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antimalarial agents
AMOEBIASIS
Amebiasis
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
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
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
amebicide).
Giardiasis
Trichomoniasis
Broad spectrum of Anaerobic bacteria e.g.,
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.
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
Concentrated
Adverse Effects
Dehydroemetine
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
For eradication
Dose:
Adverse Effects
Flatulence
Nausea,
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
Adverse effects
Gastrointestinal distress and diarrhea.
Precautions
Severe renal disease
patients with GIT ulceration
Tetracyclines
Very
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
Adverse Effects
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
Life cycle
Life cycle
A dormant
form of the
parasiteHypnozoite
can stay in
the liver for
long periods
of time
and can
Clinical
features
Clinical
features
Clinical
features
Classes of antimalarials
Aryl amino alcohols
Quinine & quinidine (cinchona alkaloids)
Mefloquine
Halofantrine.
4-aminoquinolines
Chloroquine
Amodiaquine.
8-aminoquinolines
Primaquine
Antimicrobials
Tetracycline, doxycycline, clindamycin,
azithromycin, fluoroquinolones
Peroxides
Artemisinin (Qinghaosu) derivatives and
analogues - artemether, arteether,
artesunate,
artelinic acid
Naphthoquinones
Atovaquone
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:
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);