Malaria by JITENDRA BHANGALE

9/2/2012

By- Jitendra Bhangale
Assistant Professor & Head,
Department of Pharmacology,
Smt N. M. Padalia Pharmacy College,
Ahmedabad
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© 2010 Delmar, Cengage Learning

Malaria is a parasite that enters the blood.

This parasite is a protozoan called plasmodium.

3 to 700 million people get malaria each year, but only

kills 1 to 2 million

40% of the worlds population lives in malaria zones

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By J. O. Bhangale, Head, Dept of Pharmacology, Smt N. M. Padalia Pharmacy College, A’bad

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9/2/2012

 Plasmodium vivax (tertian)

 Plasmodium ovale (tertian)

 Plasmodium falciparum (tertian)

 Plasmodium malariae (quartian)

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Falciparum: Almost 80% of cases and 90% of malaria
deaths. Primarily found in South America and
Africa.
Ovale: Rarest form. Found in West Africa. Can be up to
four years before and symptoms occur.
Malariae: Can infect other mammals. Found in Africa
and SE Asia.
Vivax: 20% of infections. Widest geographic
distribution.
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The life cycle of all species that infect humans is basically

the same.

There is an exogenous asexual phase in the mosquito called

sporogony during which the parasite multiplies.

There is also an endogenous asexual phase that takes place

in the vertebrate or human host that is called schizogeny.

This phase includes the parasite development that takes

place in the red blood cell, called the erythrocytic cycle.
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Schizogeny phase includes the parasite development that
takes place in the red blood cell, called the erythrocytic
cycle and the phase that takes place in the parencymal
cells in the liver, called the exo-erythrocytic phase.
The exo-erthrocytic phase is also called the tissue phase.
The schizogeny that takes place here can occur without
delay during the primary infection or can be delayed in
the case of relapses of malaria.
I will focus on the development of the parasite in the human
host.
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Oocyst Sporogony
Sporozoites

Mosquito Salivary
Zygote Gland

Hypnozoites
Exo- (for P. vivax
erythrocytic and P. ovale)
(hepatic) cycle
Gametocytes

Erythrocytic
Cycle

Schizogony
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Exo-erythrocytic (hepatic) Cycle:
Sporozoires injected Sporozoites infect liver cells and
into human host develop into schizonts, which
during blood meal release merozoites into the blood

Parasites
mature in
mosquito
midgut and Dormant liver
MOSQUITO HUMAN
migrate to stages (hypnozoites)
salivary of P. vivax and P.
glands ovale

Erythrocytic Cycle:
Merozoites infect
red blood cells to
Some merozoites form schizonts
Parasite undergoes
sexual reproduction differentiate into male
in the mosquito or female
gametocyctes

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Blood is infected with sporozoites about 30 minutes

after the mosquito bite

The sporozoites are eaten by macrophages or enter the

liver cells where they multiply –

-pre-erythrocytic schizogeny

P. vivax and P. ovale sporozoites form parasites in the

liver called hypnozoites
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P. malariae or P. falciparum sporozoites do not form

hypnozites, develop directly into pre-erythrocytic

schizonts in the liver

Pre-erythrocytic schizogeny takes 6-16 days post

infection

Schizonts rupture, releasing merozoites which invade

red blood cells (RBC) in liver
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P. vivax and P. ovale hypnozoites remain dormant for

months

They develop and undergoe pre-erythrocytic sporogeny

The schizonts rupture, releasing merozoites and

producing clinical relapse

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Pre-patent period – interval between date of infection
and detection of parasites in peripheral blood
Incubation period – time between infection and first
appearance of clinical symptoms
Merozoites from liver invade peripheral (RBC) and
develop causing changes in the RBC
There is variability in all 3 of these features depending
on species of malaria

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Stages of parasite in RBC
Trophozoites are early stages with ring form the
youngest
Tropohozoite nucleus and cytoplasm divide forming a
schizont
Segmentation of schizont’s nucleus and cytoplasm
forms merozoites
Schizogeny complete when schizont ruptures, releasing
merozoites into blood stream, causing fever
These are asexual forms 13

Stages of parasite in RBC

Merozoites invade other RBCs and schizongeny is

repeated

Parasite density increases until host’s immune

response slows it down

Merozoites may develop into gametocytes, the sexual

forms of the parasite
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Schizogenic periodicity is length of asexual erythrocytic
phase
48 hours in P.f., P.v., and P.o. (tertian)
72 hours in P.m. (quartian)
Initially may not see characteristic fever pattern if
schizogeny not synchronous
With synchrony, periods of fever or febrile paroxsyms
assume a more definite 3 (tertian)- or 4 (quartian)- day
pattern
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Early symptoms
Headache
Malaise
Fatigue
Nausea
Muscular pains
Slight diarrhea
Slight fever, usually not intermittent
Could mistake for influenza or gastrointestinal
infection 16

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Infection is by mosquito
bite

Infects liver,
then blood cells

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Acute febrile illness, may have periodic febrile paroxysms

every 48 – 72 hours with

Tendency to recrudesce or relapse over months to years

Anemia, thrombocytopenia, jaundice, hepatosplenomegaly,

respiratory distress syndrome, renal dysfunction,

hypoglycemia, mental status changes, tropical splenomegaly

syndrome
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4-Aminoquinolines Sulfonamides and sulfone
Chloroquine Sulfadoxine
Amodiaquine Sulfamethopyrazine
Piperaquine Dapsone
Quinoline-methanol Tetracyclines
Mefloquine. Tetracycline
Cinchona alkaloid Doxycycline
Quinine Sesquiterpine lactones
Quinidine Artesunate
Biguanides Artemether
Proguanil Arteether
(Chloroguanide) Amino alcohols
Chlorproguanil Halofantrine
Diaminopyrimidines Lumefantrine
Pyrimethamine Mannich base
8-Aminoquinoline Pyronaridine
Primaquine Naphthoquinone
Bulaquine Atovaquone 19

Chloroquine is one of several 4-aminoquinoline
derivatives that display antimalarial activity.
Chloroquine is particularly effective against
intraerythrocytic forms because it is concentrated
within the parasitized erythrocyte.
This preferential drug accumulation appears to occur as a
result of specific uptake mechanisms in the parasite.
Chloroquine appears to work by intercalation with DNA,
inhibition of heme polymerase or by interaction with
Ca–calmodulin mediated mechanisms.
It also accumulates in the parasite’s food vacuoles, where it
inhibits peptide formation and phospholipases, leading
to parasite death.
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The drug is effective against all four types of malaria
with the exception of chloroquine-resistant P.
falciparum.
Chloroquine also can be used prophylactically in areas
where resistance does not exist.
The absorption of chloroquine from the gastrointestinal
tract is rapid and complete.
The drug is distributed widely and is extensively bound
to body tissues.
Adverse effect:-
Dizziness, headache, itching (especially in darkskinned
people), skin rash, vomiting, and blurring of vision
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Amodiaquine is another 4-aminoquinoline derivative
whose antimalarial spectrum and adverse
reactions are similar to those of chloroquine,
although chloroquine-resistant parasites may not
be amodiaquine- resistant to the same degree.

Prolonged treatment with amodiaquine may result in
pigmentation of the palate, nail beds, and skin.

There is a risk of agranulocytosis and hepatocellular
dysfunction when the drug is used
prophylactically. © 2010 Delmar, Cengage Learning
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Mefloquine is a 4-quinolinemethanol derivative used
both prophylactically and acutely against resistant
P. falciparum malaria.
It is ineffective against the liver stage of P. vivax
malaria.
It is an effective blood schizonticide.
Adverse effect:-
Vertigo, visual alterations, vomiting, and such CNS
disturbances as psychosis, hallucinations, confusion,
anxiety, and depression 23

Quinine is the levo rotatory alkaloid obtained from
cinchona bark. Its d-isomer quinidine is used as an
antiarrhythmic.
Quinine is an erythrocytic schizontocide for all species
of plasmodia.
Like chloroquine, it is a weak base: gets concentrated
in the acidic vacuoles of the blood schizonts and causes
pigment changes; inhibits polymerization of haeme to
hemozoin; free haeme or haeme-quinine complex
damages parasite membranes and kills it. 24

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Quinine is used for the prevention and treatment of
nocturnal leg muscle cramps, especially those resulting
from arthritis, diabetes, thrombophlebitis,
arteriosclerosis, and varicose veins.
Adverse effect:-
sweating, ringing in the ears, impaired hearing, blurred
vision, nausea, vomiting, and diarrohea.
Quinine is a potent stimulus to insulin secretion and
irritates the gastrointestinal mucosa
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Chloroguanide hydrochloride is activated to a triazine
metabolite, cycloguanil, which also interferes with
parasite folic acid synthesis.
It is a dihydrofolate reductase inhibitor that is used for
the prophylaxis of malaria caused by all
susceptible strains of plasmodia.
Chloroguanide is rapidly absorbed from the
gastrointestinal tract.
Adverse effect:-
Mild abdominal upset, vomiting, occasional stomatitis,
haematuria, rashes and transient loss of hair. 26

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It inhibit the parasite’s ability to synthesize folic acid.

Sulfonamides should always be coadministered with
pyrimethamine (or trimethoprim), since the combined
antimalarial activity of the two drugs is significantly
greater than when either drug is used alone.
Adverse effect:-
Anorexia, vomiting, anemia, leukopenia,
thrombocytopenia, and atrophic glossitis.
CNS stimulation, including convulsions, may follow an
acute overdose 27

Primaquine is the least toxic and most effective of the
8- aminoquinoline antimalarial compounds.
Antimalarial effects is thought to be through a
quinoline–quinone metabolite that inhibits the
coenzyme Q–mediated respiratory chain of the
exoerythrocytic parasite.
Primaquine is an important antimalarial because it is
essentially the only drug effective against the liver
(exoerythrocytic) forms of the malarial parasite.
The drug also kills the gametocytes in all four species
of human malaria.
Primaquine is relatively ineffective against the asexual
erythrocyte forms.
Adverse effect:- G-6-PD deficiency, haemolysis,
methaemoglobinaemia, tachypnoea and cyanosis 28

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Pyrimethamine inhibits plasmodial dihydrofolate
reductase, for which it has a high affinity. It is well
absorbed from the gastrointestinal tract and is
extensively metabolised.
Pregnant women should receive supplementary folic
acid when taking pyrimethamine.
Adverse effects
Anorexia, abdominal cramps, vomiting, ataxia, tremor,
seizures and megaloblastic anaemia.
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Pyrimethamine acts synergistically with sulfadoxine to
inhibit folic acid metabolism

Sulfadoxine is excreted in the urine.

The combination is chiefly used with quinine to treat
acute attacks of malaria caused by susceptible strains of
Plasmodium falciparum; a single dose of pyrimethamine
75 mg plus sulfadoxine 1.5 g (3 tablets) usually suffices.

Adverse effects

Erythema multiforme, Stevens-Johnson syndrome and
toxic epidermal necrolysis © 2010 Delmar, Cengage Learning
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Pyrimethamine is combined with dapsone for

prophylaxis of Plasmodium falciparum malaria.

Adverse effects

Erythema multiforme

Stevens-Johnson syndrome

Toxic epidermal necrolysis

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Atovaquone is a naphthoquinone
Mechanism of action
It inhibit the mitochondrial electron transport system in the
protozoa.
Malaria parasites depend on pyrimidine biosynthesis
through dihydroorotate dehydrogenase coupled to
electron transport.
Atovaquone has good initial activity against the blood but
not the hepatic stage of P. vivax and P. ovale malaria
parasites.
It is effective against erythrocytic and exoerythrocytic P.
falciparum.
Adverse effect:-
Nausea, vomiting, diarrhea, abdominal pain, headache, and
rash 32

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Artemisinin which is isolated from the leaves of the
Chinese herb qinghao (Artemisia annua).
They act against the blood, including sexual forms, of
plasmodia and may also reduce transmissibility
Artemisinins do not kill hypnozoites.
E.g. Artemether, Artesunate, Arteether
Artemisininis poorly soluble in water as well as oil.
Artemether is soluble in oil, while Artesunate (sod.) is
soluble in water.
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Its sodium salt is water-soluble and administered by
oral, i m or i v. routes
After oral ingestion, absorption is incomplete.
It is rapidly converted to the active metabolite
dihydroartemisinin (DHA).
Adverse effect:-
Nausea, vomiting, abdominal pain, itching and drug
fever. Abnormal bleeding, dark urine, S-T segment
changes, Q-T prolongation, first degree A-V block
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It is lipid-soluble and is administered orally or i.m., but
not i.v
Oral absorption is slower taktng 24 hours, but is
enhanced by food.
It undergoes substantial first pass metabolism and is
converted to DHA.
Adverse effect:-
Nausea, vomiting, abdominal pain, itching and drug
fever. Abnormal bleeding, dark urine, S-T segment
changes, Q-T prolongation, first degree A-V block 35

Halofantrine is active against the erythrocytic forms of
all four Plasmodium species, especially
Plasmodium falciparum and Plasmodium vivax, and
at the schizont stage.
It is metabolised to an active metabolite and no
unchanged drug is recovered in the urine.
Halofantrine is used for the treatment of
uncomplicated chloroquine-resistant Plasmodium
falciparum and Plasmodium vivax malaria.
It should not be given for prophylaxis. 36

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9/2/2012

By Jitendra Bhangale
37
Asst. Prof. Dept of Pharmacology, Delmar, Cengage Learning Pharmacy College, Ahmedabad
© 2010 Smt N. M. Padalia

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Malaria by JITENDRA BHANGALE

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