CHEMOTHERAPY OF MALARIA

INTRODUCTION
o Malaria is a mosquito-borne infectious disease caused by
intracellular protozoan parasite Plasmodium. •
Characterized by cycles of shaking, chills, fever,
sweating and anaemia. (Malaria is an acute infectious
disease is caused by various species of plasmodia
(parasites), which are carried by the female anopheles
mosquito)
 Four species of Plasmodium typically cause
human malaria.
 Plasmodium falciparum
 P. vivax
 P. malariae
 P. ovale
 All forms are transmitted by the infective bite of
female Anopheles mosquitoes. • Transmission
through blood transfusion can also occur. • Man
develops disease after 10 to 14 days of being bitten
by an infective mosquito.
LIFECYCLE OF PLASMODIUM
 2 stages
1) Sexual phase in the mosquito
2) Asexual phase in humans
a) Exoerthrocytic (Pre-erythrocytic)
shizogony
b) Erythrocytic shizogony

The infectious stage of malaria - Sporozoite(found in the

salivary glands of female mosquitoes)
LIFE CYCLE IN HUMANS
Mosquito takes a blood meal → Sporozoites
released into human’s blood → infect liver cells
EXO-ERYTHROCYTIC STAGE :-
 Parasites inside hepatocyte → Shizont
(containing thousands of merozoites) → infected
hepatocytes release about 30,000 Merozoites
(asexual, haploid forms) → quickly infect red
cells.
* [P. vivax and P. ovale form latent Hypnozoites in
hepatocytes, which cause relapses of malaria long
after initial infection]
ERYTHROCYTIC STAGE
 Within the red cells the parasites grow in a
membrane-bound digestive vacuole, hydrolyzing
haemoglobin through secreted enzymes.
A) Continuation of asexual reproduction -
Most of the parasites develop into Trophozoites →
Schizont → multiple chromatin in schizonts
develop into Merozoites → Red cell lysis &
merozoites infect other red cells.
B) Production of gametocytes - Some parasites
develop into sexual forms called Gametocytes →
infect the mosquito.
 OBJECTIVES AND USE OF
ANTIMALARIALS
 The aims of using drugs in relation to malarial
infection are:
(i) To prevent and treat clinical attack of
malaria.
(ii) To completely eradicate the parasite from
the patient’s body.
(iii) To reduce the human reservoir of infection
— cut down transmission to mosquito.
 These are achieved by attacking the parasite at the
various stages of life cycle in the human host .
DRUGS USED IN MALARIA

 Antimalarials that act on erythrocytic schizogony are

called erythrocytic schizontocides, those that act on
preerythrocytic as well as exoerythrocytic (P. vivax)
stages in liver are called tissue schizontocides, while
those which kill gametocytes in blood are called
gametocides.
o Tissue schizontocides- drugs eliminating developing or
dormant liver forms
 Blood schizontocides- drugs acting on erythrocytic
parasites
 Gametocides- drugs that kill sexual stages and prevent
transmission to mosquitoes
FORMS OF ANTIMALARIAL DRUGS
 Clinically malarial infections can be controlled by
the drugs used in following ways:
1.Causal prophylaxis
2. Suppressive prophylaxis
3. Clinical cure
4. Radical cure
5. Gametocidal
OBJECTIVES AND USE OF
ANTIMALARIALS
 The aims of using drugs in relation to malarial
infection are:
(i) To prevent and treat clinical attack of
malaria.
(ii) To completely eradicate the parasite from
the patient’s body.
(iii) To reduce the human reservoir of infection
— cut down transmission to mosquito.
 These are achieved by attacking the parasite at
1. CAUSAL PROPHYLAXIS
 Drugs prevent the maturation of or destroy the
sporozoites within the infected hepatic cell- thus
prevent erythrocytic invasion
 Primaquine – for all species of malaria but not
used due to its toxic potential
 Proguanil- primarily for P. falciparum and not
effective against P. vivax (weak activity), rapid
development of resistance
2. SUPPRESSIVE PROPHYLAXIS
 Schizontocides inhibit erythrocyte phase and
prevent the rupture of the infected erythrocytes,
lead to freedom from rigors and pyrexia
 Includes quinine, chloroquine, proguanil,
pyrimethamine, artemicinin and tetracycline
3. CLINICAL CURE
 Erythrocytic schizontocides are used to terminate
episodes of malarial fever
 Fast acting high efficacy drugs:
 Chloroquine, quinine, mefloquine, halofantrine,
artemicinin
 Used singly to treat malaria fever
 Faster acting, preferably used in falciparum
malaria where delayed treatment may lead to
death even if parasites are clear from blood
 Slow acting low efficacy drugs:
 Proguanil, pyrimethamine, sulfonamides,
tetracyclines
 Used only in combination
4. RADICAL CURE

 Drug attack exoerythrocytic stage (hypnozoites)

given with clinical curative for the total
eradication of the parasite from the patient’s
body
 • Radical cure of the P. falciparum malaria can
be achieved by suppressives only
 For radical cure of P.vivax infection, primaquine
and proguanil are effective
5. GAMETOCIAL
 Removal of male and female gametes of
Plasmodia formed in the patient’s blood
 Primaquine and artemisinins are highly effective
against gametocytes of all species
ACCORDING TO ANTI MALARIAL
ACTIVITY:

1.Tissue schizonticides for causal

prophylaxis: These drugs act on the primary
tissue forms of the plasmodia which after growth
within the liver, initiate the erythrocytic stage. By
blocking this stage, further development of the
infection can be theoretically prevented.
Pyrimethamine and Primaquine have this activity.
However since it is impossible to predict the
infection before clinical symptoms begin, this mode
of therapy is more theoretical than practical.
2.Tissue schizonticides for preventing
relapse: These drugs act on the hypnozoites of P.
vivax and P. ovale in the liver that cause relapse of
symptoms on reactivation. Primaquine is the
prototype drug; pyrimethamine also has such
activity.
3.Blood schizonticides: These drugs act on the
blood forms of the parasite and thereby terminate
clinical attacks of malaria. These are the most
important drugs in anti malarial chemotherapy.
These include chloroquine, quinine, mefloquine,
halofantrine, pyrimethamine, sulfadoxine, sulfones,
tetracyclines etc.
4.Gametocytocides: These drugs destroy the
sexual forms of the parasite in the blood and
thereby prevent transmission of the infection to the
mosquito. Chloroquine and quinine have
gametocytocidal activity against P. vivax and P.
malariae, but not against P. falciparum.
Primaquine has gametocytocidal activity against
all plasmodia, including P. falciparum.
5.Sporontocides: These drugs prevent the
development of oocysts in the mosquito and thus
ablate the transmission. Primaquine and
chloroguanide have this action.
 Thus in effect, treatment of malaria would
include a blood schizonticide, a gametocytocide
and a tissue schizonticide (in case of P.
vivax and P. ovale). A combination of chloroquine
and primaquine is thus needed in ALL cases of
malaria.
CHLOROQUINE (CQ)

 Rapidly acting erythrocytic schizontocide against

all species of Plasmodia
 Drug of choice for treating acute attacks caused
by sensitive strains of P. vivax or P. falciparum
 Controls most clinical attack in 1-2days with
disappearance of parasite from peripheral blood
in 1-3days
 No effect on exo- erythrocytic phase

 Neither prevent primary infection nor relapse in

P. vivax and P.ovale
 Drug of choice for use in pregnancy, prophylaxis
MECHANISM OF ACTION
 i. The parasite digests the host cell’s hemoglobin
to obtain essential amino acids
 ii. The process releases large amounts of heme,
which is toxic to the parasite
 iii. To protect itself the parasite ordinarily
polymerizes the heme to nontoxic hemozoin,
which is sequestered in the parasite’s food
vacuole
 iv. Cholroquine prevents the polymerization to
hemozoin
 v. The accumulation of heme results in lysis of
both the parasite and the red blood cell
PHARMACOKINETICS
 Rapidly and completely absorbed from GI tract
 Substantial amount is deposited in erythrocytes,
liver, spleen, kidney, lung, melanin containing
tissues and leukocytes
 Slow release from these sites helps in
maintaining the
 therapeutic plasma levels – when used for
prophylaxis, it is administered just once a week
 Also crosses the blood- brain barrier and
traverses the placenta
 • Excreted predominantly in the urine
ADVERSE EFFECTS
CNS- mild headache, confusion, psychosis,
convulsion, impaired hearing
• Eye (with high dose)- loss of vision due to
retinal damage, reversible corneal damage
• GIT- Nausea, vomiting, anorexia, epigastric
pain, diarrhea( can be minimized by taking
with meal)
• Skin- uncontrolled itching, urticaria,
exfoliative dermatitis
• Parenteral administration- Hypotension,
cardiac arrhythmias, cardiac depression
USES
 Extraintestinal amoebiasis
 • Rheumatoid arthritis

 • Discoid lupus erythematosus

 • Lepra reaction

 • Photogenic reactions

 • Infectious mononucleosis
CONTRAINDICATIONS
 Patient with psoriasis, porphyria
 • In dermatitis, liver damage, alcoholism,
neurological, retinal and hematological diseases
QUININE
 Quinine is a l-isomer of alkaloid obtained from
cinchona bark and quinidine (antiarrhythmic) is
its d-isomer
 • An effective erythrocytic schizontocide as
suppressive and used to prevent or terminate
attacks of vivax, ovale, malariae, sensitive
falciparum
 • Moderately effective against hepatic form
(preexoerythrocyte and gametocytes)
MECHANISM OF ACTION
 Like CQ it is a weak base, and acts by inhibiting
polymerization of heme to hemozoin
 • Free heme or heme-quinine complex damages
parasite’s membrane and kills it
Pharmacokinetics
 Well absorbed from GI tract, even in patients
with diarrhea
 • Metabolized in liver and excreted in urine
ADVERSE EFFECTS

 Higher dose symptoms include nausea, vomiting,

tinnitus, vertigo, headache, mental confusion,
difficulty in hearing and visual defects, diarrhea,
flushing
 • Rapid i.v. injection:

 .Hypotension and cardiac arrhythmias

 • Can cause profused hypoglycemia

 Pregnancy:

 Causes abortion in early pregnancy by stimulating

myometrium and premature labor by stimulating

uterus
 Hypoglycaemia
CLINICAL USES
 Malarial attacks
 Uncomplicated resistant falciparum

 Complicated and severe malaria including

cerebral malaria
 Is not highly active, adjunctive therapy with
doxycycline, tetracycline and clindamycin is
needed
MEFLOQUINE (MQ)
 Fast acting erythrocytic(blood) schizontocide but
slower than CQ or quinine
 • Effective against CQ-sensitive as well as
resistant Plasmodia
 • Efficacious suppressive prophylactic for multi-
resistant P. falciparum
MECHANISM OF ACTION
 Like CQ, it accumulates in infected RBCs, binds
to heme and this complex damages the parasite’s
membrane
 However recent evidence suggests that the site
of action of MQ is in the parasitic cytosol rather
than in the acidic vacuole
PHARMACOKINETICS
 Prolonged absorption after oral ingestion
 • It is highly plasma protein bound and
concentrated in the liver, lung and intestines
 • Extensive metabolism occurs in liver and is
primarily secreted in bile
 • It has a long half life (17days) due to its
concentration in various tissues and its
continuous circulation through the enterohepatic
and enterogastric systems
 Its major excretory route is feces
ADVERSE EFFECTS
 MQ is bitter in taste
 • At high doses:

 o Nausea, vomiting, diarrhea, abdominal pain,

bradycardia
 o Ataxia, hallucinations, depression

 • MQ is safe in pregnancy

 • Rare events of toxicity are seen

CONTRAINDICATIONS
 patients with anxiety, depression, psychosis, and
in cardiac conduction defects
 Drug interactions

 Cardiac arrests are possible if MQ is taken

concurrently with quinine or quinidine
Uses
 Effective for multidrug resistant P. falciparum

 • However its use is restricted due to its toxicity,

cost and long half life
PROGUANIL (CHLOROGUANIDE)
 Slow acting erythrocytic schizontocide
 • Cyclized in body to a triazine
derivative(cycloguanil)
 • Cycloguanil inhibits plasmodial dihydrofolate
reductase (DHFRase)
 • Resistance developed due to mutational
changes in the plasmodial DHFRase enzyme
PHARMACOKINETICS
 Slow but adequate absorption from the gut
 • Partly metabolized and excreted in urine

 • Half life 16-20 hour ; noncumulative

Adverse effects
 Mild abdominal upset, vomiting

 • Occasional stomatitis

 • Haematuria, rashes and transient loss of hair

 • Note : Safe during pregnancy

PYRIMETHAMINE

 Slow acting erythrocytic schizontocide

 • Direct inhibitor of plasmodial dihydrofolate
reductase (DHFRase)
 • Conversion of dihydrofolic acid to tetrafolic acid
is inhibited
 • High doses inhibits Toxoplasma gondii

 • Resistance develops by mutation in DHFRase

enzyme
ADVERSE EFFECTS
 Occasional nausea and rashes
 • Folate deficiency rare

 • Megaloblastic anaemia and granulocytopenia

with higher dose
 • Can be treated with folinic acid

 • Combined with a sulfonamide (S/P) or dapsone

for treatment of falciparum malaria
SULFONAMIDE-
PYRIMETHAMINE(S/P)
 Sulphadoxine is a sulfonamide thus competes
with para– amino benzoic acid – inhibits the
formation of dihydropteric acid
 • Pyrimethamine inhibits DHFRase enzyme as a
result of which conversion of dihydrofolic acid to
tetrahydrofolic acid is blocked – thus inhibits
DNA synthesis
 • Effective blood schizontocide against
Plasmodium falciparum
 • Treatment and prophylaxis of falciparum
malaria resistant to chloroquine
ADVERSE EFFECTS
 Mild GIT upset
 • Megaloblastic anemia, bone marrow depletion

 • Rashes, urticaria, serum sickness, drug fever

 • Exfoliative dermatitis, Stevens Johnson

syndrome
 • Nephrotoxicity
PRIMAQUINE
 Poor erythrocytic schizontocide
 • Has marked effect on primary and secondary
hepatic phases
 of malarial parasite

 • Highly active against gametocytes and

hypnozoites
MECHANISM OF ACTION
 Intermediate act as oxidant that are responsible
for the schizontocial action
Pharmacokinetics
 Readily absorbed after oral absorption

 • Oxidized in liver with a plasma half life of 3-6

hours
 • Excreted in urine within 24 hour

 • Not a cumulative drug

ADVERSE EFFECTS
 Abdominal pain, gastrointestinal upset,
weakness or uneasiness chest
 • Leucopenia (high dose)

 • Hemolysis

 • Methaemoglobinaemia

 • Tachypnoea

 • Cyanosis
CONTRAINDICATIONS
 Should not be given during pregnancy because
fetus is glucose-6-phosphate dehydrogenase ( G-
6-PD) deficient
 Clinical uses

 • radical cure of relapsing malaria (P.ovale and

P.vivax)
 • single 45mg dose given with curative dose of
chloroquine to kill gametes (P. falciparum)
TETRACYCLINE AND DOXYCYCLINE
( ANTIBIOTICS)

 Used against chloroquine resistant malaria

 • Kills erythrocytic stage of the malarial parasite

 • Tetracycline is used for acute attack only

 • Doxycycline is used for prophylaxis and acute

attack
 • For treating acute attack they are used in
combination with
 quinine

 • Should not be given to children and pregnant

women
CLINDAMYCIN
( ANTIBIOTICS)
•
 Active against the erythrocytic stage of the
malaria parasite
 • Liver stage and gametocytes are not affected

 • Drug used adjunct to quinine to treat malaria

caused by chloroquine resistant Plasmodium
falciparum
 • Can be used in children and pregnant women
ARTEMISININ AND ITS
DERIVATIVES:
 Active principle of plant Artemisia annua
 • Sesquiterpene lactone endoperoxide

 • It includes:

 1. Artesunate

 2. Artemether

 3. Arteether

 4. Arterolane
MECHANISM OF ACTION
1. ARTESUNATE
 Its sodium salt is water soluble and is
administered by oral, i.m. or i.v. route
 • Rapidly converted to active metabolite
dihydroartemisinin (DHA)
 • After repeated dosing, artesunate causes
autoinduction of its own metabolism by CYP2B6
and CYP3A4
2. ARTEMETHER

 Lipid soluble and is administered orally or i.m.

 • Absorption after oral or i.m. dosing is slower
taking 2-6 hrs
 • Undergoes substantial first pass metabolism
and is converted to DHA
 • Extensive metabolism by CYP3A4 yields a
variable half life of 3-4 hrs
3. Α/Β ARTEETHER

 Available for i.m. administration only to adults

for complicated malaria
 • Due to its longer elimination (t1/2=23hrs), it is
recommended in a three day schedule
ADVERSE EFFECTS
 First degree A-V block
 • Q-T prolongation

 • Transient reticulopenia and leucopenia (rare)

 • Bleeding, dark urine

 • Headache, tinnitus, dizziness

 • Abdominal pain, itching, nausea, vomiting

DRUG INTERACTION
 Concurrent administration of artemisinins with
drugs prolonging Q-T like astemizole,
antiarrhythmics, tricyclic antidepressants and
phenothiazines may increase the risk of
 cardiac conduction
ARTEMISININ BASED COMBINATION
THERAPY (ACT)

 One of artemisinin compound in combination

with another effective erythrocytic schizontocide
is used.
 • Consideration must be made about t1/2 of
companion drug to maintain its effective
concentration in the blood for at least
 3-4 asexual cycles of the parasite.

 • Kills >95% of the plasmodia

ADVANTAGES OF ACT
 Rapid clinical and parasitological cure
 • High cure rates(>95%) and low recrudescence
rate
 • Absence of parasite resistance

 • Good tolerability profile

 • Dosing schedule is simpler

1. ARTESUNATE-SULFADOXINE +
PYRIMETHAMINE(AS-S/P)

 First line drug for uncomplicated falciparum

malaria
 • Not effective against multidrug-resitant strains
which are non responsive to S/P
 • Fewer side effects than AS/MQ
2. ARTESUNATE/MEFLOQUINE(AS/MQ)
 Highly effective and well tolerated in
uncomplicated falciparum malaria
3.ARTEMETHER-LUMEFANTRINE(AS/LF)
 Clinical efficacy: 95-99%
 • Must be administered with fatty food or milk to
allow absorption and ensure adequate blood level
of AS/LF
 • Quickly reduces parasite biomass, resolve
symptoms, prevent recrudescence, check
gametocyte population
ADVERSE DRUG REACTION
 Headache, dizziness, abdominal pain, arthralgia,
myalgia, pruritus and rashes
 Drug interaction

 • Not to be given with drugs metabolized by

CYP2D6( e.g. metoprolol) as lumefantrine
inhibits isoenzyme CYP2D6
 Contraindication

 during first trimester of pregnancy and lactation

period
4. DIHYDROARTEMISININ(DHA)-
PIPERAQUINE

 Used in dose ratio of 8:1 for multidrug resistant

Plasmodium falciparum
 • Good safety profile and even tolerated by
children (>98% response rate)
 Adverse drug reaction

 • Dizziness, rashes

 • Vomiting and GI symptoms

5. ARTESUNATE-AMODIAQUINE(AS/AQ)
 First line therapy of uncomplicated falciparum
malaria
 • To be taken twice daily for three day treatment

Other recently developed ACT are:

6.. Arterolane-piperaquine
 • Acts rapidly at all stages of asexual schizogony
of malarial
 parasite including multidrug resistant P.
falciparum
 7. Artesunate-pyronaridine

 • Under clinical trial

CEREBRAL MALARIA
 Most severe neurological complication of infection
 with Plasmodium falciparum

 • Aggregation of infected and non infected red

cells and plugging in capillary endothelium of
brain due to secreted proteins on red cell surface
by late stage schizonts
 • Enhanced by the pro-inflammatory status of
the host and virulence characteristics of the
infecting parasite variant
 • Manifested by confusion, coma and death due
to anoxia, ischaemia and haemorrhage
DRUGS USED IN CEREBRAL MALARIA
 Quinine by slow intravenous infusion
 • Artemisinin derivatives that produce a very
rapid therapeutic response and are effective
against multi-drug resistant P. falciparum are
preferred
 • Some of the drugs used as a combination
therapy for cerebralmalaria are:
 o Arteether with quinine

 o Artemether with quinine