there should be minimum 2
carbon alkyl chain at the N-1 position of the imidazole
moiety. Ex: dimetridazole has very less anti-amoebic activity
because it has only one carbon methyl group.
11
2-(2-methyl-5-nitro-1H-imidazol-1-yl)ethanol
N
N
CH3
CH3
O2N
1,2-dimethyl-5-nitro-
1H-imidazole
Metronidazole Dimetridazole
1
5
4
2
3

11. 11
N
N
CH2CHOH
CH3
O2N
CH3
N
N
CH2CHOH
CH3
O2N
CH2Cl
2-methyl-5-nitroimidazoles substituted in the 1-position via an
hydroxyethtyl, amino ethyl, methyl thio methyl or sulphonylmethyl
group for their effect against various protozoa.Ex: Metronidazole
If methyl is attached to the ethylene group of metronidazole,
activity is retained and metabolism is slower resulting in higher
plasma concentration. Ex: Secnidazole
SecnidazoleMetronidazole
If methylene chlorine is attached to 2-propanol site of the
Secnidazole, metabolized rate becomes more slower means has
more longer half life. Ex: Ornidazole
Ornidazole

12.  Nitro group is reduced to highly reactive nitro radical
that causes damage to DNA and other critical
biomolecules by cytotoxicity
 It disrupts energy metabolism
 DNA helix destabilization and strand breakage are
observed
 Found to inhibit cell mediated immunity to induce
mutagenesis & to cause radio-sensitization
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13.  Completely absorbed from small intestine
 Metabolized in liver by oxidation and glucoronide
conjugation
 Excreted in urine
 Plasma t1/2 is 8hrs
ADR
 Frequent- Anorexia, Nausea, Metallic taste, Abdominal
cramps
 Less frequent-Headache, Glossitis, Dizziness, Rashes
 Peripheral neuropathy and CNS effects
 Seizures
 Thrombophelibitis
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14.  Amoebiasis
 Giardiasis
 Trichomonas vaginitis
 Anaerobic bacterial infections
 Pseudo membranous enter colitis
 Ulcerative gingivitis, trench mouth
 Peptic ulcer
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15.  Equally efficacious as metronidazole
 Metabolism is slower, t1/2 approx.12hrs
 Better tolerated
 Lower incidence of side effects
 ADRs- Nausea, Rash, Metallic taste
Secnidazole
 Congener of metranidazole
 Same spectrum of activity and potency
 Absorption rapid after oral administration
 Slow metabolism (17-29hrs)
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16.  Activity similar to metronidazole
 Slowly metabolized (12-14hrs)
 Dose and duration resemble those for Tinidazole
 Side effect profile is also similar
Satranidazole
 Longer t1/2 (14hrs)
 Better tolerability
 No nausea, vomiting or metallic taste, absence of
neurological diseases
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17.  Neurological diseases
 Blood dyscrasia
 First trimester of pregnancy
 Chronic alcoholism
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18. MOA:
 Alkaloid from Cephalis ipecacuanha
 Potent directly acting amoebicide(trophozoites)
 Does not kill cysts
 Inhibiting protein synthesis in amoebae
 Cannot given orally, administered by s.c or i.m injection
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19. ADR:
 Cumulative toxicity high
 It is an irritant; pain, stiffness, eczematous lession at site
of injection.
 Nausea and vomiting, abdominal cramp and diarrhoea,
Weakness and stiffness of muscle
 Hypotension, tachycardia, ECG change, mayocarditis.
 Contraindicated in presence of cardiac or renal disease
and during pregnancy.
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20. USES:
 Seldom used as Reserve drug in intestinal and extra
intestinal amoebiasis
 Patients not responding / intolerant to metronidazole.
 Luminal amoebicide follows emetine to eradicate cysts.
 Also effective in liver fluke infestation.
 Dihydroemetine = effective but less toxic.
 Preferred over emetine.
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21. MOA
 By accumulating in the acidic vesicle of amoeba it raises
the vesicular pH interfere with degradation of
haemeoglobin by parasitic lysozomes.
PHARMACOKINETICS
 Oral absorbtion
 Have the high affinity for melanin and nuclear chromatin
 Partly metabolised in liver
 50% bound in the plasma
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22.  Anorexia
 Epigastric pain
 Loss of vision due to retinal damage
 Loss of hearing
 Mental disturbance
Uses
 Rhematoid arthritis
 Lepra reaction
 Photogenic reaction
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23. MOA
 Luminal amoebicidal
 Furoate ester hydrolysed in intestine
 Then released diloxanide which gets largely absorbed
 Diloxanide is weaker amoebicide than furoate ester.
Pharmacokinetics
 Its is metabolised by glucoronidation.
 Excreted in urine.
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24.  Mild intestinal/asymptomatic amoebiasis
 Combined with metroniadazole or tinidazole.
ADR
 Occasional nausea
 Itching
 Rarely urticaria
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25. Widely employed in past.
MOA
 Kill cyst forming tropozoids in intestine
 Eradicate cyst from asymptomatic carrier
PHARMACOKINETIC
 Absorption from intestine (10-30%)
 Absorbed fraction conjugate in liver with glucoronic acid.
 Excreted in urine.
 ½ life is 12 hour.
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26. Uses
 Giardiasis
 Trichomonas Vaginitis
 Non specific diarrhoea
 Dietry indiscretion.
 Fungal and bacterial skin infection
ADR
 SMON-sub acute myelo optic neuropathy in Japan
 Goitre
 Transient loose and green stool
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27.  Mechanisms of drug resistance hypothesized in
protozoan parasite are decrease of drug uptake
causing efflux of drugs from the parasite either by
the P- glycoproteins (P-gp) or by ATPases lead to
alteration of drug target hence loss of drug action.
 Resistance study done by using:
1.Metronidazole resistant cell line of E. histolytica
2. Emetine resistant mutant clones derived from
virulent HM1: IMSS strain
 Selected after mutagenesis with ethyl-
methanesulphonate
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28.  Expression of iron containing superoxide dismutase
(Fe-SOD) and peroxiredoxin(anti-oxidant enzymes)
increased three to five fold in metronidazole
resistant parasites with decrease in the expression of
ferredoxin and flavin reductase.
 Involvement of Fe-SOD & peroxiredoxin was
confirmed by episomal transfection of these anti-
oxidant enzymes into metronidazole susceptible
isolates,associated with reduced drug
susceptibility.
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Cont…

29.  Six P-gp like genes (EhPgp1-EhPgp6) have been
cloned and sequenced, out of it four were clearly
expressed in drug resistant line (EhPgp1, EhPgp2,
EhPgp5, EhPgp6),remaining two were pseudogenes
(EhPgp3, EhPgp4).
 Differential gene expression using specific probes
for each E.histolytica P-gp gene found MDR gene
overexpressed in emetine resistant clone of E.
histolytica & no expression of mRNA was seen in
the clinical of E. histolytica and E. dispar and also in
the sensitive strain of E. histolytica (HM1: IMSS)
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30.  Entamoeba histolytica alcohol
dehydrogenase 2 (EhADH2)as a target for
anti-amoebic agents
 Mononeuclear metal-thiosemicarbazone
as potent antiamoebic agents
 Carnamate derivative: ethyl 4-
chlorophenyl carbamate
 Haldina cordifolia(in hindi Kadam)family
Rubiaceae
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31.  Dr. Wyburn (American scientist) found that amoeba can
attack any tissue of the body, rheumatoid disease is not
simply a disease of joint but it is generalized in nature.
 Dr. Wyburn has been able to isolate amoeba(named as
Limax amoeba) from the joint tissue of a patient
suffering from rheumaoid arthritis.
 After treatment of antiameobic he found about 80%(8
out of 10) are very significantly relived or they go into
remission.
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32.  Combination therapy become useful in fewer
parasitological failure than Metronidazole alone .
 The choice of antiamoebic drugs would depend largely
on the availability and accessibility of drugs.
 Resistance data on most i.e.Metronidazole are also
lacking so antiamoebic susceptibility of pathogenic
clinical isolates needs to be investigated to help in
developing strategies to increase the efficacy and the
life span of the limited number of currently available
antiamoebic drugs.
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33.  Avelina Espinosa, David Clark and Samuel L. Stanley Jr; Entamoeba histolytica
alcohol dehydrogenase 2 (EhADH2)as a target for anti-amoebic agents,
Journal of Antimicrobial Chemotherapy (2004) 54, 56–59
 http://wholibdoc.who.int/bulletin/1997/Vol75, bulletin of world health
organization,1997,75 (3):291-292
 Wan Nor Amilah WAW, Alvieno SM, In Vitro Study on Anti-Amoebic Activity of
Tualang Honey against Entamoeba histolytica Trophozoite; Health and the
Environment Journal, 2012, Vol. 3, No. 2
 Devendra Bansal, Nancy Malla & R.C. Mahajan, Drug resistance in amoebiasis
review article Indian J Med Res 123, February 2006, pp 115-118
 Tripathi K D, Essentials of medical Pharmacology, 6th edition; Jaypee
Brothers Medical Publishers (p) Ltd. 2008:797-807.
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34. YOU
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