Download Amebiasis Amebiasis is an infection of the intestinal

Amoebiasis
AMEBIASIS
•An infection of the intestinal tract
•Occurs due to ingestion of foods or water
•Contaminated with Entameba Histolytica
cysts
AMEBIASIS
•Was first described by •A disease caused
Lambl and Losch in a by a one-celled
dysenteric
patient
parasite
called
(1859)
•Councilman
and Entamoeba
lafleur
in
1981 histolytica.
described
amoebic
•More common in
liver abscess.
•Schauudinn
(1903) people who live in
tropical areas with
differentiated
pathogenic
and poor
sanitary
nonpathogenic types conditions.
of Amoebae
AMOEBIASIS A MAJOR HEALTH PROBLEM
• Estimated to cause 70,000 deaths per year world wide
• Severe Amoebiasis infections (known as invasive amoebiasis).
• Invasion of the intestinal lining causes amoebic dysentery or amoebic colitis.
Transmitted by :• Fecal contamination of drinking water and foods
• Direct contact with dirty hands or objects
• By sexual contact
SYMPTOMS:• Range from mild diarrhoea to dysentery with blood and mucus in the stool.
• Gastrointestinal including
• Diarrhoea, vomiting, abdominal pain or discomfort and fever.
• Symptoms take from a few days to a few weeks to develop
• Most infected people are asymptomatic but this disease has the potential to make the sufferer dangerously
ill.
SYMPTOMS
• Gastrointestinal including
• Diarrhoea, vomiting, abdominal pain or discomfort and fever.
• Symptoms take from a few days to a few weeks to
develop
• Most infected people are asymptomatic but this disease
has the potential to make the sufferer dangerously ill,
especially
if
there
is
any
suggestion
of
immunocompromised.
LIFE CYCLE
Entamoeba histolytica exists in two forms:
1.Cysts (infective):
• Can survive outside the human body.
• Transform to trophozoites.
2. Trophozoites (non-infective; invasive):
•Reproduce
•They may feed on intestinal bacteria or
• Invade and ulcerate wall of large intestine
• May migrate to liver or other tissues.
•Transform to cysts which are excreted in feces.
LIFE CYCLE
1. Cysts ingestion.
2. Formation of trophozoites
3. Penetration of intestinal wall
4. Multiplication of trophozoites within colon wall.
5. Systemic invasion.
6. Cyst formation in rectum and excretion in feces.
EVENTS ON AMOEBIASIS
LIFE CYCLE
Precystic stage:
• Trophozoites living in the intestine undergo binary fission
• Round and 10-20µ in size
Cystic stage:
• Enters by forming a delicate cystwall around itself
• Size is 12µ
• Quadrinucleated cyst is the infective stage of the parasite
• Ingested by human host pass along with food into the small intestine
• Wall of cyst dissolved by trypsin
• Tetranucleate emerges out from cyst into lumen of large intestine called excystment
The Trophozoite Stage:
• 10-40 µm, fragile.
• Uninucleate
• Erythrophagocytosis
• Reside, feed and multiply by binary fission in lumen of colon.
• May invade – Lytic & physical mechanisms and metastasize to liver and other extraintestinal sites.
CLINICAL PRESENTATIONS
•Asymptomatic Intestinal infection
(Carriers, passing cysts)
•Mild to moderate intestinal disease
(Nondysenteric Colitis)
•Severe Intestinal infection ( Dysentery)
•Hepatic
abscess,
ameboma
(localized
granulomatous lesion of colon) and other
extraintestinal disease
DIAGNOSIS
•Light Microscopy of Stool
•Identification of trophozoites / cysts in fresh
stool
Serology
Stool antigen-detection test
•Sensitive and Specific
•A sample of freshly collected Fecal specimen
CLASSIFICATION
LUMINAL AMEBICIDES
• For treating intestinal
infections.
(a) Amide:
Diloxanide furoate,
Nitazoxanide
(b) 8-Hydroxyquinolines :
Quiniodochlor,
Diiodohydroxyquin
(c) Antibiotics :
Tetracyclines
TISSUE AMEBICIDES
• Used to destroy amoebae that
have invaded tissue, rapidly
absorbed into the bloodstream
and transported to the site of
infection.
(a) For both intestinal and extraintestinal
amoebiasis:
A)Nitroimidazoles:
• Metronidazole, Tinidazole,
Secnidazole,Ornidazole,
Satranidazole
B) Alkaloids:
• Emetine, Dehydroemetine
(b) For extraintestinal amoebiasis only:
• Chloroquine
METRONIDAZOLE
• Mixed amoebicide
• Choice for intestinal &extraintestinal
amoebiasis.
• Acts on trophozoites.
• Has no effect on cysts.
Mechanism:
• Nitro group of metronidazole is
reduced by protozoan.
• Leading to cytotoxic reduced
product
• That binds to DNA and proteins
• Resulting into parasite death.
MECHANISM
• Selectively toxic to anaerobic microorganisms.
• After entering the cell by diffusion
• Its nitro group is reduced by certain redox proteins (operative only in
anaerobic microbes)
• To highly reactive nitro radical which exerts cytotoxicity.
• Acts as an electron sink
• Competes with the biological electron acceptors of the anaerobic organism
• For the electrons generated by the pyruvate : ferredoxin oxidoreductase
(pfor) enzyme pathway of pyruvate oxidation.
• The energy metabolism of anaerobes is, thus, disrupted.
• Aerobic environment attenuates cytotoxicity
RESISTANCE:
• Develop resistance become deficient in the mechanism
that generates the reactive nitro radical from it.
PHARMACOKINETICS:
• Given orally or IV.
• Absorption is rapid and complete.
▪ Due to rapid absorption from GIT, not reliably effective against
luminal parasites.
• Wide distribution to all tissues and body fluids (CSF, saliva, milk).
• Plasma protein binding is low ( < 20%).
• Plasma half life is 8 h
• Metabolized in liver
• Excreted in urine
ADVERSE EFFECTS
• Relatively frequent and unpleasant,
but mostly nonserious.
• Anorexia (an emotional disorder
characterized by an obsessive desire to
lose weight by refusing to eat)
• Nausea
• Metallic taste
• Abdominal cramps
• Looseness of stool.
Less frequent side effects are•
•
•
•
Headache,
Glossitis (inflammation of the tongue) ,
Dryness of mouth,
Dizziness(a feeling that you are about
to fall),
• Rashes
• Neutropenia (abnormally
number of neutrophils).
• Prolonged administration
low
• Peripheral neuropathy (damage to
nerves of the peripheral nervous
system) and
• CNS effects.
• Very high doses:• Seizures (Due to the electrical
discharge in the nervous system)
• If the solution is not well diluted:• Thrombophlebitis of the injected
vein (inflammation of the wall of a
vein with associated thrombosis)
occurs
CLINICAL USES
• Ulcerative gingivitis,
• Extraluminal
amoebiasis trench mouth
(combined
with
luminal
(
a severe form of gingivitis that causes
amebicide).
painful, infected, bleeding gums and
ulcerations. )
• Giardiasis
• Guinea worm infestation
(Infection of the intestine with a
flagellate protozoan which causes
(a painful and debilitating infestation
diarrhea and other symptoms.)
• Trichomoniasis
(An infection caused by parasitic
trichomonads (genus Trichomonas),
chiefly affecting the urinary tract,
vagina, or digestive system.)
• Broad spectrum of Anaerobic
bacteria
• Helicobacter pylori infection
• Pseudomembranous colitis
(Clostridium defficile).
(is an infection of the colon.)
contracted by drinking stagnant water
contaminated with Guinea worm larvae that
can mature inside a human's abdomen until
the worm emerges through a painful blister
in the person's skin
)
CONTRAINDICATIONS /
PRECAUTIONS
• Pregnancy and nursing
women.
• Alcohol intake
• CNS diseases
• Severe hepatic disease
• Severe renal disease
TINIDAZOLE
• Efficacious as
metronidazole
• Similar to it in every way
except:
• Metabolism is slower
• T1/2 is -12 hr
• Duration of action is
longer
• More suited for single
dose or once daily
therapy
• better tolerated
• Lower side effects
SECNIDAZOLE
• A congener of
metronidazole
• Same spectrum of activity
and potency.
• Oral administration
• Absorption is rapid and
complete
• Metabolism is slower
• Plasma t1/2 of 1 7-29
hours.
• Side effect similar to
metronidazole
• USES:
•
•
•
•
•
Intestinal Amoebiasis
Giardiasis
Trichomonas Vaginitis
Nonspecific Bacterial Vaginosis
Hepatic Amoebiasis.
ORNIDAZOLE
• Activity similar to metronidazole
• Slowly metabolized• Longer t1/2 -12-14 hr
USES:
•
•
•
•
•
Amoebiasis,
Giardiasis,
Trichomoniasis,
Anaerobic Infections
Bacterial Vaginosis.
• Side effect profile is also similar.
SATRANIDAZOLE
• Nitroimidazole
• Longer t1/2 -14 hr.
ADVANTAGES ARE:
• Better tolerability,
• No nausea, vomiting or metallic
taste,
• Absence of neurological and
disulfiram-like reactions.
USE :
• Amoebiasis
• Giardiasis
• Trichomoniasis
EMETINE AND DEHYDROEMETINE
CHEMISTRY :
• Emetine hydrochloride is a
plant alkaloid derived from
Cephaelis ipecawanha.
• Dehydroemetine
is
a
synthetic analogue
PHARMACOKINETICS:
• Variable oral absorption.
• Given preferably S.C. but
could be given by IM, NEVER
I.V
• Plasma half life is 5 days.
• Concentrated in Liver, Lungs,
Spleen,
Kidney,
Cardiac
muscle and Intestinal wall.
MECHANISM
• Act
on
tissue
trophozoites
• No effect on cysts
• Acts
by
inhibiting
protein synthesis in
amoebae
• By
arresting
intraribosomal
translocation of trnaamino acid complex
ADVERSE EFFECTS
CLINICAL USES
• Amoebic liver abscess
• Dehydroemetine is less toxic than
• Intestinal wall infections
emetine
• Severe forms of amebiasis
• Pain at site of injection, abcesses.
• Acute amoebic Dysentery
• GIT: Nausea, vomiting, diarrhoea.
(dehydroemetine is preferable due to
less toxicity)
• Neuromuscular weakness
CONTRAINDICATIONS
• Serious toxicities:
• Cardiotoxicity
- Cardiac arrhythmias,
- Hypotension
- Heart failure
• Heart disease
• Kidney disease
• Pregnancy
DEHYDROEMETINE
• Semisynthetic derivative of emetine
• Equally effective
• Less toxic to the heart.
• Thus, it is preferred over emetine by most physicians.
CHLOROQUINE
• Antimalarial drug
• Used in combination
• For amebic liver Diseases
• Followed by luminal amebicide.
• Kills trophozoites
• Highly concentrated in liver.
• Therefore used in hepatic
amoebiasis only.
• Completely absorbed from the
upper intestine and not so highly
concentrated in the intestinal wall
.
• Amoebae
do
not
develop
resistance to chloroquine.
• Because of safety of chloroquine, it
may be given concurrently or
immediately after a course of
metronidazole
• To ensure complete eradication of
the trophozoites in liver.
• A luminal amoebicide must always
be given with or after chloroquine
to abolish the luminal cycle.
• It is now employed only when
metronidazole is not effective or
not tolerated.
DILOXANIDE FUROATE
CHEMISTRY
• Ester of diloxanide + furoic acid
PHARMACOKINETICS
• Given orally.
• Split in the intestine
• Diloxanide is absorbed, conjugated to
form a glucoronide which is excreted in
urine
• Diloxanide is a weaker amoebicide
than its furoate ester : no systemic
antiamoebic activity.
PHARMACODYNAMICS
• Highly effective luminal amoebicide:
directly kills trophozoites responsible
for production of cysts.
• Diloxanide
furoate
exerts no
antibacterial action.
• Less effective in invasive amoebic
dysentery, because of poor tissue
amoebicidal action.
• High cure rate in mild intestinal
amoebiasis and in asymptomatic
cyst
passers.
THERAPEUTIC USES
• For mild intestinal/ asymptomatic
intestinal infection
• Given after any tissue amoebicide to
eradicate cysts.
• For eradication of infection given
along with all forms of amebiasis.
• Combined use with metronidazole/
tinidazole is quite popular.
• Some chronic cases require repeat
courses
for
eradication.
ADVERSE EFFECTS
• Flatulence ( the accumulation of gas
in the alimentary canal)
• Nausea, vomiting, abdominal cramps.
• No serious adverse effects
CONTRAINDICATIONS:
- Pregnancy
- Children (less than 2 years).
•
NITAZOXANIDE
• Salicylamide congener
• Use in treatment of giardiasis is
also
active
against
E.
Histolytica,
T.
Vaginalis,
cryptosporidium, H. Pylori,
ascaris, H. Nana and some
other protozoa and helminths.
• It is a prodrug which on
absorption is converted to the
active form tizoxanide.
MECHANISM OF ACTION:
• An inhibitor of PFOR enzyme
that is an essential pathway of
electron
transport
energy
metabolism
in
anaerobic
organisms.
• Tizoxanide produced in the
body is conjugated and excreted
in urine and bile.
USES:
• Giardiasis
(infection
of the
intestine with a flagellate protozoan,
which causes diarrhoea and other
symptoms.)
• Cryptosporidiasis (is
a parasitic
disease caused by Cryptosporidium)
• Amoebic dysentery as luminal
amoebicide.
• Against
metronidazoleresistant giardia (an intestinal
infection marked by abdominal
cramps, nausea and watery diarrhea)
SIDE EFFECTS:
• Abdominal pain
• Vomiting
• Headache
TETRACYCLINES
• Directly inhibit amoebae only at higher concentrations.
• The older tetracyclines are incompletely absorbed in the small intestine,
reach the colon in large amounts and inhibit the bacterial flora with
which entamoebae live symbiotically.
• Indirectly reduce proliferation of entamoebae in the colon
• Especially valuable in chronic, difficult to treat cases with only the
luminal cycle and little mucosal invasion.
• Adjuvant role in conjunction with a more efficacious luminal
amoebicide.
• They are not good for acute dysentery and for hepatic amoebiasis.
8-HYDROXYQUINOUNES
SPECTRUM:
• Active against
• Entamoeba,
giardia,
trichomonas,
some
fungi
(dermatophytes, candida) and
some bacteria.
• They kill the cyst forming trophozoites in
the intestine
• Do not have tissue amoebicidal action
• Valueless in extraintestinal amoebiasis
• Intestine absorption is variable.
• Therapeutic concentrations are not
attained in the intestinal wall or in liver.
• The unabsorbed part reaches lower bowel
and acts on luminal cycle of amoebae.
USES
• Lumen amoebicide.
• For eradication of infection
given along with tissue
amoebicide (metronidazole).
ADVERSE EFFECTS
• Peripheral neuropathy including
optic neuritis
• GIT: Nausea, vomiting, diarrhoea.
• Enlargement of the thyroid gland.
• Agranulocytosis (A deficiency of
granulocytes in the blood).
• Iodine sensitivity.
• Drug interfere with thyroid
function tests (increase proteinbound serum iodine thus decrease
in measured
131I uptake).
CONTRAINDICATIONS
• Optic neuropathy (Disease or dysfunction of one or more peripheral
nerves)
• Thyroid disease
• Sensitivity to iodine
• Severe kidney disease
• Discontinued if it produces persistent diarrhea or signs of iodine toxicity
(dermatitis, urticaria (A rash of round, red welts on the skin that itch
intensely), pruritus (Severe itching of the skin), fever)
TREATMENT OF AMOEBIASIS
1. INVASIVE INTESTINAL AMOEBIASIS
• Metronidazole/tinidazole are the drugs of choice.
• Secnidazole, ornidazole, satranidazole are the alternatives.
• Adjuvant measures for diarrhoea and abdominal pain may be needed.
• The above treatment should be followed by a course of luminal amoebicide
to eradicate E. histolytica from the colon and to prevent carrier (cyst passing)
state.
2. CHRONIC INTESTINAL AMOEBIASIS/ASYMPTOMATIC
CYST PASSERS
• These cases are more difficult to treat, two or more repeated courses may
be needed.
• Diloxanide furoate produces high cure rates and is the drug of choice.
• Nitazoxanide is an alternative.
• A tetracycline may be given concurrently with the luminal amoebicide in
cases which fail to clear completely.
3. AMOEBIC LIVER ABSCESS
• A serious disease
• Complete eradication of trophozoites from the liver is essential to avoid
relapses.
• Metronidazole/tinidazole are the first choice drugs effective in> 95% cases.
• Dehydroemetine is to be used only if metronidazole cannot be given for
one reason or the other, and in patients not cured by metronidazole.
• A luminal amoebicide must be given later to finish the intestinal reservoir
of infection.
• A course of chloroquine may be administered after that to ensure that no
motile forms survive in the liver.
THANK YOU
- PHARMA STREET