MALARIA

Zikria, Ph.D.
 Antimalarial drugs
Malaria is cause by four species of protozoa:
 Plasmodium malariae. (Qurantan malaria, 72)
 P. falciparum. (malignant tertian or falciparum
malaria, 48)
 P. vivax. (benign tertian or vivax malaria)
 P. ovale. (ovale malaria, rare)
The plasmodium transmitted to human by the
bite of an infected female anopheles mosquito.
 Life cycle
• Understanding of the life cycle helps in understanding the clinical
events, treatment and control measures.
• Two phase
– Sporogony
– Schizogony
Sporogony
(Sexual phase)
• Occurs in female anopheles mosquito
• Cycle initiated when mosquito takes blood meal from an infected
individual.
• Takes RBCs that contain both male and female gametocytes of malarial
parasite  formation of sporozoites that reach the salivary glands.
• Mosquitoes injects the sporozoites into next victim and with in minutes
liver cells become infected by them.
Schizogony
• Takes place in human host.
• Schizogony (nuclear division and increase in
cytoplasmic volume) occurs twice in the host.
– First phase  cells of the liver.
on reaching maturity the mature schizonts rupture and
release merozoites into blood invade
erythrocytes.
– Second phase  Erythrocytes.
• Clinical events  chill, fever are associated with the release
of succeeding generations of merozoites from the
erythrocytes.
• Male and female gametocytes are produced after two or
more cycles and are taken up by the mosquitoes.
• In mosquito  gametocytes develop into gametes and
fertilization occurs.
• Zygote  Ookinetes, migrate to stomach wall of mosquito
(Oocyst on the outside of the mid-gut).
• Each Oocyst matures with nuclei dividing repeatedly
release motile sporozoites.
• Sporozoites salivary glands  next victim (human).
 Pathogenesis

• Infected individual experiences the outbursts of

malaria in conjunction with the synchronous release
of sporozoites.
• Vivax malaria  quartan malaria episodes occur
every 72hours.
• Falciparum malaria  less than 48 hours. (Subtertian
malaria) most severe form of disease.
• Malariae  quartan malaria episodes occur every 72
hours.
 Symptoms and Signs
• Malarial Attack
• Patient initially experiences chills for 15-60 minutes.
• Associated with release of merozoites.
• Begins with a prodrome accompanied by headache, nausea and
vomiting.
• Succeeding the chills is a febrile stage of several hours duration.
• Temperature sometimes rises to 105 F or higher.
• Fevers are usually irregular, especially early in the illness, but without
therapy may become regular, with 48-hour (P vivax and P ova/e) or
72-hour (P malariae) cycles, especially with non-falciparum disease.
• Profuse sweating concludes the attack.
• Exhausting episode induces sleep from which patient awakens with
a feeling of well being.
• Infection may be asymptomatic severely enfeebling or fatal.
• Headache, malaise, myalgias, arthralgias, cough, chest pain, abdominal pain,
anorexia, nausea, vomiting, and diarrhea are common.
• Seizures may represent simple febrile convulsions or evidence of severe
neurologic disease. Physical findings may be absent or include signs of anemia,
jaundice, splenomegaly, and mild hepatomegaly. Rash and lymphadenopathy
are not typical in malaria, and thus suggestive of another cause of fever.
• Severe malaria
• When RBCs rupture, parasites, Hemoglobin and metabolites of parasite
released.
• These products are taken up by Reticuloendothelial system marked
pigmentation and enlargement of spleen, liver, lymph nodes and bone
marrow.
• RBCs become sticky and plug up the smaller vessels especially in patients with
falciparum malaria.

• Obstructive action of the “sludge blood” has effects like:

– Tissue anoxia and necrosis, bursting of vessels, electrolyte imbalance.
– Organs including the brain (cerebral malaria) and kidneys may be affected.
• consciousness, repeated seizures, and coma
(cerebral malaria) ; severe anemia; hypotension
and shock; noncardiogenic pulmonary edema and
the acute respiratory distress syndrome; acute
kidney injury due to acute tubular necrosis or, less
commonly, severe hemolysis; hypoglycemia;
acidosis; hemolysis with jaundice; hepatic
dysfunction; retinal hemorrhages and other
fundoscopic abnormalities; bleedin abnormalities,
including disseminated intravascular coagulation;
and secondary bacterial infections, including
pneumonia and Salmonella bacteremia.
 Diagnosis
• Microscopic examination
• Giemsa stained blood smears.
• Banana shaped intra-erythrocytic gametocytes  P. falsiparam.
• Enlarged erythrocytes with intra cellular coarse brick-red stippling
(schuffner’s dots)  P vivax.
• Schuffner’s dots  oval-shaped  P. ovale.
• The severity of malaria correlates only loosely with the quantity of
infecting parasites, but high parasitemias (especially greater than 1 0-
20% of erythrocytes infected or greater than 200,000-500,000
parasites/meL) or the presence of malarial pigment (a breakdown
product of hemoglobin) in more than 5% of neutrophils is associated
with a particularly poor prognosis.
• PCR and related molecular tests (eg, LAMP) are highly sensitive but not
available for routine diagnosis.
• Thrombocytopenia, anemia, leukocytosis or leukopenia, liver function
abnormalities, and hepatosplenomegaly
 Blood Schizonticides
Chloroquine (4- aminoquinoline derivative)
Nivaquin , Rasochin
Mechanism of action:
Inhibits synthesis of DNA and RNA in the plasmodium.
Increases pH of the vacuoles in the parasite, so
prevent its utilization of erythrocyte hemoglobin.
Uses:
Acute attack 600 mg base (4 tab.) then 300 mg after 6
h. then 150 mg bid for two more days.
Add 100 mg proguanil/ day (2 tab.) in chloroquine-
resistant area.
• Chloroquine is the drug. of choice for
uncomplicated malaria in areas without
resistance. Chloroquine resistant malaria is
found in most areas of falciparum malaria, and
also in many areas of vivax malaria.
Chemoprophylaxis:
300 mg base (2 tab.) / week,
one week before entering the endemic area
& 4 weeks after leaving.
 .
Other uses:
Amebic liver abscess (as chloroquine is concentrated
in the liver).
Anti-inflammatory in autoimmune diseases e.g.
rheumatoid arthritis (unknown mechanism).
A/E: GIT upset, rash, headache, peripheral neuritis,
cardiac depressant, retinal damage (don’t use
chloroquin> 5 years without regular ophthalmic
examination), toxic psychosis and precipitates
porphyria.
Quinine:
.
Mechanism of action:
Inhibits DNA strand separation.
Inhibits transcription and protein synthesis.
Uses:
Chloroquine-resistant P. falciparum (orally).
Cerebral malaria (i.v infusion 10 mg/kg over 4 h.). it could
repeat at an intervals of 8-12 h. until patient can take the drug
orally.
A/E:
Cinchonism i.e. headache, dizziness, & tinnitus.
Inhibits cardiac conductivity, hemolysis in G-6-P D deficiency
and black water fever (intravascular hemolysis).
 .
Quinidine:
It is the dextro-isomer of quinine.
It is used when quinine is not available.
Mefloquine:
Its mechanism of action is unknown.
Uses:
treatment & prophylaxis of chloroquine-resistant P.
falciparum.
A/E: GIT upset, headache, dizziness, syncope,
extrasystoles & seizures.
 .
Halofantrine:
Unknown mechanism of action.
Used only by oral route in P. falciparum
cerebral malaria.
No parenteral preparation.
Not used for prophylaxis.
Not used during pregnancy unless benefit
outweighs the risk.
Qinghaosu (Artemisinin):
.
It is a Chinese herbal medicine was used as antipyretic.
It is a blood schizonticide against all types of malaria including
chloroquine-resistant p. falciparum.
Unknown mechanism of action.
Uses:
P. falciparum cerebral malaria (oral & parenteral).
Not used prophylactically.
Not used in pregnancy as it is emberytoxic in rats.
Antifolates (sulfonamides & sulfones):
.
Synergistic blockade of folic acid synthesis
Sulfonamide inhibits dihydropteroate
synthetase, so inhibits folic acid synthesis.
Pyrimethamine and proguanil inhibit
dihydrofolate reductase, so inhibit
tetrahydrofolate (folinic acid synthesis).
Fansidar:
.
It is a combination of sulfadoxin and pyrimethamine.
It is used in chloroquine-resistant p. falciparum.
Not used for prophylaxis as it causes agranulocytosis &
Stevens-Johnson syndrome.
A.E:
Sulfonamide: rashes, kidney damage, hemolysis & GIT upset.
Pyrimethamine: folic acid deficiency, agranulocytosis &
Stevens-Johnson syndrome.
Disadvantages: slow blood schizonticide activity, drug resistance
& numerous & serious adverse effects.
C/I: pregnancy & nursing women, G-6-PD, renal impairment &
children under 2 months of age.
 .
Atovaquone:
Unknown mechanism of action.
Used alone for treatment of pneumocytosis and
toxoplasmosis in patients with AIDS.
Atovaquone + proguanil (malarone) for treatment &
prophylaxis of chloroquine-resistant P. falciparum.
A/E: fever, rashes, cough, nausea, vomiting, diarrhea,
headache & insomnia.
 Tissue Schizonticide

Primaquine (8- aminoquinoline derivative):

It is a tissue schizonticide.
It has a cellular oxidant activity and possibly interferes with
mitochondria function.
Gametocide, so inhibits infection transmission by mosquito.
Uses:
Eradication of liver stages (hypnozoites) of P.vivax & P.
ovale, after standard chloroquine therapy to prevent relapse.
It should not be given if there is risk of reinfection.
A/E: GIT upset, pruritis, headache, methemoglobinemia,
hemolysis especially in G-6-PD.
 Treatment of malaria

P. vivax, P. ovale & P. malariae:

Chloroquine
NB: It is also allowed in pregnancy.
P. Falciparum (most cases are chloroquine-resistant):
Quinine 600 mg salt/8h till patient become better and blood
is free of parasites (usually in 3-5 days).
Followed by a single dose of fansidar (3 tablets).
In pregnancy 7-day course of quinine alone should be given.
 .
Alternative therapy
Mefloquine 20 mg base/kg up to a maximum of 1.5 g
in two divided doses 8 hours apart.
Mefloquine is contraindicated in pregnancy.
Cerebral malaria:
Quinine 10 mg/kg i.v infusion over 4 h. could be
repeated at intervals of 8-12 h. until patient can take
drug orally.
Or Halofantrine: orally only
Or Qinghaosu (Artemisinin): oral & i.v
 Non-Falciparum Malaria
• The first-line drug for non-falciparum malaria from most areas
remains chloroquine.
• Due to increasing resistance of P vivax to chloroquine, infections
can be treated with artemisinin based combination therapies
(ACTs) or other first-line regimens for P falciparum infections
• For P vivax or P ovale, eradication of erythrocytic parasites with
chloroquine should be accompanied by treatment with
primaquine (after evaluating for glucose-6-phosphate
dehydrogenase [ G6PD] deficiency; to eradicate dormant liver
stages (hypnozoites), which may lead to relapses with recurrent
erythrocytic infection and malaria symptoms after weeks to
months if left untreated.
• Tafenoquine, which is related to primaquine, appears to offer similar efficacy with simpler dosing, but it also engenders
potential toxicity in those with G6PD deficiency, and it remains under study.

• P malariae infections need only be treated with chloroquine.

Uncomplicated Falciparum Malaria
• P falciparum is resistant to chloroquine and sulfadoxine pyrimethamine in
most areas.
• A short-acting artemisinin and longer -acting partner drug, are first -line
therapies in nearly all endemic countries.
• Quinine generally remains effective for falciparum malaria, but it must be
taken for an extended period to cure disease and is poorly tolerated, and
should best be reserved for the treatment of severe malaria and for
treatment after another regimen has failed
• In developed countries, malaria is an uncommon but potentially life-
threatening infection of travelers and immigrants, many of whom are
nonimmune, so they are at risk for rapid progression to severe disease.
• Nonimmune individuals with falciparum malaria should generally be admitted
t o the hospital due t o risks of rapid progression of disease. A number of
options are available for the treatment of uncomplicated falciparum malaria
in the United States
 Severe Malaria
• Severe malaria is a medical emergency.
• Parenteral treatment is indicated for severe malaria, as
defined above, and with inability to take oral drugs.
• With appropriate prompt therapy and supportive care, rapid
recoveries may be seen even in very ill individuals.
• The standard of care for severe malaria is intravenous
artesunate, which has demonstrated superior efficacy and
better tolerability than quinine. The drug is administered in
four doses of 2.4 mg/kg over 3 days, every 1 2 hours on day
1 , and then daily. I f artesunate cannot b e obtained
promptly, severe malaria should be treated with intravenous
quinine or quinidine.
• In endemic regions, if parenteral therapy not available,
intrarectal administration of artemether/artesunate is
effective.
• Patients receiving intravenous quinine or quinidine should
receive continuous cardiac monitoring; if QTc prolongation
exceeds 25% of baseline, the infusion rate should be reduced.
• Blood glucose should be monitored every 4-6 hours, and 5-
10% dextrose may be coadministered to decrease the
likelihood of hypoglycemia.
• Appropriate care of severe malaria includes maintenance of
fluids and electrolytes; respiratory and hemodynamic support;
and consideration of blood transfusions, anticonvulsants,
antibiotics for bacterial infections, and hemofiltration or
hemodialysis.
• With high parasitemia (greater than 5 - 1 0%), exchange
transfusion has been used, but beneficial effects have not
clearly been demonstrated, and it is generally no longer
recommended.
 Chemoprophylaxis of malaria

Chloroquine-sensitive area:
Chloroquine 150 mg base ( 2 tab/week)
Chloroquine-resistant area:
Chloroquine ( 2 tab/week) plus proguanil
100 mg (one or two tab/ day)
or
Mefloquine 250 mg (one tab./ week)
 Anti biotics
• Doxycycline is commonly used in the treatment of falciparum malaria in
conjunction with quinidine or quinine, allowing a shorter and better-
tolerated course of those drugs.
• Doxycycline is also a standard chemoprophylactic drug, especially for use
in areas of Southeast Asia with high rates of resistance to other
antimalarials, including mefloquine.
• Doxycycline side effects include gastrointestinal symptoms, candida!
vaginitis, and photosensitivity.
• The drug should be taken while upright with a large amount of water to
avoid esophageal irritation.
• Clindamycin can be used i n conjunction with quinine or quinidine in
those for whom doxycycline is not recommended, such as children and
pregnant women. The most common toxicities with clindamycin are
gastrointestinal.
• Host factors that influence susceptibility to malaria
» Duffy negative individuals are naturally resistant to infection
with P. vivax invasion of erythrocytes is mediated through
interaction with Duffy Fy group antigens, which are absent from
the red blood cells of many Africans and most African-
Americans.
» Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Trophozoites do not develop effectively in red blood cells
deficient in G6PD because the parasite is unable to use the
hexose monopbosphate shunt as an energy source.
» Hemoglobinopathies. Abnormalities of hemoglobin do not
support parasite growth. This increased resistance to malaria
appears to account for the high incidence of individuals with
sickle cell trait in Africa.
• Control and prevention
» Control entails elimination of mosquito breeding sites
through residual insecticide spraying, improvements in land
drainage, and removal of standing water, particularly in
inhabited areas. Insecticide-impregnated bed nets are now
being used increasingly in control campaigns.
» Prevention
Prophylactic chemotherapy. The prophylactic of choice is
Proguanil, occasionally with chloroquine. Long-term use of
anti-malarials as prophylactics can produce serious side
effects.
Supportive measures Include administration of antipyretics
during febrile crisis, transfusion for severe hemolytic
anemia, and dialysis for acute renal failure.
 `
» Vaccination. Several vaccines are under development.
The first widely tested vaccine (Spf66) is a synthetic
polypeptide construct that contains epitopes of antigens
present on sporozoites-and erythrocytic-stage parasites.
This vaccine has achieved a moderate reduction in new
infections during field trials in Colombia, Tanzania, and
Gambia.
» Vaccines  other candidate molecules, including an anti-
gametocyte vaccine aimed at breaking transmission to
the mosquito, are also being developed.