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Antimalarial Drugs

Chloroquine

Antimalarial Action: When not limited by resistance, chloroquine is a highly

effective blood schizonticide. It is also moderately effective against gametocytes
of P vivax, P ovale, and P malariae but not against those of P falciparum.
Chloroquine is not active against liver stage parasites.

Mechanism of Action: Chloroquine probably acts by concentrating in parasite

food vacuoles, preventing the biocrystallization of the hemoglobin breakdown
product, heme, into hemozoin, and thus eliciting parasite toxicity due to the
buildup of free heme.

Resistance: Resistance to chloroquine is now very common among strains of P

falciparum and uncommon but increasing for P vivax. In P falciparum, mutations
in a putative transporter, PfCRT, have been correlated with resistance.
Chloroquine resistance can be reversed by certain agents, including verapamil,
desipramine, and chlorpheniramine, but the clinical value of resistance-reversing
drugs is not established.

Other Quinolines

Amodiaquine is closely related to chloroquine, and it probably shares mechanisms

of action and resistance with that drug.

Amodiaquine has been widely used to treat malaria because of its low cost,
limited toxicity, and, in some areas, effectiveness against chloroquine-resistant
strains of P falciparum.

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Reports of toxicities of amodiaquine, including agranulocytosis, aplastic anemia,

and hepatotoxicity, have limited use of the drug in recent years. However, recent
reevaluation has shown that serious toxicity from amodiaquine is rare, and it may
be used as a replacement for chloroquine in areas with high rates of resistance
but limited resources.

The most important current use of amodiaquine is in combination therapy.

Mefloquine

Antimalarial Action: Mefloquine has strong blood schizonticidal activity against

P falciparum and P vivax, but it is not active against hepatic sta-ges or
gametocytes. The mechanism of action of mefloquine is unknown.

Resistance: Sporadic resistance to mefloquine has been reported from many

areas. At present, resistance appears to be uncommon except in regions of
Southeast Asia with high rates of multidrug resistance (especially border areas of
Thailand). Mefloquine resistance appears to be associated with resistance to
quinine and halofantrine but not with resistance to chloroquine.

Antibiotics

The antibiotics that are bacterial protein synthesis inhibitors appear to act against
malaria parasites by inhibiting protein synthesis in a plasmodial prokaryote-like
organelle, the apicoplast. None of the antibiotics should be used as single agents
in the treatment of malaria.

Tetracycline and doxycycline are active against erythrocytic schizonts of all

human malaria parasites. They are not active against liver stages.

Doxycycline is used in the treatment of falciparum malaria in conjunction with

quinine, allowing a shorter and better-tolerated course of that drug. Doxycycline is
also used to complete treatment courses after initial treatment of severe malaria
with intravenous quinine, quinidine, or artesunate. Doxycycline has also become a
standard chemoprophylactic drug, especially for use in areas of Southeast Asia
with high rates of resistance to other antimalarials, including mefloquine.
Doxycycline adverse effects include gastrointestinal symptoms, candidal vaginitis,
and photosensitivity. Its safety in long-term chemoprophylaxis has not been
extensively evaluated.

Clindamycin is slowly active against erythrocytic schizonts and can be used after
treatment courses of quinine, quinidine, or artesunate in those for whom
doxycycline is not recommended, such as children and pregnant women.

Azithromycin also has antimalarial activity and is now under study as an

alternative chemoprophylactic drug. Antimalarial activity of fluoroquinolones has
been demonstrated, but efficacy for the therapy or chemoprophylaxis of malaria
has been suboptimal.

Artemisinin & Its Derivatives

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Artemisinin (qinghaosu) is a sesquiterpene lactone endoperoxide, the active

component of an herbal medicine that has been used as an antipyretic in China
for over 2000 years. Artemisinin is insoluble and can only be used orally. Analogs
have been synthesized to increase solubility and improve antimalarial efficacy.
The most important of these analogs are artesunate (water-soluble; useful for
oral, intravenous, intramuscular, and rectal administration), artemether (lipidsoluble; useful for oral, intramuscular, and rectal administration), and
dihydroartemisinin (water-soluble; useful for oral administration). Artemisinin
and its analogs are rapidly absorbed, with peak plasma levels occurring in 12
hours and half-lives of 13 hours after oral administration. Artemisinin, artesunate,
and artemether are rapidly metabolized to the active metabolite
dihydroartemisinin.

Artemisinin monotherapy for the treatment of uncomplicated malaria is now

strongly discouraged. Rather, co-formulated artemisinin-based combination
therapies are recommended to improve efficacy and prevent the selection of
artemisinin-resistant parasites. No artemisinins are yet approved by the FDA, but
intravenous artesunate was made available by the CDC in 2007; use of the drug
can be initiated by contact with the CDC, which will release the drug for
appropriate indications (falciparum malaria with signs of severe disease or
inability to take oral medications) from stocks stored around the USA.

Artemisinin and its analogs are very rapidly acting blood schizonticides against all
human malaria parasites. Artemisinins have no effect on hepatic stages. The
antimalarial activity of artemisinins may result from the production of free radicals
that follows the iron-catalyzed cleavage of the artemisinin endoperoxide bridge in
the parasite food vacuole or from inhibition of a parasite calcium ATPase.
Artemisinin resistance is not yet an important problem, but P falciparum isolates
with diminished in vitro susceptibility to artemether have recently been described.
In addition, increasing rates of treatment failure and increases in parasite
clearance times after use of artesunate-mefloquine in parts of Cambodia may be
early signs of a worrisome decrease in artesunate efficacy.

Artemisinins are generally very well tolerated. The most commonly reported
adverse effects are nausea, vomiting, diarrhea, and dizziness, and these may
often be due to underlying malaria rather than the medications. Rare serious
toxicities include neutropenia, anemia, hemolysis, elevated liver enzymes, and
allergic reactions. Irreversible neurotoxicity has been seen in animals, but only
after doses much higher than those used to treat malaria. Artemisinins have been
embryotoxic in animal studies, but rates of congenital abnormalities, stillbirths,
and abortions were not elevated, compared with those of controls, in women who
received artemisinins during pregnancy. Based on this information and the
significant risk of malaria during pregnancy, the WHO recommends artemisininbased combination therapies for the treatment of uncomplicated falciparum
malaria during the second and third trimesters of pregnancy, intravenous
artesunate or quinine for the treatment of severe malaria during the first
trimester, and intravenous artesunate for treatment of severe malaria during the
second and third trimesters.

Quinine & Quinidine

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Chemistry & Pharmacokinetics: Quinine is derived from the bark of the

cinchona tree, a traditional remedy for intermittent fevers from South America.
The alkaloid quinine was purified from the bark in 1820, and it has been used in
the treatment and prevention of malaria since that time. Quinidine, the
dextrorotatory stereoisomer of quinine, is at least as effective as parenteral
quinine in the treatment of severe falciparum malaria. After oral administration,
quinine is rapidly absorbed, reaches peak plasma levels in 13 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. The pharmacokinetics
of quinine varies among populations. Individuals with malaria develop higher
plasma levels of the drug than healthy controls, but toxicity is not increased,
apparently because of increased protein binding. The half-life of quinine also is
longer in those with severe malaria (18 hours) than in healthy controls (11 hours).
Quinidine has a shorter half-life than quinine, mostly as a result of decreased
protein binding. Quinine is primarily metabolized in the liver and excreted in the
urine.

Antimalarial Action: Quinine is a rapid-acting, highly effective blood

schizonticide against the four species of human malaria parasites. The drug is
gametocidal against P vivax and P ovale but not P falciparum. It is not active
against liver stage parasites. The mechanism of action of quinine is unknown.

Resistance: Increasing in vitro resistance of parasites from a number of areas

suggests that quinine resistance will be an increasing problem. Resistance to
quinine is already common in some areas of Southeast Asia, especially border
areas of Thailand, where the drug may fail if used alone to treat falciparum
malaria. However, quinine still provides at least a partial therapeutic effect in
most patients.

Adverse Effects: Therapeutic dosages of quinine and quinidine commonly cause

tinnitus, headache, nausea, dizziness, flushing, and visual disturbances, a
constellation of symptoms termed cinchonism. Mild More severe findings, often
after prolonged therapy, include more marked visual and auditory abnormalities,
vomiting, diarrhea, and abdominal pain. Hypersensitivity reactions include skin
rashes, urticaria, angioedema, and bronchospasm. Hematologic abnormalities
include hemolysis (especially with G6PD deficiency), leukopenia, agranulocytosis,
and thrombocytopenia. Therapeutic doses may cause hypoglycemia through
stimulation of insulin release; this is a particular problem in severe infections and
in pregnant patients, who have increased sensitivity to insulin. Quinine can
stimulate uterine contractions, especially in the third trimester.

Contraindications & Cautions: Quinine (or quinidine) should be discontinued if

signs of severe cinchonism, hemolysis, or hypersensitivity occur. It should be
avoided if possible in patients with underlying visual or auditory problems. It must
be used with great caution in those with underlying cardiac abnormalities. Quinine
should not be given concurrently with mefloquine and should be used with caution
in a patient with malaria who has previously received mefloquine
chemoprophylaxis. Absorption may be blocked by aluminum-containing antacids.
Quinine can raise plasma levels of warfarin and digoxin. Dosage must be reduced
in renal insufficiency.

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Primaquine

Chemistry & Pharmacokinetics: Primaquine phosphate is a synthetic 8aminoquinoline. The drug is well absorbed orally, reaching peak plasma levels in
12 hours. The plasma half-life is 38 hours. Primaquine is widely distributed to
the tissues, but only a small amount is bound there. It is rapidly metabolized and
excreted in the urine. Its three major metabolites appear to have less antimalarial
activity but more potential for inducing hemolysis than the parent compound.

Antimalarial Action: Primaquine is active against hepatic stages of all human

malaria parasites. It is the only available agent active against the dormant
hypnozoite stages of P vivax and P ovale. Primaquine is also gametocidal against
the four human malaria species. Primaquine acts against erythrocytic stage
parasites, but this activity is too weak to play an important role. The mechanism
of antimalarial action is unknown.

Resistance: Some strains of P vivax in New Guinea, Southeast Asia, Central and
South America, and other areas are relatively resistant to primaquine. Liver forms
of these strains may not be eradicated by a single standard treatment with
primaquine and may require repeated therapy. Because of decreasing efficacy,
the standard dosage of primaquine for radical cure of P vivax infection was
recently doubled to 30 mg base daily for 14 days.

Adverse Effects: Primaquine in recommended doses is generally well tolerated.

It infrequently causes nausea, epigastric pain, abdominal cramps, and headache,
and these symptoms are more common with higher dosages and when the drug is
taken on an empty stomach. More serious but rare adverse effects are leukopenia,
agranulocytosis, leukocytosis, and cardiac arrhythmias. Standard doses of
primaquine may cause hemolysis or methemoglobinemia (manifested by
cyanosis), especially in persons with G6PD deficiency or other hereditary
metabolic defects.

Contraindications & Cautions: Primaquine should be avoided in patients with a

history of granulocytopenia or methemoglobinemia, in those receiving potentially
myelosuppressive drugs (eg, quinidine), and in those with disorders that
commonly include myelosuppression. It is never given parenterally because it
may induce marked hypotension. Patients should be tested for G6PD deficiency
before primaquine is prescribed. When a patient is deficient in G6PD, treatment
strategies may consist of withholding therapy and treating subsequent relapses, if
they occur, with chloroquine; treating patients with standard dosing, paying close
attention to their hematologic status; or treating with weekly primaquine (45 mg
base) for 8 weeks. G6PD-deficient individuals of Mediterranean and Asian ancestry
are most likely to have severe deficiency, whereas those of African ancestry
usually have a milder biochemical defect. This difference can be taken into
consideration in choosing a treatment strategy. In any event, primaquine should
be discontinued if there is evidence of hemolysis or anemia. Primaquine should be
avoided in pregnancy because the fetus is relatively G6PD-deficient and thus at
risk of hemolysis.

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Reference:
Katzung Basic & Clinical Pharmacology, 11th Edition