Malaria: Causes, Symptoms, and Treatment
Anti-malarial drugs
Prof. Anuradha Nischal
Drugs used for
prophylaxis
treatment
and
prevention
of relapse of malaria
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Malaria
Plasmodium
4 species
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Causative agent
Life-cycle of Plasmodium
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Malaria Transmission Cycle
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MOSQUITO
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Signs and symptoms
•
Initial manifestation of malaria are
non-
specific
and resembles to
flu like symptoms
.
•
The presentation includes
headache, fever,
shivering, arthralgia, myalgia.
•
The
paroxysm
which includes
fever spikes,
chills
and
rigors
are classical for malaria
The typical
paroxysmal attack
comprises of three distinct
stages:
a)
Cold
stage-
The onset is with lassitude, headache, nausea
and chilly sensation followed by rigors. The stage lasts for
¼ - 1 hour
b)
Hot
stage-
The patient feels burning hot, the skin is hot
and dry to touch. Headache is intense. Pulse rate is high.
The stage lasts for 2-6 hours
c
)
Sweating
stage-
Fever comes down with profuse
sweating. The pulse rate gets slower, patient feels relieved.
The stage lasts 2-4 hours
These paroxysms have
different frequencies
in
different species of malarial parasites
•
In
P. vivax
and
P. ovale
after every 2 days- Tertian
fever
•
In
P. malariae
after every 3 days- Quartan fever
•
While in
P. falciparum
it recurs in every 36-48
hours
•
These paroxysmal attacks
coincide
with the
release of successive broods of merozites
into
the blood stream.
Relapse Vs Recrudesence
•
Depending upon the cause , recurrence can be
classified either as recrudescence or relapse
•
Recrudescence is when symptoms return after a
symptoms free period. It is due to parasites surviving
in the blood as a result of inadequate or ineffective
treatment.
•
Relapse is when symptoms reappear after the
parasites have been eliminated from blood but persist
as dormant hypnozites in liver cells.
•
Relapse is common in
P.ovale
and
P.vivax
infection
•
Recrudescence is commonly seen in
P.falciparum
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•
Diaminopyrimidines
Pyrimethamine
•
8-Aminoquinoline
Primaquine
Tafenoquine
•
Sulfonamides & sulfone
Sulfadoxine
Sulfamethopyrazine
Dapsone
•
Antibiotics
Tetracyclins
Doxycycline
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.
45 mg single dose
Immediately after clinical cure
Cuts down transmission to mosquito
•
Clinical cure
Terminate the episode of malarial fever
•
Radical cure
eliminate both
hepatic
and
erythrocytic
stages
•
Causal prophylaxis
•
Suppressive propylaxis
Clinical Cure
•
Erythrocytic
schizonticide
is used to terminate
the episode of malarial fever
•
High efficacy
•
Low efficacy
High efficacy
1)
Artemesinin
2)
Chloroquine
3)
Amodiaquine
4)
Quinine
5)
Mefloquine
6)
Halofantrine
7)
Lumifantrine
8)
Atovaquone
Low efficacy
•
Proguanil
•
Pyrimethamine
•
Sulfonamides
•
Tetracyclins
•
Clindamycin
Radical cure
•
Eliminates
both
hepatic
and
erythrocytic
stages
•
Vivax
&
ovale
•
Erythrocytic
schizonticide +
Tissue
schizonticide
CQ + primaquine
•
Chloroquine resistance
Quinine + Doxycycline/clindamycin
+ Primaquine
Artemesinin based combination therapy
+ Primaquine
Causal prophylaxis
•
Pre-erythrocytic
phase which is the
cause
of
malarial infection and clinical attacks is the
target for this purpose
•
Primaquine
is the causal prophylactic for all
species of malaria
Supressive prophylaxis
•
Schizonticides
which suppress the
erythrocytic
phase and thus attacks of
malarial fever can be used as
prophylactics
•
Clinical disease
does not
appear
Supressive prophylaxis
•
CQ:
NOT
used in
INDIA
•
Mefloquine
•
Doxycycline
Supressive prophylaxis
Mefloquine
•
250 mg weekly
•
Starting
week
before
travel
& taken till 4
weeks after return from endemic area for CQ
resistant P. falciparum
Supressive prophylaxis
Doxycycline
•
100 mg daily
•
Starting
day
before travel & taken till 4 weeks
after return from endemic area for CQ
resistant P. falciparum
•
CI
in
pregnant
women
&
children
<8years of
age
Supressive prophylaxis
•
Pregnancy
•
One dose each in second & third trimester
•
1 month gap
•
Pyrimethamine(75
mg)+
sulphadoxine(1500mg
)
•
In areas with high P.f
endemicity
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'
s
b
o
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.
T
o
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d
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m
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d
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a
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s
m
i
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i
o
n
t
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m
o
s
q
u
i
t
o
.
C
H
L
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Q
U
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R
a
p
i
d
l
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a
c
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a
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p
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m
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a
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r
a
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o
f
P
.
f
a
l
c
i
p
a
r
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m
C
o
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t
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s
m
o
s
t
c
l
i
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i
c
a
l
a
t
t
a
c
k
s
i
n
1
-
2
d
a
y
s
w
i
t
h
d
i
s
a
p
p
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1
-
3
d
a
y
s
.
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o
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f
f
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c
t
o
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P
r
e
-
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r
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t
h
r
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o
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p
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t
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l
a
p
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s
i
n
v
i
v
a
x
a
n
d
o
v
a
l
e
m
a
l
a
r
i
a
.
O
n
l
y
f
o
r
c
l
i
n
i
c
a
l
c
u
r
e
.
M
e
c
h
a
n
i
s
m
o
f
a
c
t
i
o
n
:
•
I
t
i
s
a
c
t
i
v
e
l
y
c
o
n
c
e
n
t
r
a
t
e
d
b
y
s
e
n
s
i
t
i
v
e
i
n
t
r
a
-
e
r
y
t
h
r
o
c
y
t
i
c
p
l
a
s
m
o
d
i
a
b
y
a
c
c
u
m
u
l
a
t
i
n
g
i
n
t
h
e
a
c
i
d
i
c
v
e
s
i
c
l
e
s
o
f
t
h
e
p
a
r
a
s
i
t
e
a
n
d
w
e
a
k
l
y
b
a
s
i
c
n
a
t
u
r
e
i
t
r
a
i
s
e
s
t
h
e
v
e
s
i
c
u
l
a
r
p
H
a
n
d
t
h
e
r
e
b
y
i
n
t
e
r
f
e
r
e
s
w
i
t
h
d
e
g
r
a
d
a
t
i
o
n
o
f
h
a
e
m
o
g
l
o
b
i
n
b
y
p
a
r
a
s
i
t
i
c
l
y
s
o
s
o
m
e
s
•
P
o
l
y
m
e
r
i
z
a
t
i
o
n
o
f
t
o
x
i
c
h
a
e
m
e
t
o
n
o
n
t
o
x
i
c
p
a
r
a
s
i
t
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p
i
g
m
e
n
t
h
e
m
o
z
o
i
n
i
s
i
n
h
i
b
i
t
e
d
b
y
f
o
r
m
a
t
i
o
n
o
f
c
h
l
o
r
o
q
u
i
n
e
-
h
e
m
e
c
o
m
p
l
e
x
•
Haeme
itself or its
complex
with chloroquine
then
damages
the
plasmodial membranes
.
Clumping
of pigment and
changes in parasite
membranes follow: death
•
Other related anti-malarials like
amodiaquine
quinine
,
mefloquine
,
lumefantrine
act in an
analogous manner
Resistance
•
Reduced
uptake
and
transport
of chloroquine
to food vacuole of plasmodium.
Pharmacokinetics
•
Oral
•
Widely
distributed
& concentrated in tissues
like liver, spleen, kidney, lungs
(several
hundred-fold),
skin
,
leucocytes
and some
other tissues
•
Its selective accumulation in
retina
is
responsible for the
ocular
toxicity
seen with
prolonged use
•
metabolized by
liver
•
excreted
in urine.
•
The early plasma t
1/2
varies from
3-10
days. Because
of
tight
tissue
binding
, small amounts persist in the
body for
longer
time.
A
d
v
e
r
s
e
E
f
f
e
c
t
s
•
G
I
i
n
t
o
l
e
r
a
n
c
e
N
a
u
s
e
a
,
v
o
m
i
t
i
n
g
,
a
b
d
o
m
i
n
a
l
p
a
i
n
,
h
e
a
d
a
c
h
e
,
a
n
o
r
e
x
i
a
,
m
a
l
a
i
s
e
,
a
n
d
u
r
t
i
c
a
r
i
a
a
r
e
c
o
m
m
o
n
.
D
o
s
i
n
g
a
f
t
e
r
m
e
a
l
s
m
a
y
r
e
d
u
c
e
s
o
m
e
a
d
v
e
r
s
e
e
f
f
e
c
t
s
.
•
T
h
e
l
o
n
g
-
t
e
r
m
a
d
m
i
n
i
s
t
r
a
t
i
o
n
o
f
h
i
g
h
d
o
s
e
s
o
f
c
h
l
o
r
o
q
u
i
n
e
f
o
r
r
h
e
u
m
a
t
o
l
o
g
i
c
d
i
s
e
a
s
e
s
c
a
n
r
e
s
u
l
t
i
n
l
o
s
s
o
f
v
i
s
i
o
n
d
u
e
t
o
r
e
t
i
n
a
l
d
a
m
a
g
e
.
•
C
o
r
n
e
a
l
d
e
p
o
s
i
t
s
m
a
y
o
c
c
u
r
a
f
f
e
c
t
v
i
s
i
o
n
:
r
e
v
e
r
s
i
b
l
e
C
o
n
t
r
a
i
n
d
i
c
a
t
i
o
n
s
&
C
a
u
t
i
o
n
s
•
C
h
l
o
r
o
q
u
i
n
e
c
a
n
p
p
t
a
t
t
a
c
k
s
o
f
s
e
i
z
u
r
e
s
,
p
s
o
r
i
a
s
i
s
o
r
p
o
r
p
h
y
r
i
a
Cautious use
•
Liver damage
•
Severe GI, neurological, retinal & haematological
diseases
•
S
a
f
e
i
n
p
r
e
g
n
a
n
c
y
a
n
d
f
o
r
y
o
u
n
g
c
h
i
l
d
r
e
n
Other actions
•
E. histolytica & Giardia lambia
•
Anti-inflammatory
•
Local irritant
•
Local anaesthetic (on injection)
•
Weak smooth muscle relaxant
•
Anti-histaminic
•
Anti-arrythmic properties
Therapeutic Uses
Chloroquine is the preferred drug for
clinical
cure of
•
Vivax
•
Ovale
•
malariae
+
some
sensitive
falciparum strains
Causes rapid clearance of fever & Parasitaemia
•
Extraintestinal amoebiasis/Hepatic
amoebiasis/Amoebic Liver Abscess
Due to high liver concentrations, it may be used
for
ameobic
abscesses that fail initial therapy
with
metronidazole
.
•
Rheumatoid arthritis
Other uses:
•
Discoid lupus erythematosus
•
Lepra reaction
•
Photogenic reactions
•
Infectious mononucleosis
Resistance
•
Resistance
to chloroquine is now very
common among strains of
P falciparum
and
uncommon but increasing for
P vivax.
•
ACT
•
first line for plasmodium falciparum cases
countrywide.
Oral
•
Chloroquine phosphate: (250 mg = 150 mg base)
•
Vivax & Ovale:
6oo mg base ; followed after 6-8 hrs by 300 mg;
then 300mg daily for two days
•
i.m
local tissue toxicity
•
i.v
no indication
•
Large
intramuscular
injections or rapid
intravenous
infusions
of chloroquine
hydrochloride can result in severe hypotension,
arrythmias & seizures.
Not
recommended.
Amodiaquine
Identical
to chloroquine:
•
mech
•
resistance
•
uses & adverse effects
less
bitter
faster
acting than chloroquine.
•
Widely
used; reduced cost, safety & activity
against chloroquine resistant P. falciparum
•
Reports of toxicities, including
agranulocytosis
, and
hepatotoxicity
(on long
term administration), have
limited
the
use
of
the drug for
prophylaxis(Long
term
).
Not seen with short term use (25-35mg/kg
over 3 days) for
clinical
cure.
•
Can be used for
clinical
cure
of falciparum
malaria with or without CQ resistance
•
X
used for
prophylaxis
•
Combined formulation with
artesunate
has been
recently
approved for use in
uncomplicated
falciparum
malaria
irrespective of CQ resistance
status
preferred in
african
countries
PRIMAQUINE
•
8-aminoquinoline
•
Poor
erythrocytic
schizontocide
not useful for acute attack
•
Highly active against
gametocytes
and
hypnozoites
•
Primary indication
Radical
cure of relapsing (
vivax
) malaria &
ovale
15 mg/kg/day X 2 weeks(
hypnozoites
)
+
CQ
/ another
blood
schizonticide
to eliminate the
erythrocytic phase
•
Gametocidal
for all species of plasmodia.
Cuts
transmission to mosquitoes.
Chloroquine Sensitive Falciparum Malaria:
•
Cq + Primaquine
•
A
single 45 mg dose (As gametocidal)
of
primaquine is given with the curative dose of
chloroquine to kill the
gametes
and cut down
transmission to mosquito.
A
d
v
e
r
s
e
e
f
f
e
c
t
s
Nausea, headache, epigastric pain
And abdominal cramps occasionally
T
o
x
i
c
i
t
y
D
o
s
e
r
e
l
a
t
e
d
h
a
e
m
o
l
y
s
i
s
,
m
e
t
h
-
h
a
e
m
o
g
l
o
b
i
n
a
e
m
i
a
,
t
a
c
h
y
p
n
o
e
a
a
n
d
c
y
a
n
o
s
i
s
;
d
u
e
t
o
t
h
e
o
x
i
d
a
n
t
p
r
o
p
e
r
t
y
o
f
p
r
i
m
a
q
u
i
n
e
.
T
h
o
s
e
w
i
t
h
G
-
6
-
P
D
d
e
f
i
c
i
e
n
c
y
a
r
e
h
i
g
h
l
y
s
e
n
s
i
t
i
v
e
a
n
d
h
a
e
m
o
l
y
t
i
c
a
n
a
e
m
i
a
c
a
n
o
c
c
u
r
e
v
e
n
w
i
t
h
1
5
-
3
0
m
g
/
d
a
y
.
Tafenoquine
•
New
•
Long acting
•
Erythrocytic schizonticide
•
Developed as
single dose anti-relapse drug
for vivax malaria
Mefloquine
•
Chemically related to
quinine
•
Fast acting
Erythrocytic
schizonticidal
Hepatic stage ×
Gametocyte stage ×
•
Mechanism
same as chloroquine
•
Active against chloroquine
sensitive
as well
resistant
P.vivax
and
falciparum
•
Single dose: 15mg/kg controls fever & eliminates
circulating parasites(both P. vivax & pf)
•
Well absorbed orally, absorption enhances by
food
•
Not used parentally
•
Excreted in bile and urine
Therapeutic Uses
Mefloquine is effective
therapy
for many
chloroquine resistant
strains of P falciparum
Chemoprophylactic
drug for most
malaria-
endemic
regions with chloroquine-resistant
strains
Sporadic
resistance
to mefloquine has been
reported from many areas
Current recommendation
•
Shd be used in combination with
artesunate
as
ACT to
prevent
MQ-resistance
for
•
Uncomplicated falciparum malaria
•
CQ resistant &
•
CQ + sulfa-pyrimethamine resistant cases
Prophylaxis
•
5 mg/kg per week
started 1-2 weeks before
travel to areas with
multidrug
resistance
•
250 mg
weekly
•
Available as 250 mg tablet
•
Travelers
to areas with multidrug resistance
•
Not in residents of endemic areas
Interactions:
•
Halofantrine/quinidine/quinine/Cq
given to patients who have received
mefloquine causes
QTc
lengthening-
--
cardiac
arrests
are reported.
•
These drugs
should not be
administered if MQ
has been given less than 12 hrs earlier.
Piperaquine
•
Cq
congener; Mech
same as cq
•
High efficacy,
erythrocytic
schizonticide, with
prolonged action, onset is slow
•
Effective in both CQ sensitive and CQ resistant P.
falciparum malaria
•
Used in
combination
with
DHA
for
resistant
falciparum malaria
•
FDCs
Arterolane + piperaquine
Dihydroartemesinin + piperaquine
Quinine
•
Cinchona bark; SA
•
Erythrocytic
schizontocide for all species of
plasmodia
Pre-erythrocytic stages X
Gametocidal
against P. vivax & P. malariae
+
Primaquine
for
vivax malaria
•
Less
effective
and
more
toxic
than
chloroquine
•
Chloroquine
preferred over quinine
•
Resurgence
:
Most
chloroquine and multidrug-resistant strains
of P. falciparum still respond to it
•
Though effective in terminating an acute attack of
falciparum malaria, it may not prevent
recrudescence
indicating
incomplete
clearance of
the parasites
Doxycycline/clindamycin
is mostly added to it for
complete parasite clearance.
Mechanism of Action:
Same as
chloroquine
•
It is a weak base: gets co
n
centrated in the
acidic food vacuoles
of sensitive plasmodia
•
inhibits polymerization of haeme to hemozoin
•
free haeme
increases(toxic)
or
haeme-quinine complex
damages parasite
membranes and kills it
•
After
oral
administration, quinine is rapidly
absorbed, reaches peak plasma levels in 1–3
hours, and is widely distributed in body
tissues.
•
The use of a
loading
dose in
severe
malaria
allows the achievement of peak levels within a
few hours.
Other Pharmacological actions
•
Intensely
bitter
and
irritant
.
•
Orally it causes
nausea, vomiting, epigastric
discomfort.
•
Injections
can cause pain and local necrosis in
the muscle and thrombosis in the vein.
•
Cardiodepressant
•
Anti-arrythmic
•
Higher dose/rapid i.v.
Hypotension
&
Hypoglycemia
;
CV collapse
•
Hemolysis in G6PD patient
•
Hypersentivity reaction
•
Cinchonism
occurs when plasma concentration is more than
30-60µmol/L.
•
C/B
headache, dizziness,
tinnitus(ringing
sound in
ear), nausea, flushing and
visual
disturbances which
are blurred vision, photophobia, diplopia, night
blindness, altered colour perception , reduced
visual field, optic atrophy ( due to constriction of
retinal blood vessels) and even
blindness
auditory
(tinitus,deafness and vertigo )
disturbances
due
to involvement of the 8
th
th
nerve , vomiting, diarrhea and abdominal
pain.
Auditory and visual disturbances are possibly
due to direct
neurotoxicity
.
•
Cinchonism may be:
a)
Idiosyncratic:
may occur after singles dose
and usually mild type.
b)
Dose dependent:
occur after
large single oral dose
or fast i.v. administration
or prolonged use of therapeutic dose
Therapeutic Uses
(a)
Resistant falciparum malaria
second line(1st : ACT)
7 day
Quinine + doxy/clindamycin regimen
Quinine: 600 mg 8 hrly x 7 days
Doxy: 100 mg daily x 7 days
Clinda: 600 mg 12 hrly x 7 days
(a)
Complicated
and
severe
malaria including
cerebral
malaria
Quinine (i.v.) has been used as the
drug of choice
for
cerebral
malaria and other forms of
complicated malaria
20mg/kg(loading dose) diluted in 5 % dextrose
saline and infused i.v over 4 hrs.
Switch oral:10 mg /kg 8 hrly to complete a 7 day
course
Currently
artemisin
compounds are preferred and
used by parental route
B
I
G
U
A
N
I
D
E
S
P
r
o
g
u
a
n
i
(
C
h
l
o
r
o
g
u
a
n
i
d
e
)
:
s
l
o
w
-
a
c
t
i
n
g
e
r
y
t
h
r
o
c
y
t
i
c
s
c
h
i
z
o
n
t
o
c
i
d
e
,
a
l
s
o
i
n
h
i
b
i
t
s
t
h
e
p
r
e
e
r
y
t
h
r
o
c
y
t
i
c
s
t
a
g
e
o
f
P.F alciparum. Do not kill gametocytes but inhibit their
development in the mosquito.
M
e
c
h
a
n
i
s
m
o
f
a
c
t
i
o
n
:
I
t
i
s
c
y
c
l
i
z
e
d
i
n
t
h
e
b
o
d
y
t
o
c
y
c
l
o
g
u
a
n
i
l
w
h
i
c
h
i
n
h
i
b
i
t
s
p
l
a
s
m
o
d
i
a
l
D
H
F
R
a
s
e
i
n
p
r
e
f
e
r
e
n
c
e
t
o
t
h
e
m
a
m
m
a
l
i
a
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Current use of proguanil is restricted to prophylaxis of malaria in
combination with chloroquine in areas of low level chloroquine
resistance among P. falciparum. Safe during during pregnancy.
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If used alone, resistance develops rather rapidly by
mutation in the DHFRase enzyme of the parasite
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Efficacy against P. vivax is rather low.
As clinical curative:
•
Sulfadoxine 1500 mg +
pyrimethamine 75 mg
(3 tab) single dose
Children
•
9-14 yr 2 tab
•
4-8 yr 1 tab
•
1-4 yr ½
tab
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FDC
•
Artesunate - sulfadoxine+pyrimethamine
•
First line drug for uncomplicated falciparum
malaria under the “National anti-malaria
drug policy” of India.
•
Replaced
chloroquine
throughout the country.
T
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•
All plasmodial species: Cq, MQ, S/P resistant P.
falciparum
•
Never used alone
•
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Artemesinin
•
Potent
and
rapid
erythrocytic schizonticide
•
Quick
defervescense and parasitemia
clearance(<48 hr)
•
Quinghaosu
; Artemesia annua
•
It is active against
P. falciparum resistant to all
other anti-malarial
drugs as well as
sensitive
strains of
other
malarial
species
•
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Artemesinin
•
Poorly soluble in water & oil
•
Derivatives
•
Artemether:
soluble in oil; oral; i.m
•
Artesunate:
water soluble; oral; i.m + i.v
•
Active metabolite generated in the body
DHA is also
used orally
•
Arte-ether
(injectable; i.m in oil) was produced in India
•
Arterolane :
totally synthetic has been developed here
•
Collectively k/a
Artemesinins
•
Duration of action:
short
•
Recrudescence
rate is high
•
When used alone in short courses
•
Used
only
in
combination
•
Artemisinin Based Combination
Therapy
Artemisinin Based Combination Therapy
•
Most important consideration ----
Elimination t
1/2
•
Effective concentrations in blood must be
maintained for at least 3-4 asexual cycles of the
parasite, i.e. 6-8 days, to exhaust the parasite
burden.
•
Therefore,
short t
1/2
drugs
given for
7 days
longer acting drugs
given for
1-3 days
•
Risk of de facto monotherapy --- Therefore
choose a short t
1/2
drug that reduces the parasite
load rapidly and drastically such as artemisinin
compounds.
Artesunate-sulfadoxine + Pyrimethamine
•
First line drug for uncomplicated falciparum
malaria.
Artesunate-mefloquine
•
Highly effective
and well tolerated in
uncomplicated falciparum malaria
Artemether-lumefantrine
Both protect each other from plasmodial
resistance
High clinical efficacy
Active even in
multidrug
resistant
Plasmodium
falciparum areas
Artemether – Quickly reduces parasite biomass
and resolves symptoms
Lumefantrine – Prevents recrudescence
Gametocyte population is checked
Artesunate-amodiaquine
•
First
line
therapy of uncomplicated falciparum
malaria in many
African
countries
•
Dihydroartemisinin-piperaquine
•
Piperaquine with DHA in a dose ratio of 8:1
•
>98% response rate
in
uncomplicated
falciparum
malaria
in India
•
Likely to be approved soon
•
Safe combination
•
Well tolerated even by
children
Arterolane-piperaquine
•
Arterolane acts rapidly at all stages of asexual
schizogony of malarial parasite including
multidrug resistant
Plasmodium falciparum but
has no effect on hepatic stages
•
Arterolane accumulates in the food vacuole of
the parasite, and thus differs from other
artemisinins.
•
For vivax : ACT + primaquine
Artesunate-pyronaridine
•
Dose ratio is 1:3
•
>95% cure rate
•
Well tolerated
•
Not yet approved in India
Artesunate
•
Its sodium salt is water-soluble and is
administered by oral, i m or i v. Routes.
•
After oral ingestion, absorption is incomplete but
fast, reaching peak in <60 min.
•
Prodrug
: It is rapidly converted to the active
metabolite
dihydroartemisinin
(
DHA
) with a t1/2
of 30-60 min. The t1/2 of DHA is 2-4 hours.
•
After repeated dosing, artesunate causes
autoinduction of its own metabolism
Artemether
•
It is lipid-soluble and is administered orally or
i.m., but
not
i.v.
•
Oral absorption is slower taking 24 hours, but
is enhanced by food.
•
Prodrug
: It undergoes substantial first pass
metabolism and is converted to
DHA
.
Extensive metabolism by CYP3A4 yields a
variable 1/2 of 3-10 hours.
Arteethe
r
•
This compound developed in India has been
released for institutional use only, for i.m
administration in
complicated/cerebral
malaria.
Because of its longer elimination t1/2
(23 hours), it is effective in a 3 day schedule
with a recrudescence rate of 57%.
•
Dose: 1,50 mg i m daily for 3 days in adults.
FM during
Pregnancy
•
Serious
•
Prompt treatment
•
Quinine + Clindamycin
(7d)
300mg tds x 7days+ 300mg tds/qid x 7 days
All trimesters; especially
first
•
ACT
(3d) is better tolerated
three
day
regimen
But:
second & third
trimesters
Severe & complicated falciparum
malaria
Malaria+ 1/more of the
following
•
Hyperparasitaemia
•
Hyperpyrexia
•
Fluid & electrolyte
imbalance
•
Acidosis
•
Hypoglycaemia
•
Prostration
•
CV Collapse
•
Jaundice
•
Severe anaemia
•
Spontaneous bleeding
•
Pulmonary edema
•
Haemoglobinuria
•
Black water fever
•
Renal failure
•
Cerebral malaria
•
Parenteral drugs have to be used
•
Oral on improvement
•
I.m.
artemesinins
are preferred
i.v artesunate (NVBDCP)
•
Quinine
replaced
: used only when
artemesinins cannot be used
Pregnancy: 1
st
trimester
Summary
Uncomplicated malaria
•
Viva/Ovale/Malariae
•
CQ + Primaquine (
hypnozoites
)
•
Quinine + Doxy/Clinda + Primaquine (2
nd
line)
Or,
•
ACT + Primaquine
Falciparum
Cq Sensitive FM
•
CQ + Primaquine(G)
Cq Resistant FM
•
Artesunate + SP
•
Artesunate + Mefloquine
•
Artemether + Lumefantrine
•
Arterolane + Piperaquine
•
Quinine + Doxy/Clinda
•
Uncomplicated & Severe Falciparum malaria
•
Artesunate
•
Artemether
•
Arteether
•
Quinine
•
Thank You
PHARMACOKINETICS OF
CHLOROQUINE
•
Chloroquine is well absorbed on oral
administration from GIT while absorption
from i.m or s.c route is rapid.
•
After absorption it is widely distributed and
gets concentrated in various tissues like spleen,
kidney, lungs and melanin containing cells.
•
Its apparent volume of distribution is 13000
litres
•
Its t1/2 gets prolonged upto 214 hours
•
Due to wide distribution in various tissues and
extensive binding and long plasma half life the high
initial dose or loading dose is required so as to achieve
the therapeutic concentration in plasma and early
steady state concentration.
•
60% of drug is plasma protein bound
•
During metabolism it gets converted to
desethylchloroquine and bisdesethylchloroquine by
cytochrome P- 450 in liver.
•
The systemic elimination of chloroquine is 50% and the
remaining 50% is elminated by renal route.
•
When chloroquine is administered by the
parentral route, its entry is rapid and removal
is slow and this may lead to toxic
concentration which may prove fatal.
Therefore to prevent this problem whenever
chloroquine has to be administered by
parentral route it sholud be given as :
•
i.v route- slow infusion; s.c / i.m – small
divided doses
•
Oral route is safer as the absorption and
distribution correlates closely.
•
The peak plasma concentration is achieved in
3-5 hours after oral administration.
PHARMACOKINECTICS
unnati
•
Chloroquine is well absorbed on oral administration
from GIT and absorption on i.m. or s.c.
administration is rapid .
•
Chloroquine after absorption is widely distributed
and concentration in various tissues like liver, spleen,
kidney, lung and melanin. Distribution also occur in
brain and spinal cord
•
Thus , it has large apparent volume of distribution
which is about 13000 liters in an adult.
•
Chloroquine T1/2 is also prolonged about 214 h. Due
to wide distribution in various tissues and extensive
binding and long plasma half life the high initial dose
or loading dose is required so as to achieve the
therapeutic concentration in plasma and early steady
state concentration.
•
About 60% of the drug is bound to plasma proteins .
•
During metabolism chloroquine is converted into two
active metabolites which are desethylchoroquine
and bisdesethylchoroquine by cytochrome P-450 in
liver .
•
The systemic elimination of chloroquine is about 50%
and remaining amount is eliminated by the renal
route . By renal route 50% of chloroquine is excreted
unchanged while 25% as metabolite and remaining
in unchanged form .
•
when chloroquine is administered by the parenteral
route, its entry is rapid and removal is slow and this
may lead to toxic concentration which may prove
fatal. Therefore , to prevent this problem whenever
chloroquine has to be administered by parenteral
route it should be given as follows.
I.V route – slow infusion ;
S.C/ I.M – small divided doses.
•
Oral route is safer as the absorption and distribution
correlated closely. The peak concentration is
achieved in 3-5 hours after oral administration ..
•
As the concentration of drug falls the elimination
becomes slower and the half life is increased from
few days to few weeks. The terminal half life is about
30-60 hours.
Malaria, caused by the Plasmodium parasite and transmitted through the bite of infected mosquitoes, is a major global health concern leading to millions of illnesses and deaths annually. The life cycle of the parasite involves different stages in the human host and the mosquito vector. Effective anti-malarial drugs are crucial for prophylaxis, treatment, and prevention of relapse. Awareness of the transmission cycle is essential for combatting this deadly disease.
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Anti-malarial drugs Prof. Anuradha Nischal
Drugs used for prophylaxis treatment and prevention of relapse of malaria
Malaria Most important parasitic disease of humans, causing hundreds of millions of illnesses and probably over a million deaths each year.
Causative agent Plasmodium 4 species 1) P. vivax (tertian) 2) P. falciparum (tertian) 3) P. ovale (tertian) 4) P. malariae(quartian)
Malaria is transmitted by the bite of infected femaleanopheles mosquitoes. During feeding, mosquitoes inject sporozoites, which circulate to the liver, and rapidly infect hepatocytes, causing asymptomatic liver infection (hepatic phase)(absent in falciparum; malariae) Merozoites released from the liver, rapidly infect erythrocytes to begin the asexual erythrocytic stage of infection that is responsible for human disease Multiplerounds of erythrocytic development, with production of merozoites that invade additional erythrocytes, lead to large numbers of circulating parasites and clinical illness
Release of merozoites subsequent to rupture of erythrocytes causes the clinicalattack of malaria. Some erythrocytic parasites also develop into sexual gametocytes, which are infectious to mosquitoes, allowing completion of the life cycle and infection of others In P vivaxand P ovaleparasites also form dormant liver hypnozoites, which are not killed by most drugs, allowing subsequent relapses of illness after initial elimination of erythrocytic infections
Malaria Transmission Cycle Exo-erythrocytic (hepatic) Cycle: Sporozoites infect liver cells and develop into schizonts, which release merozoites into the blood Sporozoires injected into human host during blood meal Parasites mature in mosquito midgut and migrate to salivary glands Dormant liver stages (hypnozoites) of P. vivax and P. ovale HUMAN MOSQUITO Erythrocytic Cycle: Merozoites infect red blood cells to form schizonts Some merozoites differentiate into male or female gametocyctes Parasite undergoes sexual reproduction in the mosquito
Signs and symptoms Initial manifestation of malaria are non- specific and resembles to flu like symptoms. The presentation includes headache, fever, shivering, arthralgia, myalgia. The paroxysm which includes fever spikes, chills and rigors are classical for malaria
The typical paroxysmal attack comprises of three distinct stages: a) Coldstage- The onset is with lassitude, headache, nausea and chilly sensation followed by rigors. The stage lasts for - 1 hour b) Hotstage- The patient feels burning hot, the skin is hot and dry to touch. Headache is intense. Pulse rate is high. The stage lasts for 2-6 hours c) Sweatingstage- Fever comes down with profuse sweating. The pulse rate gets slower, patient feels relieved. The stage lasts 2-4 hours
These paroxysms have different frequencies in different species of malarial parasites In P. vivax and P. ovale after every 2 days- Tertian fever In P. malariae after every 3 days- Quartan fever While in P. falciparum it recurs in every 36-48 hours These paroxysmal attacks coincide with the release of successive broods of merozites into the blood stream.
Relapse Vs Recrudesence Depending upon the cause , recurrence can be classified either as recrudescence or relapse Recrudescence is when symptoms return after a symptoms free period. It is due to parasites surviving in the blood as a result of inadequate or ineffective treatment. Relapse is when symptoms reappear after the parasites have been eliminated from blood but persist as dormant hypnozites in liver cells. Relapse is common in P.ovale and P.vivax infection Recrudescence is commonly seen in P.falciparum
Classification 1) 4-Aminoquinolines Chloroquine 2) Quinoline methanol Mefloquine Amodiaquine 3) Cinchona alkaloid Quinine Quinidine 4) Biguanides Proguanil (Chloroguanide)
Diaminopyrimidines 8-Aminoquinoline Sulfonamides & sulfone Sulfadoxine Antibiotics Pyrimethamine Primaquine Tafenoquine Sulfamethopyrazine Dapsone Tetracyclins Doxycycline
Sesquiterpine lactones Artesunate Artemether Arteether Halofantrine Lumefantrine Amino alcohols Pyronaridine Naphthyridine Naphthoquinone Atovaquone
Tissue schizonticides That eliminate pre erythrocytic/exo-erythrocytic stages in liver Erythrocytic schizonticides act on erythrocytic parasites Gametocides kill gametocytes in blood and prevent transmission to mosquitoes
Tissue schizonticides Primaquine: 15 mg/kg/day X 2 weeks(hypno) Proguanil Doxycycline Gametocides Primaquine gametocidal for all species. 45 mg single dose Immediately after clinical cure Cuts down transmission to mosquito
Clinical cure Terminate the episode of malarial fever Radical cure eliminate both hepatic and erythrocytic stages Causal prophylaxis Suppressive propylaxis
Clinical Cure Erythrocytic schizonticide is used to terminate the episode of malarial fever High efficacy Low efficacy
High efficacy Low efficacy 1) Artemesinin 2) Chloroquine 3) Amodiaquine 4) Quinine 5) Mefloquine 6) Halofantrine 7) Lumifantrine 8) Atovaquone Proguanil Pyrimethamine Sulfonamides Tetracyclins Clindamycin
Radical cure Eliminates bothhepatic and erythrocytic stages Vivax & ovale Erythrocytic schizonticide + Tissue schizonticide CQ + primaquine
Chloroquine resistance Quinine + Doxycycline/clindamycin + Primaquine Artemesinin based combination therapy + Primaquine
Causal prophylaxis Pre-erythrocytic phase which is the cause of malarial infection and clinical attacks is the target for this purpose Primaquine is the causal prophylactic for all species of malaria
Supressive prophylaxis Schizonticides which suppress the erythrocytic phase and thus attacks of malarial fever can be used as prophylactics Clinical disease does not appear
Supressive prophylaxis CQ: NOT used in INDIA Mefloquine Doxycycline
Supressive prophylaxis Mefloquine 250 mg weekly Starting week before travel & taken till 4 weeks after return from endemic area for CQ resistant P. falciparum
Supressive prophylaxis Doxycycline 100 mg daily Starting day before travel & taken till 4 weeks after return from endemic area for CQ resistant P. falciparum CI in pregnantwomen & children <8years of age
Supressive prophylaxis Pregnancy One dose each in second & third trimester 1 month gap Pyrimethamine(75 mg)+ sulphadoxine(1500mg) In areas with high P.f endemicity
Goal To prevent and treat clinical attack of malaria. To completely eradicate the parasite from the patient's body. To reduce the humanreservoir of infection - cut down transmission to mosquito.
CHLOROQUINE Rapidly acting erythrocytic schizontocide against all species of plasmodia including the senstive strains of P. falciparum Controls most clinical attacks in 1-2 days with disappearance of parasites from peripheral blood in 1-3 days. No effect on Pre-erythrocytic and exo-erythrocytic phases of the parasite does not prevent relapses in vivax and ovale malaria. Only for clinical cure.
Mechanism of action: It is activelyconcentrated by sensitiveintra- erythrocytic plasmodia by accumulating in the acidic vesicles of the parasite and weakly basic nature it raises the vesicular pH and thereby interferes with degradation of haemoglobin by parasiticlysosomes Polymerization of toxic haeme to nontoxic parasite pigment hemozoin is inhibited by formation of chloroquine-heme complex
Haeme itself or its complex with chloroquine then damages the plasmodial membranes. Clumping of pigment and changes in parasite membranes follow: death Other related anti-malarials like amodiaquine quinine, mefloquine, lumefantrine act in an analogous manner
Resistance Reduceduptake and transport of chloroquine to food vacuole of plasmodium.
Pharmacokinetics Oral Widely distributed & concentrated in tissues like liver, spleen, kidney, lungs (several hundred-fold), skin, leucocytes and some other tissues Its selective accumulation in retina is responsible for the oculartoxicity seen with prolonged use
metabolized by liver excreted in urine. The early plasma t1/2varies from 3-10 days. Because of tighttissuebinding, small amounts persist in the body for longer time.
Adverse Effects GI intolerance Nausea, vomiting, abdominal pain, headache, anorexia, malaise, and urticaria are common. Dosing after meals may reduce some adverse effects. The long-term administration of high doses of chloroquine for rheumatologic diseases can result in loss of vision due to retinal damage. Cornealdeposits may occur affect vision: reversible
Contraindications & Cautions Chloroquine can ppt attacks of seizures, psoriasis or porphyria Cautious use Liver damage Severe GI, neurological, retinal & haematological diseases Safe in pregnancy and for young children
Other actions E. histolytica & Giardia lambia Anti-inflammatory Local irritant Local anaesthetic (on injection) Weak smooth muscle relaxant Anti-histaminic Anti-arrythmic properties
Therapeutic Uses Chloroquine is the preferred drug for clinical cure of Vivax Ovale malariae + some sensitivefalciparum strains Causes rapid clearance of fever & Parasitaemia
Extraintestinal amoebiasis/Hepatic amoebiasis/Amoebic Liver Abscess Due to high liver concentrations, it may be used for ameobic abscesses that fail initial therapy with metronidazole. Rheumatoid arthritis Other uses: Discoid lupus erythematosus Lepra reaction Photogenic reactions Infectious mononucleosis
Resistance Resistance to chloroquine is now very common among strains of P falciparumand uncommon but increasing for P vivax. ACT first line for plasmodium falciparum cases countrywide.
Oral Chloroquine phosphate: (250 mg = 150 mg base) Vivax & Ovale: 6oo mg base ; followed after 6-8 hrs by 300 mg; then 300mg daily for two days i.m local tissue toxicity i.v no indication Large intramuscular injections or rapid intravenousinfusions of chloroquine hydrochloride can result in severe hypotension, arrythmias & seizures. Not recommended.
Amodiaquine Identical to chloroquine: mech resistance uses & adverse effects less bitter faster acting than chloroquine. Widely used; reduced cost, safety & activity against chloroquine resistant P. falciparum
Reports of toxicities, including agranulocytosis, and hepatotoxicity (on long term administration), have limited the use of the drug for prophylaxis(Longterm). Not seen with short term use (25-35mg/kg over 3 days) for clinical cure.
Can be used for clinical cure of falciparum malaria with or without CQ resistance X used for prophylaxis Combined formulation with artesunate has been recently approved for use in uncomplicated falciparum malaria irrespective of CQ resistance status preferred in african countries
PRIMAQUINE 8-aminoquinoline Poorerythrocyticschizontocide not useful for acute attack Highly active against gametocytes and hypnozoites
Primary indication Radical cure of relapsing (vivax) malaria & ovale 15 mg/kg/day X 2 weeks(hypnozoites) + CQ/ another bloodschizonticide to eliminate the erythrocytic phase Gametocidal for all species of plasmodia. Cuts transmission to mosquitoes.
Chloroquine Sensitive Falciparum Malaria: Cq + Primaquine A single 45 mg dose (As gametocidal) of primaquine is given with the curative dose of chloroquine to kill the gametes and cut down transmission to mosquito.
