ANTI-MALARIAL

Dr. John Tiong

Malaria
• Malaria causes the most fatalities amongst the parasitic diseases and
annually kills around 1.5 - 2 million people, most of them young
children.

• In the villages of the Gambia one child in twenty, under the age of five,
dies from malaria.

• There is an increasing problem of drug resistance especially in sub-

Saharan Africa, the Thai-Burmese and Thai-Cambodian borders and in
Brazil in the area of the basin of the river Amazon.

• Malaria is an acute infectious disease caused by four species of the

protozoal genus Plasmodium.

• The parasite is transmitted to humans through the bite of a female

Anopheles mosquito, which thrives in humid, swampy areas.
 Plasmodium
• Plasmodium falciparum is the most dangerous species, causing an
acute, rapidly fulminating disease that is characterized by persistent
high fever and massive erythrocytosis (an abnormal elevation in the
number of red blood cells accompanied by swollen, reddish limbs). It
can lead to capillary obstruction and death if treatment is not instituted
promptly.

• Plasmodium vivax causes a milder form of the disease. It has the

hypnozoite stage

• Plasmodium malariae is common to many tropical regions

• Plasmodium ovale is rarely encountered. It has the hypnozoite

stage.

• Resistance acquired by the mosquito to insecticides, and by the

parasite to drugs, has led to new therapeutic challenges, particularly
in the treatment of P. falciparum.
 Life cycle of the malarial parasite
• The life cycle of the malarial parasite (Plasmodium species) can be
roughly divided into a sexual cycle which occurs within the female
Anopheles mosquito, and the mainly asexual cycle, which occurs in
humans

• When an infected mosquito bites, it injects Plasmodium sporozoites into

the bloodstream.

• The sporozoites migrate through the blood to the liver, where they live
off the the cells nutrients and cytoplasm, and by repeated asexual
mitosis (schizogeny) develop into tissue schizonts (containing
thousands of merozoites). In P. vivax and P. ovale some of the
sporozoites may remain dormant (this latent or dormant stage of
the Plasmodium sporozoite in the liver is called the hypnozoite).

• Upon release, each merozoite invades a red blood cell, becoming a

trophozoite (the feeding stage parasite) and using haemoglobin as a
nutrient.
Life cycle of the malarial parasite
• Eventually, the infected cell ruptures, releasing heme and merozoites that
can enter other erythrocytes.

• Alternatively, released merozoites can become gametocytes, which are

picked up by mosquitoes from the blood they ingest.

• The female gametocytes contain food granules and a small nucleus,

while the male gametocytes have a large nucleus and a clear cytoplasm.
If these are ingested by a mosquito, they will arrive in its gut where
fertilisation will occur.

• The cycle thus begins again, with the gametocytes becoming sporozoites
in the insect.

• The effectiveness of drug treatment is related to the particular species of

infecting plasmodium and the stage of its life cycle that is targeted.
Symptoms of malaria
• The feverish symptoms of malaria are characterised by successive
cold, hot and sweating stages.

• There is some recovery in between successive bouts of fever, but the

patient becomes weaker with each fresh attack and eventually death
can ensue.

• The appearance of these symptoms follows the different stages in the

life cycle of the malaria parasite.

• There are three main clinical complications with malaria: respiratory

distress, severe anaemia and cerebral malaria
Linking the life cycle to illness
• After the merozoites enlarge the infected red blood cells become
sticky. This leads to blockade of minor blood vessels, resulting in
strokes and brain damage from oxygen deprivation of tissues.

• The immune system attacks infected red blood cell resulting in their
destruction. However the reaction of the immune system is over-
strong and healthy rbc’s are destroyed too. Meanwhile cytokines
suppressing bone marrow production of rbc’s making it hard to
replace the lost blood cells and leading to anaemia and additional
loss of oxygen capacity in the blood. Metabolic acidosis results (due
to high level of lactic acid)

• As infected cells die, merozoites burst out into blood. Excretory

granules are simultaneously released and these cause fever.
Linking the life cycle to illness
• Breathing becomes rapid to blow off CO2  death can ensue.

• The released red blood cells re-infect new rbc’s and the cycle is
repeated. In theory, 1 parasite could lead to loss of all rbc’s in about
12 days.
Tissue schizonticide: Primaquine
• Eradicates exoerythrocytic forms of the plasmodia.

• Primaquine is the only agent that can lead to radical cures of the P.
vivax and P. ovale malarias, which may remain in the liver in the
exoerythrocytic form after the erythrocytic form of the disease is
eliminated.

• The sexual (gametocytic) forms of all four plasmodia are destroyed in

the plasma or are prevented from maturing later in the mosquito,
thereby interrupting transmission of the disease.

• Primaquine is not effective against the erythrocytic stage of malaria

and, therefore, is often used in conjunction with a blood schizonticide,
such as chloroquine, quinine, mefloquine, or pyrimethamine.

• All Plasmodium species may develop resistance to primaquine.

Tissue schizonticide: Primaquine
Mechanism of action:
• This is not completely understood. Metabolites of primaquine are
believed to act as oxidants that are responsible for the schizonticidal
action (as well as for the hemolysis and methemoglobinemia
encountered as toxicities).

Adverse effects:
• Primaquine has a low incidence of adverse effects, except for drug-
induced hemolytic anemia in patients with genetically low levels of
glucose-6-phosphate dehydrogenase. (Note: Glucose 6-P-
dehydrogenase deficiency results the in the red blood cell being
more sensitive to oxidative agents, such as primaquine. This
causes hemolysis.)
• Other toxic manifestations observed after large doses of the drug include
abdominal discomfort, especially when administered in combination with
chloroquine (which may affect patient compliance).
• Contraindicated in pregnancy
Blood schizonticide: Chloroquine
• Chloroquine has been the mainstay of antimalarial therapy, and it is the
drug of choice in the treatment of erythrocytic P. falciparum malaria,
except in resistant strains.

• Chloroquine is less effective against P. vivax malaria.

• It is highly specific for the asexual form of plasmodia.

• Chloroquine is also effective in the treatment of extraintestinal amebiasis

• Resistance: Resistance of plasmodia to available drugs has become a

serious medical problem throughout Africa, Asia, and most areas of
Central and South America. Chloroquine-resistant P. falciparum exhibit
multigenic alterations that confer a high level of resistance. Alternative
treatment: an orally administered combination of quinine, pyrimethamine,
and a sulfonamide such as sulfadoxine
Blood schizonticide: Chloroquine
Mechanism of action:
• After traversing the erythrocytic and plasmodial membranes,
chloroquine is concentrated in the organism’s acidic food vacuole.
• It is in the food vacuole that the parasite digests the host cell’s
hemoglobin to obtain essential amino acids.
• However, this process also releases large amounts of soluble heme
which is toxic to the parasite.
• To protect itself, the parasite ordinarily polymerizes the heme to
hemozoin (a pigment), which is sequestered in the parasite’s food
vacuole.
• Chloroquine specifically binds to heme, preventing its polymerization
to hemozoin.
• The increased pH and the accumulation of heme result in oxidative
damage to the membranes, leading to lysis of both the parasite and
the red blood cell The binding to heme and prevention of its
polymerization appear to be a crucial step in the drug’s anti-
plasmodial activity
Blood schizonticide: Chloroquine
Adverse effects:
• Side effects are minimal at the low doses used in the
chemosuppression of malaria.
• At higher doses, many more toxic effects occur, such as
gastrointestinal upset, pruritus and blurred vision (An ophthalmologic
examination should be routinely performed).
• Discoloration of the nail beds and mucous membranes may be seen
on chronic administration.
• Chloroquine should be used cautiously in patients with hepatic
dysfunction
• Chloroquine can cause electrocardiographic (ECG) changes,
because it has a quinidine-like effect.
Blood schizonticide: Mefloquine
• Mefloquine appears to be promising as an effective single agent for
suppressing and curing infections caused by multi-drug resistant
forms of P. falciparum.

• Its exact mechanism of action remain to be determined but it can

apparently damage the parasite’s membrane proteins responsible for
parasite membrane lipid trafficking and nutrient uptake.

• Adverse reactions at high doses range from nausea, vomiting,

disorientation, hallucinations, and depression.

• ECG abnormalities and cardiac arrest are possible if mefloquine is

taken concurrently with quinine or quinidine.
Blood schizonticides: Quinine
• Quinine interferes with heme polymerization, resulting in death of the
erythrocytic form of the plasmodial parasite.

• It is reserved for severe infestations and for malarial strains that are
resistant to other agents such as chloroquine.

• The major adverse effect of quinine is cinchonism, a syndrome

causing nausea, vomiting, tinnitus, and vertigo. These effects are
reversible and are not considered to be reasons for suspending
therapy.

• However, quinine treatment should be suspended if hemolytic anemia

occurs.

• Quinine is teratogenic.
Blood schizonticide: Artemisinin
• Artemisinin is derived from the qinghaosu plant, which has been
used in Chinese medicine for more than 2 millennia in the treatment
of fevers and malaria.

• Artemisinin is available for the treatment of severe, multidrug-resistant

P. falciparum malaria.

• Mechanism of action: Its antimalarial action involves the production

of free radicals within the plasmodium food vacuole, following
cleavage of the drug’s endoperoxide bridge by heme iron in
parasitized erythrocytes. It is also believed to covalently bind to and
damage specific malarial proteins.

• Adverse effects: Nausea, vomiting, and diarrhea, but, overall,

artemisinin is remarkably safe. Extremely high doses may cause
neurotoxicity.
Blood schizonticide and sporonticide:
Pyrimethamine
• The antifolate agent pyrimethamine is frequently employed to effect a
radical cure as a blood schizonticide.

• It also acts as a strong sporonticide in the mosquito’s gut when the

mosquito ingests it with the blood of the human host.

Mechanism of action:
• Pyrimethamine inhibits plasmodial dihydrofolate reductase at much
lower concentrations than those needed to inhibit the mammalian
enzyme. The inhibition deprives the protozoan of tetrahydrofolate, a
cofactor required in the de novo biosynthesis of the nucleotide T from
U and in the inter-conversions of certain amino acids.
Blood schizonticide and sporontocide:
Pyrimethamine
• Pyrimethamine alone is effective against P. falciparum

• Available in combination therapy with sulfadoxine (in Fansidar

combination) for prophylaxis and treatment against P. falciparum.

• In combination with a sulfonamide, it is also used against P. malariae

and Toxoplasma gondii.

• If megaloblastic anemia occurs with pyrimethamine treatment, it may

be reversed with leucovorin.
THANK YOU!!!