FARMAKOLOGI

ANTIPARASIT

Protozoal infections
Amebiasis
Malaria
Giardiasis
Leshmaniasis
Toxoplasmosis
Trypanosomiasis

Protozoal infections
1.
2.

3.
4.
5.
6.

Difficult to be treated than bacterial infections.

Protozoal cells (Eukaryotes) have metabolic
processes closer to human host than prokaryotic
bacterial pathogens.
Many of antiprotozoal drugs cause toxic effects
on the host.
Cells with high metabolic processes in the host
are susceptible.
Examples: bone marrow stem, renal tubular
cells, intestinal & neuronal cells.
Antiprotozoal are not safe during pregnancy.

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

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

ANTIAMOEBIC 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 glucouroidation.
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, flushing, or
headache, tachycardia, hyperventilation
alcohol
dehydrogenase
Ethanol

aldehyde
dehydrogenase

Acetaldehyde

Acetate

Adverse effects of
metronidazole

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

ANTIMALARIA

Malaria-endemic
countries

Life cycle of malaria parasites

Goodmand and Gilmans , The Pharmalogical Basis of

th

The sites of action of antimalarial drugs

DRUG CLASSIFICATION
Major antimalarial drugs
Drug

Class

Use

Chloroquine

4-Aminoquinoline

Treatment and chemoprophylaxis of infection with sensitive parasites

Amodiaquine1

4-Aminoquinoline

Treatment of infection with some chloroquine-resistant P falciparum strains

Quinine

Quinoline methanol

Oral treatment of infections with chloroquine-resistant P falciparum

Quinidine

Quinoline methanol

Intravenous therapy of severe infections with P falciparum

Mefloquine

Quinoline methanol

Chemoprophylaxis and treatment of infections with P falciparum

Primaquine

8-Aminoquinoline

Sulfadoxine
-pyrimethamine
(Fansidar)
Proguanil1
Doxycycline
Halofantrine
Artemisinins

Radical cure and terminal prophylaxis of infections with P vivax and P ovale

Folate antagonist combination

Folate antagonist
Tetracycline
Phenanthrene methanol

Treatment of infections with some chloroquine-resistant P falciparum

Chemoprophylaxis (with chloroquine)

Treatment (with quinine) of infections with P falciparum; chemoprophylaxis
Treatment of infections with some chloroquine-resistant P falciparum

Sesquiterpene lactone endoperoxides

Atovaquone-proguanil
(Malarone)
Quinone-folate antagonist combination

Treatment of infection with multidrug-resistant P falciparum

Treatment and chemoprophylaxis of P falciparum infection

The spectrum of antimalarial drug

activity

Goodmand and Gilmans , The Pharmalogical Basis of

th

Because no antimalarial drug kills

sporozoites, it is not truly possible to
prevent infection; drugs can only
prevent the development of
symptomatic malaria caused by the
asexual erythrocytic forms
No single antimalarial is effective
against all liver and intra-erythrocytic
stages of the life cycle that may coexist in the same patient. Complete
elimination of the parasite infection,
therefore, may require more than one
drug

Regimens recommended for

chemoprophylaxis in travelers

Goodman and Gilmans , The Pharmalogical Basis of

Regimens for the Treatment of

DRUG
INDICATI ADULT
PEDIATRI ADVERS COMMENT
Malaria
ON
DOSAGE C
E
S
Artemeth
erlumefantri
ne
(COARTEM
)

P.
falciparum
from
chloroquin
e resistant
or
unknown
areas

Tablet: 20
mg
artemeth
er,
limefantri
ne. Dose:
4 tablets
Day 1: 2
doses
separate
d by 8
hours;
thereafte
r bid x 2d

DOSAGE

EFFECT
S

5-15 kg, 1
tablet
(per dose)
15-25 kg,
2 tablets
(per dose)
25-<35
kg, 3
tablets
(per dose)
>35 kg, 4
tablets
(per dose)
Use same
3-day

Adults;
headach
e
anorexia,
dizziness
,
asthenia,
arthralgi
a
myalgia
Children:
fever,
cough,
vomiting
, loss of

Take with
food or
whole milk.
If patient
vomits
within 30
minutes,
repeat
dose.
Contraindic
ated in
pregnancy

DRUG

INDICATI
ON

ADULT
DOSAGE

Artesunate
(IV;
available
from U.S.
Center for
Disease
Control
and
Prevention
)

Severe
malaria
(see CDC
guidelines)

U.S.
treatment
IND (CDC):
4 equal
doses of
artesunate
(2.4 mg/kg
each) over
a 3-day
period
followed by
oral
treatment
with
atovaquon
eproguanil,
doxycyclin
e,
clindamyci
n, or

PEDIATRI ADVERS COMMEN

C
E
TS
DOSAGE EFFECTS
See
See
Artemethe Artemether
r
and CDC
guidelines

DRUG

INDICATIO ADULT
N
DOSAGE

PEDIATRIC
DOSAGE

ADVERSE
EFFECTS

COMMENT
S

Atovaquone
-proguanil
MALARONE
(oral)

Plasmodium
falciparum
from
chloroquine
-resistant
areas; can
be used for
P. vivax

Pediatric
tablet =
62.5 mg
atovaquone/
25 mg
proguanil
5-8 kg: 2
ped tab
orally per
day x 3 d
>8-10 kg: 3
ped tab
orally daily x
3d
>10-20 kg: 1
adult tab
orally daily x
3d
>20-30 kg: 2
adult tab
orally daily x
3d
>30-40 kg: 3
adult tab

Abdominal
pain,
nausea,
vomiting,
diarrhea,
headache,
rash, mild
reversible
elevations
in liver
aminotransf
erase levels

Not
indicated
for use in
pregnant
women due
to limited
data
Contraindic
ated if
hypersen to
atovaquone
or
proguanil;
severe renal
impairment
(creatinine
clearance<
30 mL/min)
Should be
taken with
food to
increase
absorption
of

Adult tablet
250 mg
atovaquon
e/100 mg,
proguanil
4 Adult
tablets
orally per
day x 3 d

DRUG

INDICATI
ON

ADULT
DOSAGE

PEDIATRI ADVERS COMMEN

C
E
TS
DOSAGE EFFECTS

Chloroquine
phosphate

P. falciparum
from
chloroquine
sensitive
areas
P vivax from
chloroquine
sensitive
areas
All P. ovale
All P malariae
All P. knowlesi

600 mg base
(1000 mg
salt) orally
immediately,
followed by
300 mg base
(500 mg salt)
orally at 6,
24, and 48 h
Total dose:
1500 mg
base (2500
mg salt)

10 mg
base/kg orally
immediately,
followed by 5
mg base/kg
orally at 6,
24, and 48 h
Total dose: 25
mg base/kg

Nausea,
vomiting,
rash,
headache,
dizziness,
urticaria,
abdominal
pain,
pruritus

Safe in
children and
pregnant
women
Give for
chemoprophyl
axis (500 mg
salt orally
every week) in
pregnant
women with
chloroquinesensitive P.
vivax
Contraindicate
d if retinal or
visual field
change;
hypersensitivit
y to 4aminoquinolin
es
Use with
caution in
those with
impaired liver

DRUG

INDICATI
ON

ADULT
DOSAGE

PEDIATRI ADVERS COMMEN

C
E
TS
DOSAGE EFFECTS

Clindamyc
in (oral or
IV)

P.
falciparum
from
chloroquine
-resistant
areas P
vivax from
chloroquine
-resistant
areas

Oral: 20
mg
base/kg/d
orally
divided 3
times daily
x7d
IV: 10 mg
base/kg
loading
dose IV
followed by
5 mg
base/kg IV
every 8 h;
switch to
oral
clindamyci
n (as
above) as
soon as

Oral: 20
Diarrhea,
mg
nausea,
base/kg/d
rash
orally
divided 3
times daily
x7d
IV: 10 mg
base/kg
loading
dose IV
followed by
5 mg
base/kg IV
every 8 h;
switch to
oral
clindamyci
n (oral
dose as
above) as

Always use
in
combinatio
n with
quininequinidine
Safe in
children
and
pregnant
women

DRUG

INDICATIO ADULT
N
DOSAGE

Doxycyclin P falciparum
e (oral or
from
IV)
chloroquineresistant
areas
P vivax from
chloroquineresistant
areas

Oral: 100 mg
orally twice
daily x 7 d
IV: 100 mg
IV every 12
h and then
switch to
oral
doxycycline
(as above)
as soon as
patient can
take oral
medication;
treatment
course = 7 d

PEDIATRI
C
DOSAGE

ADVERS COMMENT
E
S
EFFECT
S

Oral: 2.2
mg/kg orally
every12 h x 7
d
IV: IV only if
patient is not
able to take
oral
medication;
for children
<45 kg, give
2.2 mg/kg IV
every 12 h
and then
switch to oral
doxycycline
(dose as
above) as
soon as
patient can
take oral
medication;
for children

Nausea,
vomiting,
diarrhea,
abdominal
pain,
dizziness,
photosensit
ivity,
headache,
esophagitis
,
odynophagi
a
Rarely
hepatotoxi
city,
pancreatiti
s, and
benign
intracranial
hypertensi
on seen
with

Always use in
combination
with quinine or
quinidine
Contraindicated
in children < 8
y, pregnant
women, and
persons with
known
hypersensitivity
to tetracyclines
Food and milk
decrease
absorption of
doxycycline, will
decrease GI
disturbances
To prevent
esophagitis,
take
tetracyclines
with large
amounts of
fluids, (patients
should not lie

DRUG

INDICATI
ON

Hydroxyc Secondhloroquin line

e (oral)
alternative
for
treatment
of:
P.
falciparum
and P.
vivax from
sensitive
areas
chloroquin
e
All P. ovale
All P.
malariae

ADULT
DOSAGE

PEDIATRI ADVERS COMMEN

C
E
TS
DOSAGE EFFECTS

620-mg
base (=
800 mg
salt)
orally
immediat
ely,
followed
by 310
mg base
(= 400
mg salt)
orally at
6, 24, and
48 h
Total
dose:
1550-mg

10-mg
base/kg
orally
immediat
ely,
followed
by 5-mg
base/kg
orally at
6, 24, and
48 h
Total
dose: 25mg
base/kg

Nausea,
vomiting,
rash,
headache
,
dizziness,
urticaria,
abdomin
al pain,
pruritusb

Safe in
children
and
pregnant
women
Contraindi
cated if
retinal or
visual field
change;
hypersensi
tivity to 4aminoquin
olines
Use with
caution in
those with
impaired

DRUG

INDICATIO
N

ADULT
DOSAGE

PEDIATRI
C
DOSAGE

ADVERSE
EFFECTS

COMMEN
TS

Mefloquin
e

P. falciparum
from
chloroquineresistant areas,
except ThailandBurmese and
ThailandCambodian
border regions
P. vivax from
chloroquineresistant areas

684 mg base
(= 750 mg
salt) orally
as initial
dose,
followed by
456 mg base
(= 500 mg
salt) orally
given 6-12 h
after initial
dose
Total dose =
1250 mg salt

13.7 mg
base/kg (= 15
mg salt/kg)
orally as initial
dose, followed
by 9.1 mg
base/kg (= 10
mg salt/kg)
orally given 612 h after
initial dose
Total dose =
25 mg salt/kg

GI complaints
(nausea,
vomiting,
diarrhea,
abdominal
pain), mild
CNS
complaints
(dizziness,
headache,
somnolence,
sleep
disorders),
myalgia, mild
skin rash, and
fatigue;
moderate to
severe
neuropsychiat
ric reactions,
ECG changes,
including
sinus
arrhythmia,
sinus
bradycardia,

Contraindicat
ed if
hypersensitiv
e to the drug
or to related
compounds;
cardiac
conduction
abnormalities
; psychiatric
disorders;
and seizure
disorders
Do not
administer if
patient has
received
related drugs
(chloroquine,
quinine,
quinidine)
less than 12
h ago

DRUG

INDICATI
ON

ADULT
DOSAGE

PEDIATR ADVERSE
IC
EFFECTS
DOSAGE

COMMEN
TS

Primaqui
ne
phosphat
e

Radical
cure of P.
vivax and
P. ovale (to
eliminate
hypnozoite
s

30 mg
base
orally per
day x 14
d

0.5 mg
base/kg
orally per
day x 14
d

Must
screen for
G6PD
deficiency
prior to
use
Contraindi
cated in
persons
with G6PD
deficiency;
pregnant
women
Should be
taken with
food to
minimize
GI adverse

GI
disturbanc
es,
methemog
lobinemia
(selflimited),
hemolysis
in persons
with G6PD
deficiency

DRUG

INDICATI
ON

ADULT
DOSAGE

PEDIATRI
C
DOSAGE

ADVERSE
EFFECTS

COMMENTS

Quinine
sulfate
(oral)

P. falciparum
from
chloroquineresistant
areas
P. vivax from
chloroquineresistant
areas

542 mg base
(650 mg salt)d
orally 3 times
daily x 3 d
(infections
acquired
outside
Southeast
Asia) to 7 d
(infections
acquired in SE
Asia)

8.3 mg
base/kg (10
mg salt/kg)
orally 3
times daily x
3d
(infections
acquired
outside
Southeast
Asia) to 7 d
(infections
acquired in
SE Asia)

Cinchonisme,
sinus
arrhythmia,
junctional
rhythms,
atrioventricul
ar block,
prolonged QT
interval,
ventricular
tachycardia,
ventricular
fibrillation
(these are
rare and
more
commonly
seen with
quinidine),
hypoglycemia

Combine with
tetracycline,
doxycycline, or
clindamycin,
except for P.
vivax
infections in
children <8 y
or pregnant
women
Contraindicate
d in
hypersensitivit
y including
history of
blackwater
fever,
thrombocytope
nic purpura, or
thrombocytope
nia associated
with quinine or
quinidine use;
many cardiac
conduction
defects and

DRUG

INDICATI
ON

ADULT
DOSAGE

PEDIATRI
C
DOSAGE

ADVERSE
EFFECTS

COMMENTS

Quinidine
gluconate
(IV)

Severe
malaria (all
species,
independen
tly of
chloroquine
resistance)
Patient
unable to
take oral
medication
Parasitemia
>10%

6.25 mg
base/kg (= 10
mg salt/kg)
loading dose
IV over 1-2 h,
then 0.0125
mg
base/kg/min
(0.02 mg
salt/kg/min)
continuous
infusion for at
least 24 h
Alternative
regimen:g

Same as
adult

Cinchonism,
tachycardia,
prolongation
of QRS and
QTc
intervals,
flattening of
T-wave
(effects are
often
transient)
Ventricular
arrhythmias,
hypotension,
hypoglycemi
a

Combine with
tetracycline,
doxycycline,
or clindamycin
Contraindicate
d in
hypersensitivi
ty; history of
blackwater
fever
including
history of
blackwater
fever,
thrombocytop
enic purpura
or
thrombocytop
enia
associated
with quinine
or quinidine
use; many
cardiac
conduction

DRUG

INDICATI
ON

Tetracycl P.
ine (oral falciparum
or IV)
(chloroqui
neresistant
areas) P.
vivax from
chloroquin
e-resistant
areas
(with
quinine/qu
inidine)

ADULT
DOSAGE

PEDIATRI ADVERS COMMENT

C
E
S
DOSAGE EFFECTS

Oral: 250
mg 4
times
daily x 7 d
IV: dosage
same as
for oral

25
See
mg/kg/d
doxycycli
orally
ne
divided 4
times
daily x 7 d
IV: dosage
same as
for oral

See
doxycyclin
e

CHLOROQUIN
E
Chemistry & Pharmacokinetics
Chloroquine is a synthetic 4-aminoquinoline formulated as the
phosphate salt for oral use.
It is rapidly and almost completely absorbed from the
gastrointestinal tract, reaches maximum plasma concentrations
in about 3 hours, and is rapidly distributed to the tissues.
It has a very large apparent volume of distribution of 100-1000
L/kg and is slowly released from tissues and metabolized.
Chloroquine is principally excreted in the urine with an initial
half-life of 3-5 days but a much longer terminal elimination halflife of 1-2 months.

Antimalarial Action & Resistance

A.Antimalarial Action:
. Chloroquine is a highly effective blood
schizonticide and remains the principal
antimalarial drug in much of the world.
. It is also moderately effective against
gametocytes of P vivax, P ovale, and P malariae
but not against those of P falciparum.
. Chloroquine is not active against liver stage
parasites.

B. Mechanism of Action:

The mechanism of action remains

controversial.
Chloroquine probably acts by concentrating in
parasite food vacuoles, preventing the
polymerization of the hemoglobin breakdown
product, heme, into hemozoin and thus eliciting
parasite toxicity due to the buildup of free heme.

Action of chloroquine on the formation

of hemozoin by Plasmodium species

C. Resistance:

Resistance to chloroquine is now

very common among strains of P
falciparum and uncommon but
increasing for P vivax.

Clinical Uses
A. Treatment: Chloroquine is the drug
of choice for the treatment of
nonfalciparum and sensitive falciparum
malaria.

B. Chemoprophylaxis: Chloroquine is the

preferred chemoprophylactic agent in
malarious regions without resistant
falciparum malaria. Eradication of P vivax
and P ovale requires a course of primaquine
to clear hepatic stages.
C. Amoebic Liver Abscess

Adverse Effects :

Pruritus is common,
primarily in Africans.
Nausea, vomiting, abdominal
pain, headache, anorexia,
malaise, blurring of vision, and
urticaria are uncommon.
The long-term administration of
high doses of chloroquine for
rheumatologic diseases
irreversible ototoxicity, retinopathy,
myopathy, and peripheral
neuropathy

Adverse effects commonly

associated with chloroquine

AMODIAQUINE
Amodiaquine is closely related to chloroquine,
and it probably shares mechanisms of action and
resistance with that drug.
Amodiaquine has been widely used to treat
malaria in many countries because of its low
cost, limited toxicity, and, in some areas,
effectiveness against chloroquine-resistant strains
of P falciparum.

QUININE & QUINIDINE

Introduction
Quinine and quinidine remain first-line therapies for
falciparum malaria especially severe disease
through toxicity concerns complicate therapy.
Resistance to quinine is uncommon but increasing.

Antimalarial Action & Resistance

A. Antimalarial Action: Quinine is a rapidly
acting, highly effective blood schizonticide
against the four species of human malaria
parasites.
The drug is gametocidal against P vivax and P
ovale but not P falciparum. It is not active
against liver stage parasites. The mechanism of
action of quinine is unknown.
B. Resistance:
Increasing in vitro resistance of parasites from a
number of areas suggests that quinine resistance
will be an increasing problem in the future

Clinical Uses
A. Parenteral Treatment of Severe Falciparum
Malaria:
B. Oral Treatment of Falciparum Malaria
C. Malarial Chemoprophylaxis
D. Babesiosis

Adverse Effects :
Tinnitus, headache, nausea, dizziness, flushing,
and visual disturbances, a constellation of
symptoms termed cinchonism.
Severe hypotension can follow too-rapid
intravenous infusions of quinine or quinidine.
Electrocardiographic abnormalities (QT
prolongation) are fairly common with intravenous
quinidine.
Blackwater fever is a rare severe illness that
includes marked hemolysis and hemoglobinuria in
the setting of quinine therapy for malaria.

MEFLOQUINE
Introduction
Mefloquine is effective therapy for many chloroquine-resistant strains of P
falciparum and against other species.
Chemistry & Pharmacokinetics
Mefloquine hydrochloride is a synthetic 4-quinoline methanol that is
chemically related to quinine.
It can only be given orally because severe local irritation occurs with
parenteral use. It is well absorbed, and peak plasma concentrations are
reached in about 18 hours.
Mefloquine is highly protein-bound, extensively distributed in tissues, and
eliminated slowly, allowing a single-dose treatment regimen.
Mefloquine and acid metabolites of the drug are slowly excreted, mainly in
the feces. The drug can be detected in the blood for months after the
completion of therapy.

Antimalarial Action & Resistance

A. Antimalarial Action: Mefloquine has strong blood
schizonticidal activity against P falciparum and P vivax, but it
is not active against hepatic stages or gametocytes. The
mechanism of action of mefloquine is unknown.
B. Resistance: Sporadic resistance to mefloquine has been
reported from many areas. At present, resistance appears to
be uncommon except in regions of Southeast Asia with high
rates of multidrug resistance (especially border areas of
Thailand). Mefloquine resistance appears to be associated
with resistance to quinine and halofantrine but not with
resistance to chloroquine.

Clinical Uses
A. Chemoprophylaxis
B. Treatment: Mefloquine is effective in treating
most falciparum malaria, but the drug has not
been approved by the FDA for this purpose. The
drug is not appropriate for treating individuals
with severe or complicated malaria since quinine
and quinidine are more rapidly active and drug
resistance is less likely with those agents.

PRIMAQUINE
Introduction
Primaquine is the drug of choice for the eradication of
dormant liver forms of P vivax and P ovale.
Antimalarial Action & Resistance
A. Antimalarial Action:
. Primaquine is active against hepatic stages of all human
malaria parasites. It is the only available agent active
against the dormant hypnozoite stages of P vivax and P
ovale..
. Primaquine acts against erythrocytic stage parasites, but
this activity is too weak to play an important role. The
mechanism of antimalarial action is unknown.

B. Resistance
Some strains of P vivax in New Guinea, Southeast
Asia, and perhaps Central and South America are
relatively resistant to primaquine.
Liver forms of these strains may not be
eradicated by a single standard treatment with
primaquine and may require repeated therapy with
increased doses (eg, 30 mg base daily for 14 days)
for radical cure.

Clinical Uses
A. Therapy (Radical Cure) of Acute Vivax and
Ovale Malaria
B. Terminal Prophylaxis of Vivax and Ovale
Malaria
C. Chemoprophylaxis of Malaria.
D. Gametocidal Action
E. Pneumocystis carinii Infection.

Adverse Effects :
nausea, epigastric pain, abdominal cramps, and
headache, and these symptoms are more common
with higher dosages and when the drug is taken on
an empty stomach.
More serious but rare adverse effects include
leukopenia, agranulocytosis, leukocytosis, and
cardiac arrhythmias.
Standard doses of primaquine may cause
hemolysis or methemoglobinemia (manifested by
cyanosis), especially in persons with G6PD
deficiency or other hereditary metabolic defects.

INHIBITORS OF FOLATE SYNTHESIS

Introduction
Inhibitors of enzymes involved in folate metabolism
are used, generally in combination regimens, for
the treatment and prevention of malaria.
Chemistry & Pharmacokinetics
Pyrimethamine is a 2,4-diaminopyrimidine related
to trimethoprim
Proguanil is a biguanide derivative

Antimalarial Action & Resistance

A. Antimalarial Action: Pyrimethamine and proguanil
act slowly against erythrocytic forms of susceptible
strains of all four human malaria species
B. Mechanism of Action: Pyrimethamine and
proguanil selectively inhibit plasmodial dihydrofolate
reductase, a key enzyme in the pathway for
synthesis of folate.
Sulfonamides and sulfones inhibit another enzyme
in the folate pathway, dihydropteroate synthase

C. Resistance:
In many areas, resistance to folate antagonists
and sulfonamides is common for P falciparum
and less common for P vivax.
Resistance is due, at least in part, to mutations
in dihydrofolate reductase and dihydropteroate
synthase. Because different mutations may
mediate resistance to different agents, crossresistance is not uniformly seen.

Clinical Uses
a. Chemoprophylaxis:
b. Treatment of Chloroquine-Resistant Falciparum
Malaria
c. Presumptive Treatment of Falciparum Malaria
d. Toxoplasmosis
e. Pneumocystosis

ANTIBIOTICS
Tetracycline and doxycycline are active against erythrocytic
schizonts of all human malaria parasites.
Clindamycin is slowly active against erythrocytic schizonts and
can be used in conjunction with quinine or quinidine in those for
whom doxycycline is not recommended, such as children and
pregnant women.
Azithromycin also has antimalarial activity and is now under
study as an alternative chemoprophylactic drug
Antimalarial activity of fluoroquinolones has been demonstrated,
but efficacy for the therapy or chemoprophylaxis of malaria has
been suboptimal.
Antibiotics also are active against other protozoans.

ATOVAQUONE
Atovaquone, a hydroxynaphthoquinone was
initially developed as an antimalarial but has been
approved by the FDA for the treatment of mild to
moderate P carinii pneumonia
The drug is only administered orally
Atovaquone is an alternative therapy for P carinii
infection, though its efficacy is lower than that of
trimethoprim-sulfamethoxazole

HALOFANTRINE
Halofantrine hydrochloride, a phenanthrene-methanol
related to quinine, is effective against erythrocytic stages of all
four human malaria species. It is not active against hepatic
stages or gametocytes
Halofantrine is rapidly effective against most chloroquineresistant strains of P falciparum, but its use is limited by
irregular absorption and cardiac toxicity
In addition, cross-resistance with mefloquine may occur

ARTEMISININ & ITS DERIVATIVES

Artemisinin (qinghaosu) is a sesquiterpene
lactone endoperoxide , Artemisinin and analogs are
very rapidly acting blood schizonticides against all
human malaria parasites. Artemisinin has no effect
on hepatic stages.
Artemisinin-resistant P falciparum has not yet
been identified.
The antimalarial activity of artemisinin probably
results from the production of free radicals that
follows the iron-catalyzed cleavage of the artemisinin
endoperoxide bridge in the parasite food vacuole.

Approach to the treatment

of malaria

Goodman and Gilmans , The Pharmalogical Basis of

th

TOXOPLASMOSIS

WHAT IS TOXOPLASMOSIS?
Toxoplasmosis is an infection caused by a parasite
most often found in cats and farm animals.
Humans can catch this disease from:
.coming into contact with infected cat feces
. eating raw or undercooked meat thats

infected
. eating contaminated vegetables or fruits
. being born with it

Note: Once a person is infected, the infection

remains in the body for life, usually in an inactive
form. It can reactivate when that persons
immune system is weak.

About 98% of cases of Toxoplasmosis are

acquired through Congenital
Toxoplasmosis

One study showed that 76% of

infants infected with
congenital toxoplasmosis had
ocular lesions, 51% had
neurological involvement, and
26% had either hydrocephalus
(increased intracranial
pressure) or michrocephaly
(small brain). It is evident that
vision problems are very
common with Congenital
Toxoplasmosis.
Once the mother develops
immunity to the organism, all
future pregnancies are
protected from transmission of
the organism.

Signs and Symptoms

1. Toxoplasmosis in an otherwise healthy
person may have no symptoms or only a
few swollen glands usually in the
patients neck.
2. Toxoplasmosis in a person with a
weakened immune system may only
have symptoms of swollen glands, or in
the case of an infection that attacks the
brain and nervous system, the symptoms
may include fever, seizures, headache,
psychosis, and problems with vision,

3. Children born with Toxoplasmosis, which

accounts for about 98% of cases, may show
symptoms including:
Fever
Swollen glands
Jaundice
An unusually large or small head
Rash
Bruises or bleeding under the skin
Anemia
Enlarged liver or spleen
Seizures
Limp muscle tone
Mental retardation
Hearing loss
Vision problems (toxoplasmosis of the eye)

Treatment
Treatment will not result in the elimination
of the organism from the eye. Since new
lesions can form if the organism
reactivates, especially during
adolescence, patients should be closely
monitored.
Medications:
Spiramycin during pregnancy
Antibiotics and steroid tablets during an

infection
Pyrimethamine/sulphadoxine for 6-12 months
as follow-up procedure

Anthelmintic Drugs

Anthelmintics are drugs that act either

locally within the gut lumen to cause
expulsion of worms from the GI tract,
or systemically against helminths
residing outside the GI tract

The major soil-transmitted helminths (STH)

infections (ascariasis [roundworm], trichuriasis
[whipworm], and hookworm infection) are among
the most prevalent infections in developing
countries
Because STH worm burdens are higher in schoolaged children than in any other single group, the
WHO advocate school-based administration of
broad-spectrum anthelmintics on a periodic and
frequent basis

Benzimidazoles (BZAs)
thiabendazole, mebendazole, and albendazole
Mechanism of action
inhibition of microtubule polymerization by
binding to -tubulin
Drug resistance in nematodes may involve
expression of a mutated -tubulin

Mechanisme of action mebendazole and other

Benzimidazole

PK/PD
Thiabendazole
Absorbed rapidly after oral ingestion. A
fatty meal enhances absorption
Reaches peak plasma concentrations
after 1 hour
Excreted in the urine within 24 hours as 5hydroxythiabendazole, conjugated either
as the glucuronide or the sulfate

Mebendazole
Tablet formulations of mebendazole are poorly
and erratically absorbed, and plasma
concentrations are low
The low systemic bioavailability (22%) of
mebendazole results from a combination of poor
absorption and rapid first-pass hepatic
metabolism

THERAPEUTIC USES
Thiabendazole generally has been replaced by
newer agents
Mebendazole always is taken orally, and the same
dosage schedule applies to adults and children >2
years of age. For treatment of enterobiasis, a
single 100-mg tablet is taken, repeated after 2
weeks

 For

control of ascariasis, trichuriasis, or

hookworm infections, the recommended
regimen is 100 mg of mebendazole taken in the
morning and evening for 3 consecutive days (or
a single 500-mg tablet administered once)
If the patient is not cured 3 weeks after
treatment, a second course should be given.
The 3-day mebendazole regimen is more
effective than single doses of either
mebendazole (500 mg) or albendazole (400 mg)

Albendazole

For treatment of enterobiasis, ascariasis, trichuriasis,

and hookworm, taken as a single oral 400-mg dose by
adults and children >2 years of age.
In children between the ages of 12 and 24 months, the
WHO recommends a reduced dose of 200 mg.
Cure rates for light-to-moderate Ascaris infections
typically are >97%, although heavy infections may
require therapy for 23 days. A 400-mg dose of
albendazole appears to be superior to a 500-mg dose
of mebendazole for curing hookworm infections.

TOXICITY, SIDE EFFECTS

Thiabendazole

is hepatotoxic and should be used

with caution in patients with hepatic disease
Mebendazole Transient symptoms of abdominal
pain, distention, and diarrhea have occurred with
massive infestation and expulsion of GI worms.
Rare side effects in patients treated with high
doses of mebendazole include allergic reactions,
alopecia, reversible neutropenia, agranulocytosis,
and oligospermia

The most common side

effect is an increase in serum
aminotransferases, which return to
normal upon drug cessation; rarely
jaundice or cholestasis may occur
Liver function tests should be monitored
during protracted albendazole therapy,
and the drug is not recommended for
patients with cirrhosis
Albendazole

Use in Pregnancy
Both

albendazole and mebendazole are

embryotoxic and teratogenic in rats
A review of the risk of congenital
abnormalities from BZAs concluded that
their use during pregnancy is not associated
with an increased risk of major congenital
defects; nonetheless, it is recommended
that treatment should be avoided during the
first trimester of pregnancy.

Use in Young Children

The WHO concluded that the BZAs may be used

to treat children past the first year who are at risk
for adverse consequences caused by STHs; a
reduced dose of albendazole (200 mg) is used in
children between the ages of 1224 months

Praziquantel
a

pyrazinoisoquinoline derivative
Mechanism of Action
low concentrations, it causes increased muscular
activity, followed by contraction and spastic
paralysis
At slightly higher concentrations, praziquantel
causes tegumental damage, which exposes a
number of tegumental antigens. The tegument of
schistosomes seems to be the primary site of
action; the drug causes an influx of Ca2+ across
the tegument via unknown mechanisms

Mechanism of Action Praziquantel

PK/PD
Readily

absorbed after oral administration, and

maximal levels in human plasma occur in 12 hours
The drug is ~80% bound to plasma proteins
Its plasma t is 13 hours but may be prolonged in
patients with severe liver disease, including those
with hepatosplenic schistosomiasis
About 70% of an oral dose of praziquantel is
recovered as metabolites in the urine within 24
hours; most of the remainder is metabolized in the
liver and eliminated in the bile

THERAPEUTIC USES
FDA approved

for therapy of schistosomiasis and

liver fluke infections, but also is used to treat
infections with many other trematodes and
cestodes
Praziquantel is the drug of choice for
schistosomiasis caused by all Schistosoma
species. Although dosage regimens vary, a single
oral dose of 40 mg/kg or three doses of 20 mg/kg
each, given 46 hours apart, generally produce
cure rates of 7095% and consistent reductions
(>85%) in egg counts.

TOXICITY AND SIDE

EFFECT
Abdominal

discomfort, nausea, diarrhea, headache,

dizziness, and drowsiness may occur shortly after taking
praziquantel; these direct effects are transient and doserelated
In neurocysticercosis, inflammatory reactions to
praziquantel may produce meningismus, seizures,
mental changes, and CSF pleocytosis. These effects
usually are delayed in onset, last 23 days, and respond
to symptomatic therapy such as analgesics and
anticonvulsants.
High doses of praziquantel increase abortion rates in rats

kontraindikasi

Praziquantel is contraindicated in ocular

cysticercosis because the host
response can irreversibly damage the
eye

Pyrantel Pamoate
a

broad-spectrum anthelmintic directed

against pinworm, roundworm, and
hookworm infections.
Mechanism of Action :
depolarizing neuromuscular blocking agent
that opens nonselective cation channels
and induces marked, persistent activation
of nicotinic acetylcholine receptors, which
results in spastic paralysis of the worm

PK/PD
Poorly absorbed from the GI tract, a
property that contributes to its
selective action on GI nematodes.
Less than 15% is excreted in the
urine as parent drug and
metabolites. Most of an
administered dose is recovered in
the feces

Side effect, Precaution

Transient

and mild GI symptoms occasionally

are observed, as are headache, dizziness,
rash, and fever.
Pyrantel pamoate use in pregnant patients and
children <2 years of age is not recommended.
Because pyrantel pamoate and piperazine are
mutually antagonistic in their neuromuscular
effects on parasites, they should not be used
together.

DIETHYLCARBAMAZINE
Diethylcarbamazine

is a first-line agent for control and

treatment of lymphatic filariasis and for therapy of
tropical pulmonary eosinophilia caused by W. bancrofti
and Brugia malayi
Mechanism of action :
Diethylcarbamazine appears to exert a direct toxic
effect on W. bancrofti microfilariae; it also kills worms
of adult L. loa and probably adult W. bancrofti and B.
malayi. Diethylcarbamazine may impair intracellular
processing and transport of certain macromolecules to
the helminth plasma membrane.

PK/PD
Absorbed

rapidly from the GI tract.

Peak plasma levels occur within 12
hours, and the plasma t1/2 varies from 2
to 10 hours, depending on urinary pH.
Metabolism is rapid and extensive
Dosage reduction may be required in
people with renal dysfunction or sustained
alkaline urine.

THERAPEUTIC USES
W. Bancrofti, B. Malayi, and B. Timori
The standard regimen for LF has been a 12-day, 72mg/kg
(6 mg/kg/day) course of diethylcarbamazine. A single dose
of 6 mg/kg had comparable macrofilaricidal and
microfilaricidal efficacy to previous regimens. Single-dose
therapy may be repeated every 612 months, as necessary.
Diethylcarbamazine remains the best drug for therapy of
loiasis. Treatment is initiated with test doses of 50 mg (1
mg/kg in children) daily for 23 days, escalating as tolerated
to daily doses of 9 mg/kg in Three doses for a total of 23
weeks.

TOXICITY AND SIDE

EFFECTS
At

<810 mg/kg/daycarbamazine,
including anorexia, nausea, headache,
and vomiting, are rarely severe and
usually disappear within a few days
despite continued therapy

Ivermectin
Mechanism of action :
Avermectins affect a group of glutamategated Cl channels found in nematode
nerve or muscle cells, causing
hyperpolarization and paralysis by
increasing Cl permeability of the cell
membrane

PK/PD
Peak

plasma levels of ivermectin are

achieved 4-5 H
Ivermectin is ~93% bound to plasma
proteins. The drug is extensively
converted by hepatic CYP3A4 to at least
10 metabolites, mostly hydroxylated and
demethylated derivatives.

THERAPEUTIC USES
Onchocerciasis
Single oral doses of ivermectin (150 g/kg) given every
612 months are considered effective, safe, and practical
for reducing the number of circulating microfilariae in
adults and children 5 years of age or older
Lymphatic Filariasis
Single annual doses of ivermectin (400 g/kg) are
effective and safe for mass therapy of infections with W.
bancrofti and B. malayi.
Ivermectin is as effective as diethylcarbamazine for
controlling lymphatic filariasis and can be used in regions
where onchocerciasis, loiasis, or both are endemic.

cutaneous larva migrans

Taken as a single 200-g/kg oral dose,
ivermectin is a first-line drug for treatment of
cutaneous larva migrans
Infections with Intestinal Nematodes
The finding that a single dose of 150200
ivermectin can cure strongyloidiasis is
encouraging, because this drug also is
efcoexisting ascariasis, trichuriasis, and
enterobiasis

Toxicity, Side Effects, and

Precautions
After

treatment of O. volvulus infections with

ivermectin, side effects usually are limited to
pruritus and swollen, tender lymph nodes
Rarely, more severe reactions include high fever,
tachycardia, hypotension, prostration, dizziness,
headache, myalgia, arthralgia, diarrhea, and
edema; these may respond to glucocorticoids
Because of its effects on GABA receptors in the
CNS, ivermectin is contraindicated in conditions
associated with an impaired bloodbrain barrier
(e.g., African trypanosomiasis and meningitis)

Infecting Organism

Drug of Choice

Alternative Drugs

Ascaris lumbricoides
(roundworm)

Albendazole or pyrantel
pamoate or mebendazole

Ivermectin, piperazine

Trichuris trichiura
(whipworm)

Mebendazole or
albendazole

Ivermectin

Necator americanus
(hookworm); Ancylostoma
duodenale (hookworm)

Albendazole or
mebendazole or pyrantel
pamoate

Strongyloides stercoralis
(threadworm)

Ivermectin

Albendazole or
thiabendazole

Enterobius vermicularis
(pinworm)

Mebendazole or pyrantel
pamoate

Albendazole

Trichinella spiralis
(trichinosis)

Mebendazole or
albendazole; add
corticosteroids for severe
infection

Roundworms
(nematodes)

Infecting Organism

Drug of Choice

Alternative Drugs

Roundworms
(nematodes)

Albendazole

Trichostrongylus species

Pyrantel pamoate or
mebendazole

Albendazole

Cutaneous larva migrans

(creeping eruption)

Albendazole or ivermectin

Thiabendazole (topical)

Visceral larva migrans

Albendazole

Mebendazole

Angiostrongylus
cantonensis

Albendazole or
mebendazole

Wuchereria bancrofti
(filariasis); Brugia malayi
(filariasis); tropical
eosinophilia; Loa loa
(loiasis)

Diethylcarbamazine

Onchocerca volvulus
(onchocerciasis)

Ivermectin

Dracunculus medinensis
(guinea worm)

Metronidazole

Thiabendazole or
mebendazole

Capillaria philippinensis
(intestinal capillariasis)

Albendazole

Mebendazole

Ivermectin

Infecting Organism

Drug of Choice

Alternative Drugs

Schistosoma haematobium
(bilharziasis)

Praziquantel

Metrifonate

Schistosoma mansoni

Praziquantel

Oxamniquine

Schistosoma japonicum

Praziquantel

Clonorchis sinensis (liver

fluke); Opisthorchis species

Praziquantel

Albendazole

Paragonimus westermani
(lung fluke)

Praziquantel

Bithionol

Fasciola hepatica (sheep

liver fluke)

Bithionol or triclabendazole

Fasciolopsis buski (large

intestinal fluke)

Praziquantel or niclosamide

Heterophyes heterophyes;
Metagonimus yokogawai
(small intestinal flukes)

Praziquantel or niclosamide

Flukes (trematodes)

Infecting Organism

Drug of Choice

Alternative Drugs

Taenia saginata (beef

tapeworm)

Praziquantel or niclosamide

Mebendazole

Diphyllobothrium latum (fish

tapeworm)

Praziquantel or niclosamide

Taenia solium (pork

tapeworm)

Praziquantel or niclosamide

Cysticercosis (pork
tapeworm larval stage)

Albendazole

Praziquantel

Hymenolepis nana (dwarf

tapeworm)

Praziquantel

Niclosamide, nitazoxanide

Echinococcus granulosus
(hydatid disease);
Echinococcus multilocularis

Albendazole

Tapeworms (cestodes)

Endoparasites and ectoparasites:

therapeutic agents

SEKIAN
TERIMA KASIH !!

Lets make the world around

us better..

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