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Antiamoebic and

antimalarial agents

Nurlely, M.Sc (Pharm)., Apt

AMOEBIASIS

Amebiasis

Amebiasis is a protozoal infection of the


intestinal tract that occurs due to ingestion
of foods or water contaminated with
Entameba Histolytica cysts

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):
Can reproduce
They may feed on intestinal bacteria or
invade and ulcerate wall of large intestine,
and may migrate to liver or other tissues.
transform to cysts which are excreted in
feces.

Life Cycle
1.
2.
3.
4.
5.
6.

Cysts ingestion.
Formation of trophozoites
Penetration of intestinal wall
Multiplication of trophozoites within colon wall.
Systemic invasion.
Cyst formation in rectum and excretion in feces.

LIFE CYCLE

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

PATHOGENESIS OF AMOEBIASIS

ANTIAMEBIC DRUGS

Luminal Amebicides

Tissue or systemic amebicides


Mixed Amebicides

LUMEN AMOEBICIDES
Acts on the parasites in the lumen of the bowl.
used for treatment of asymptomatic amebiasis.

Include
Diloxanide Furoate
Iodoquinol
Antibiotics
- Paromomycin
- Tetracyclines
- Erythromycin

Tissue Amoebicides (systemic)


acts on the intestinal wall and liver (or any other
extra-intestinal tissue).
Used for treatment of systemic form of the disease
(intestinal wall infection or liver abscesses).
Emetine
Dehydroemetine
Chloroquine (liver only)

Mixed amoebicides
Effective against both luminal and systemic forms
of the disease. Although luminal concentration is
too low for single drug treatment.

Metronidazol

Tinidazole

METRONIDAZOLE
Mixed

amoebicide.
Drug of choice for intestinal &
extraintestinal amoebiasis.
Acts on trophozoites.
Has no effect on cysts.
Nitro group of metronidazole is reduced by
protozoan leading to cytotoxic reduced product that
binds to DNA and proteins resulting into parasite
death.

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

Pharmacokinetics
Metabolized in liver by mixed function oxidase
followed by glucouronidation.
Excreted in urine as unchanged drug plus
metabolites.
Clearance is decreased in liver impairment.
Tinidazole has longer duration, simpler dosing
regimen, less toxicity, than metronidazole, but is
equally active.

Clinical Uses
Extraluminal

amoebiasis (combined with luminal

amebicide).
Giardiasis
Trichomoniasis
Broad spectrum of Anaerobic bacteria e.g.,

Helicobacter pylori infection


Pseudomembranous colitis (Clostridium
defficile).

Adverse effects

1. GIT:
Nausea
Vomiting
Dry mouth
Metallic taste
Diarrhoea
Oral Thrush (Moniliasis, yeast infection).

Adverse effects
2. CNS: Neurotoxicological effect

Insomnia, dizziness
peripheral neuropathy, paresthesia
encphalopathy, convulsion ( IV infusion,
rare).
3. Dysuria, dark urine.
4. Neutropenia
5. Disulfiram-like effect if taken with alcohol.

disulfiram like -effect


When metronidazole is given with alcohol
abdominal distress, nausea, vomiting, or headache,
tachycardia
alcohol
dehydrogenase
Ethanol
Acetate

aldehyde
dehydrogenase

Acetaldehyde

Drug interactions:
Enzyme inhibitors (cimetidine, ketoconazole)
increase duration of action of metronidazole
Inducers (phenytoin and phenobarbitone).
inhibits CYP family 2C9 & 3A4
potentiate anticoagulant effect of warfarin.
potentiates lithium toxicity.

CONTRAINDICATIONS / PRECAUTIONS:
Pregnancy and nursing women.
Alcohol intake
CNS diseases
Severe hepatic disease
Severe renal disease

EMETINE AND DEHYDROEMETINE


Chemistry:
Emetine hydrochloride is a plant alkaloid derived
from ipeca.
Dehydroemetine is a synthetic analogue
Pharmacokinetics:
Erratic oral absorption.
Given preferably subcutaneously but could be
given by IM, NEVER I.V.
Plasma half life is 5 days.

EMETINE
Concentrated

in Liver, Lungs, Spleen, Kidney,


Cardiac muscle and Intestinal wall.
Metabolized & Excreted slowly via kidney so it
has a cumulative effect.
Trace amounts could be detected in urine 1-2
month after last dose.
Should not be used for more than 10 days (usually
3-5 days).
Mechanism
Act on tissue trophozoites causing irreversible
block of protein synthesis.

Adverse Effects
Dehydroemetine

is less toxic than emetine


pain at site of injection, abcesses.
GIT: nausea, vomiting, diarrhoea.
Neuromuscular weakness
Serious toxicities: cardiotoxicity
- cardiac arrhythmias,
- Hypotension
- heart failure

Clinical Uses
Amoebic

liver abscess.
Intestinal wall infections.
Severe forms of amebiasis acute amoebic
dysentery dehydroemetine is preferable due to less
toxicity (3-5 days).

Contraindications
Heart

disease
Kidney disease
Pregnancy
Children

Chloroquine
Antiamebic

drug
Antimalarial drug
Used in combination with metronidazole and
luminal amebicide for amebic liver diseases.

Luminal amoebicides
acts on the luminal parasites
used for treatment of asymptomatic

Include
Diloxanide Furoate
Iodoquinol
Antibiotics
- Paromomycin
- Tetracyclines
- Erythromycin

amebiasis.

Diloxanide furoate
Chemistry
Ester of diloxanide + furoic acid .
Pharmacokinetics
Given orally.
Split in the intestine, most of diloxanide is absorbed,
conjugated to form a glucoronide which is excreted in
urine (90%).
The unabsorbed diloxanide is the amoebicidal agent
(10%).

Pharmacodynamics:
Unkown

mechanism of action
Direct amoebicidal action against luminal forms.
Not active against trophozoites intestinal wall or
extraintestinal tissues.

Therapeutic Uses
Drug

of choice for asymptomatic intestinal


infection.

For eradication

of infection given along with all


forms of amebiasis.

Dose:

500 mg three times/day for 10 days.

Adverse Effects
Flatulence
Nausea,

vomiting, abdominal cramps.


No serious adverse effects
Contraindications:
- Pregnancy
- Children (less than 2 years).

Paromomycin Sulphate
Aminoglycoside,

not absorbed.
Effective against luminal forms of ameba
Mechanism of action
Direct amebicidal action (causes leakage by its action
on cell membrane of parasite).
Indirect killing of bacterial flora essential for
proliferation of pathogenic amoebae.

Kinetics
Orally
Not

significantly absorbed from the GIT


Small amount absorbed is excreted unchanged in
urine (may accumulate with renal insufficiency).

Adverse effects
Gastrointestinal distress and diarrhea.
Precautions
Severe renal disease
patients with GIT ulceration

Tetracyclines
Very

weak direct amoebicidal action.


Mainly act indirectly on bacterial flora.
Used in severe cases of amoebic dysentery not
responding to metronidazole combined with
dehydroemetine.

HALOGENATED HYDROXYQUINOLINES
Iodoquinol

Mechanism of action
Unknown
Effective against organisms in GIT only Not
intestinal wall or liver.
Pharmacokinetics
Absorption is poor (90%), excreted in feces.
10% enter circulation, excreted as glucouronide in
urine.
Half life is 11-14 h

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.
Iodine sensitivity.
interference with thyroid function tests (increase
protein-bound serum iodine)

Contraindications

Optic neuropathy
Thyroid disease
Sensitivity to iodine
Severe liver disease
Severe kidney disease
discontinued if it produces persistent diarrhea or signs of
iodine toxicity (dermatitis, urticaria, pruritus, fever)

ANTIMALARIA

GEOGRAPHICAL DISTRIBUTION

EPIDEMIOLOGI MALARIA
41% of worlds population live in areas where malaria is
transmitted
There are 300-500 million new cases of malaria every year.
An estimated 700,000-2.7 million persons die of Malaria every
year, 75% of them are African children
In areas of Africa with high transmission there are about
2700 deaths per day, 2 deaths per minute.
Malaria is fourth leading cause of death.

CAUSES OF MALARIA

CAUSES OF MALARIA

Four parasitic protozoa of the genus Plasmodium are


responsible
Plasmodium ovale,
Plasmodium vivax,
Plasmodium malariae,
Plasmodium falciparum
P falciparum causes the most severe morbidity and
mortality.
Plasmodium parasites are highly
specific with female Anopheles mosquitoes

Life cycle

Life cycle
A dormant
form of the
parasiteHypnozoite
can stay in
the liver for
long periods
of time
and can

Clinical
features

The first symptoms of malaria after


the pre-patent period (period
between inoculation and symptoms,
the time when the sporozoites
undergo schizogony in the liver) are
called the primary attack.
It is usually atypical and may
resemble any febrile illness. As the
disease gets established, the patient
starts getting relapse of symptoms at
regular intervals of 48-72 hours.

Clinical
features

The patient may suffer from


relapses of the clinical illness
periodically after 8-10 days
owing to the persisting blood
forms of the parasite. These
are called as short term
relapses (recrudescences).
Some patients will get long
term relapses after a gap of
20-60 days or more and these
are due to the reactivation of
the hypnozoites in the liver in
case of vivax and ovale malaria

Clinical
features

The febrile episode starts with shaking chills,


usually at mid-day between 11 a.m. to 12 noon, and
this lasts from 15 minutes to 1 hour (the cold stage),
Followed by high grade fever, even reaching above
1060 F, which lasts 2 to 6 hours (the hot stage). This
is followed by profuse sweating and the fever
gradually subsides over 2-4 hours.
These typical features are seen after the infection
gets established for about a week. The febrile
paroxysms are usually accompanied by head aches,
vomiting, delirium, anxiety and restlessness.

Classes of antimalarials
Aryl amino alcohols
Quinine & quinidine (cinchona alkaloids)
Mefloquine
Halofantrine.
4-aminoquinolines
Chloroquine
Amodiaquine.
8-aminoquinolines
Primaquine

Folate synthesis inhibitors


Competitive inhibitors of
dihydropteroate synthase
Sulphones & sulphonamides
Inhibit dihydrofolate reductase
biguanides
proguanil and chloroproguanil
diaminopyrimidine
pyrimethamine

Antimicrobials
Tetracycline, doxycycline, clindamycin,
azithromycin, fluoroquinolones
Peroxides
Artemisinin (Qinghaosu) derivatives and
analogues - artemether, arteether,
artesunate,
artelinic acid
Naphthoquinones
Atovaquone

THE AIMS OF TREATMENT


To alleviate symptoms due to blood
borne forms of the parasite:
Blood schizonticidal drugs
Chloroquine, quinine,
pyrimethamine/sulphadoxine, artemisinin

To prevent relapses due to hypnozoites


of P. vivax/ P. ovale
Tissue Schizoticides
Primaquine

THE AIMS OF TREATMENT


To prevent spread through
gametocytes
Gametocytocidal drugs
Primaquine for P. falciparum, Chloroquine for
all other

CHLOROQUIN
The mechanism of action :
Chloroquine inhibits the parasitic
enzyme heme polymerase that converts
the toxic heme into nontoxic hemazoin,
thereby resulting in the accumulation of
toxic heme within the parasite.
Being alkaline, the drug reaches high
concentration within the food vacuoles of
the parasite and raises its pH.
It may also interfere with the
biosynthesis of nucleic acids.

CHLOROQUIN
Pharmacokinetics :
90% of the drug is absorbed from G.I.T and
rapidly absorbed from intra muscular and
subcutaneous sites.
It has a large distribution volume due to
extensive sequestration in tissues of liver,
spleen, kidney, lung etc.
Therapeutic blood levels persist for 6-10
days and elimination half-life is 1-2 months.
Half of the drug is excreted unchanged by
the kidneys, remaining is converted to
active metabolites in the liver.

CHLOROQUIN
Adverse Effect :
Chloroquine is a relatively
safe anti-malarial.
Can cause dizziness,
headache, diplopia,
disturbed visual
accomodation, dysphagia,
nausea, malaise, and
pruritus of palms, soles and
scalp.

QUININE

QUININE
Chief alkaloid of cinchona
bark (known as 'Fever Bark'),
a tree found in South America.
Even today, quinine is
obtained entirely from the
natural sources due the
difficulties in synthesising the
complex molecule

QUININE
Mechanism of Actions :
Quinine acts as a blood schizonticide
it also has gametocytocidal activity against P. vivax
and P. malariae.
As it is a weak base, it is concentrated in the food
vacuoles of P. falciparum.
Act by inhibiting heme polymerase, thereby
allowingaccumulation of its cytotoxic substrate, heme.

QUININE
Pharmacokinetics:
Readily absorbed when given
orally or intramuscularly.
Peak plasma concentrations
are achieved within 1 3
hours after oral dose and
plasma half-life is about 11
hours.

QUININE
Adverse Effect:

The typical syndrome of


quinine side effects is called
as cinchonism consisting of :
nausea
disturbed vision.
tinnitus,
vertigo.
Fetotoksik

Pyrimethamine and sulphadoxine


The mechanism of action :
Pyrimethamine inhibits the dihydrofolate reductase of
plasmodia and thereby blocks the biosynthesis of purines
and pyrimidines, which are so essential for DNA synthesis
and cell multiplication.
Sulfadoxine inhibits the utilisation of para-aminobenzoic
acid in the synthesis of dihydropteroic acid.
The combination of pyrimethamine and sulfa thus offers
two step synergistic blockade of plasmodial division.
Useful adjuncts in the treatment of uncomplicated,
chloroquine resistant, P.falciparum malaria.

Pyrimethamine and sulphadoxine


Sulphadoxin
e

Pyrimethami
ne

MEFLOQUINE
The mechanism of action :
Produce swelling of the P. falciparum
food vacuoles.
It may act by forming toxic complexes
with freeheme that damage
membranes and interact withother
plasmodial components.
It is effective against the blood forms
offalciparum malaria, including the
chloroquineresistant types.
Restricted for use against multi drug
resistant falciparum only.

ARTEMISININ OR QINGHAUSO
Active principle of the Chinese
medicinal herb Artemisia annua
A water soluble ester called
artesunate and
Oil soluble preparations called
artemether and arteether.
It inhibits the development of the
trophozoites and thus prevents
progression of the disease.

CHLORGUANIDE
Popular as proguanil
It exerts its antimalarial action by inhibiting parasitic
dihydrofolate reductase enzyme.
Chloroguanide along with chloroquine is used as
prophylaxis effective against P. falciparum malaria.

PRIMAQUINE

PRIMAQUINE
Highly effective against the gametocytes of all
plasmodia and thereby prevents spread of the
disease to the mosquito from the patient.
It is also effective against the dormant tissue forms of
P. vivax and P. ovale malaria, and thereby offers
radical cure and prevents relapses.
It has insignificant activity against the asexual blood
forms of theparasite and therefore it is always used in
conjunction with a blood
schizonticide and never as a single agent.

PRIMAQUINE
Subjects with
deficiency of Glucose
6-phosphate
dehydrogenase will
develop hemolytic
anemia on taking usual
doses of primaquine.

CHEMOPROPHYLAXIS
doxicycline 100 mg once daily (started one
day before travel, and continued for four
weeks after returning);
Mefloquine 228 to 250 mg once weekly
(started two-and-a-half weeks before travel,
and continued for four weeks after returning);
In areas where chloroquine remains effective:
chloroquine 300 to 310mg once weekly, and
proguanil 200mg once daily (started one
week before travel, and continued for four
weeks after returning);

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