Antimalarial drugs

Year 2013

Solomon M. Abay (PhD)

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 Introductory case-1
A 57-year-old medical missionary developed fever, diarrhea, headache,
vomiting, and dark urine about 10 days after returning to the United
States from a month-long trip to East Africa. The patient has been taking
chloroquine and proguanil chemoprophylaxis.

Physical examination: the patient is feverish, agitated, sweating, weak,

and in mild distress, with a blood pressure 95/60 (normal, 120/80), a
pulse of 120 (normal, 60–100), and temperature of 104°F (40°C) (normal,
98.6°F, 37°C).

Laboratory findings are a hematocrit of 25% (normal for male, 40–54%);

platelet count 29,000 (normal, 150,000–400,000/mm3); parasitemia 6% (P.
falciparum); serum creatinine 3.5 mg/dL (Normal for male, 0.8–1.5
mg/dL); and plasma glucose 39 mg/dL (Normal fasting, 65–110 mg/dL).

What is the diagnosis and best choice of drug therapy?

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 Introductory case-2

Case: AJ is an American film stardom who lives in New York.

She wants to visit a hospital in the Southern part of Ethiopia
for five days. She requires antimalarial prophylaxis. Assume
you are her personal physician, which medication are you
intending to prescribe for chemoprophylaxis?

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• Caused by
– Plasmodium falciparum
– P. vivax
– P. ovale
– P. malariae
– P. knowlesi

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Figure: Plasmodium life cycle. The morphology of Plasmodium life cycle stages varies between species. Those
shown in the illustration are P. falciparum, except for the hypnozoite, which occurs only in P. vivax and P. ovale
(Griffith et al. 2007).
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 Malaria Control
• Vaccines: e.g. RTS,S/AS01
• Bednets
• Window and door screening
• Repellents
• Antiprotozoals

• Malaria 1955-1975: DDT & chloroquine; $2

billion spent; insecticide resistance
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Classification of AntimalarialAgents
1. Tissue Schizontocidal Drugs
2. Blood Schizontocidal Drugs
3. Gametocytocidal drugs: Destroy sexual erythrocytic stages
preventing transmission to mosquito
4. Sporontocidal drugs: Prevent formation of oocyst and
sporozoites in mosquito

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antimalarials

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 Tissue schizonticide: Primaquine

• Primaquine: an 8-aminoquinoline
– eradicates primary exoerythrocytic forms of P. falciparum
and P. vivax and the secondary exoerythrocytic forms of
recurring malarias (P. vivax and P. ovale).
• Primaquine: is the only agent that can lead to radical cures of
the P. vivax and P. ovale malarias
• Sexual (gametocytic) forms of all four plasmodia are destroyed
in the plasma thus interrupting the transmission of the disease.
• not effective against the asexual erythrocytic stage of malaria.

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 Tissue schizonticide: Primaquine
• Mechanism of action: not well 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.

• Pharmacokinetics: Primaquine is well absorbed on

oral administration and is not concentrated in tissues.

• It is rapidly oxidized to many compounds.

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 Tissue schizonticide: Primaquine

Clinical Uses
• Therapy (Radical Cure=prevention of relapse) of acute vivax
and ovale malaria
– A 14-day course of primaquine is given (G6PD level ??).
• Terminal Prophylaxis of vivax and ovale malaria
– Some authorities advocate the use of primaquine after the completion of travel
to an endemic area.
• Chemoprophylaxis of malaria
– Daily treatment with 0.5 mg/kg of base provided good levels of protection
against falciparum and vivax malaria. However, potential toxicities of long-term
use remain a concern

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 Tissue schizonticide: Primaquine
Clinical Uses…
• Gametocytocidal action
– A single low dose of primaquine (0.25mg/kg) can be used as a control
measure to render P. falciparum gametocytes noninfective to mosquitoes.
• Pneumocystis jiroveci Infection
– Clindamycin and primaquine is an alternative regimen in the treatment of
pneumocystosis, particularly mild to moderate disease.
– This regimen offers improved tolerance compared with high-dose
trimethoprim-sulfamethoxazole or pentamidine

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Tissue schizonticide: Primaquine
• Adverse effects: Primaquine has a low incidence of adverse
effects, except for drug-induced hemolytic anemia in patients
with genetically low levels of G6PD
• Other toxic manifestations observed after large doses of the
drug include abdominal discomfort, especially when
administered in combination with chloroquine, and occasional
methemoglobinemia.
• Granulocytopenia and agranulocytosis are rarely seen
• Primaquine is contraindicated during pregnancy.

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 Blood schizonticide: Chloroquine
• A synthetic 4-aminoquinoline
• Highly specific for the asexual form
• P. falciparum resistant in many areas
• Chloroquine:
– Extraintestinal amebiasis
– Rheumatoid arthritis and discoid lupus
erythematosus

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 Blood schizonticide: Chloroquine
• Mechanism of action:
– Concentrated in the organism's acidic food vacuole, binds
to heme, preventing its polymerization to hemozoin.
– Quinidine and mefloquine acts similarly.

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 Blood schizonticide: Chloroquine
• Pharmacokinetics:
– rapidly and completely absorbed following oral
administration.
– concentrates in erythrocytes, liver, spleen, kidney, lung,
melanin-containing tissues, and leukocytes.
• Very large volume of distribution; ca 200 L/kg
• It persists in erythrocytes.
• Chloroquine is dealkylated by the hepatic mixed-function oxidase
system
• Some metabolic products retain antimalarial activity.
• Excretion rate is enhanced in acidified urine
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 Blood schizonticide: Chloroquine
Clinical uses
• Treatment: Chloroquine is the drug of choice in the treatment of
nonfalciparum and sensitive falciparum malaria.
– Chloroquine does not eliminate dormant liver forms of P. vivax and P
ovale, [primaquine]
• Chemoprophylaxis: in malarious regions without resistant
falciparum malaria.
– Eradication of P vivax and P ovale requires a course of primaquine to
clear hepatic stages.
• Amebic liver abscess: Chloroquine reaches high liver
concentrations and may be used for amebic abscesses that fail
initial therapy with metronidazole.
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 Blood schizonticide: Chloroquine
• Adverse effects:
– Side effects are minimal at the low doses: in chemosuppression.
– At higher doses: GI upset, pruritus, headaches, and blurring of
vision.
– Discoloration of the nail beds and mucous membranes may be
seen on chronic administration.
– Can cause ECG changes, because it has a quinidine-like effect.
– May exacerbate dermatitis produced by gold/phenylbutazone
therapy.
– Patients with psoriasis or porphyria should not be treated with
chloroquine, because an acute attack may be provoked.

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 Blood schizonticide: Chloroquine
• 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.
– Chloroquine resistance can be reversed experimentally
by verapamil, desipramine, and chlorpheniramine
• Clinical value???

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 Blood schizonticide: Amodiaquine
• 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:
– its low cost,
– limited toxicity, and,
– in some areas, effective against chloroquine-resistant P. falciparum
• Rare toxicity: agranulocytosis, aplastic anemia, and hepatotoxicity
• The WHO recommends:
– Amodiaquine plus artesunate
– Amodiaquine plus fansidar (sulfadoxine-pyrimethamine) as an
interim alternative if artemisinin-containing therapies are
unavailable.
• Chemoprophylaxis with amodiaquine is best avoided because of its
apparent increased toxicity with long-term use.
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 Blood schizonticide: Mefloquine
• An effective single agent for suppressing and curing infections
caused by multidrug-resistant forms of P. falciparum.
• Its exact mechanism of action remains to be determined, but like
quinine, it can apparently damage the parasite's membrane.
• Mefloquine is absorbed well after oral administration and
concentrates in the liver and lung.
• It has a long half-life (17 days)
• Adverse reactions at high doses range from nausea, vomiting, and
dizziness to disorientation, hallucinations, and depression.
• ECG abnormalities and cardiac arrest are possible if mefloquine is
taken concurrently with quinine or quinidine.
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 Blood schizonticides: Quinine and quinidine
• Quinine and its stereoisomer, quinidine, interfere with heme polymerization,
• Used in severe malaria and for malarial strains that are resistant to other
agents.
• Taken orally, quinine is well distributed throughout the body and can reach
the fetus.
• Acidification of urine increases its excretion.
• Adverse effect of quinine is cinchonism: a syndrome causing nausea,
vomiting, tinnitus, and vertigo.
• Blackwater fever: seems hypersensitivity reaction.
• Drug interactions
– quinine potentiate neuromuscular-blocking agents and
– elevation of digoxin levels if taken concurrently
– Quinine absorption is retarded when the drug is taken with aluminum-
containing antacids.
• High doses of quinine terminate pregnancy may cause fetal abnormalities
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 Blood schizonticide: Artemisinin
• Artemisinin is derived from the qinghaosu plant, which
has been used in Chinese medicine for more than two
millennia in the treatment of fevers and malaria.

• Artemisinin derivatives: available for the treatment of

severe (artesunate iv), multidrug-resistant P. falciparum
malaria.

• Its antimalarial action involves the production of free

radicals within the plasmodium food vacuole
• It is also believed to covalently bind to and damage
specific malarial proteins.
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 Blood schizonticide: Artemisinin
• Activation and targeting parasite proteins

• Target proteins
– Artemisinin increases lipid damage (Berman Adams 1997)
– Binds and inhibits calcium transporter PfATPase6
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– Does not prevent hemecrystallization even though binds heme
 Blood schizonticide: Artemisinin
• Oral, rectal, and intravenous preparations are
available, but the short half-lives preclude their
use in chemoprophylaxis.
• They are metabolized in the liver and are
excreted primarily in the bile.
• Adverse effects: nausea, vomiting, and diarrhea,
but overall, artemisinin is remarkably safe.
– Neurotoxicity and prolongation of the QT interval at
high dose
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• Major artemisinin derivatives:
– Arthemeter with lumefantrine p.o
– Artesunate iv, suppository

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 Blood schizonticide: Artemisinin
Resistance:
• Over the centuries there has been no documented
artemisinin resistance in the treatment of malaria.
• Recently, however, reduced parasite susceptibility in
artesunate and DHA-treated patients was observed on the
Thai and Cambodian border.
– Possible reason:
• Widespread use of fake antimalarials and self-medication of poor
quality (e.g., ACT containing only traces of artemisinin) which can kill
sensitive parasites but at the same time encourage selection of
resistant forms
• Monotherapy

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• Started in Cambodia (Thai
borders) > spreading (?)
• Significant reduction in
parasite clearance rate
with artemisinins;
• Due to?: reduced killing
of ring-stage parasites; Laos

quiescence ?
Thailand
• SNPs on chromosome 13 Cambodia

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Original & (potential) new foci of artemisinin
resistance

Dondorp et al, NEJM 2009

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 Blood schizonticide and sporontocide:
Pyrimethamine
• Activity: blood schizonticide.
– strong sporonticide in the mosquito's gut when the mosquito
ingests it with the blood of the human host.
• Mechanism: inhibits plasmodial dihydrofolate reductase at
much lower concentrations than those needed to inhibit
the mammalian enzyme.
• Pyrimethamine alone is not effective against P. falciparum
• In combination with a sulfonamide, it is also used against
Toxoplasma gondii.
• If megaloblastic anemia occurs with pyrimethamine
treatment, it may be reversed with leucovorin.
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 Inhibition of dihydrofolate reductases by
pyrimethamine and trimethoprim

• Concentration (nM) for 50% inhibition of DHFR

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 Primary tissue schizontocide and blood
schizontocide: Proguanil
• Prodrug metabolized to an active metabolite, cycloguanil
• Mechanism: Selectively inhibits dihydrofolate reductase
• Slow antimalarial action
• Therapeutic uses:
– Proguanil + chloroquine used as alternative to mefloquine for
prophylaxis
– Proguanil + atovaquone used as prophylaxis (malarone)
• Malarone: for the treatment of mild/moderate malarial
attacks due to chloroquine- and multidrug-resistant strains of
P. falciparum and P. vivax
• Considered safe for use during pregnancy
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 Antibiotics
• Modestly active antimalarials.
• None of the antibiotics should be used as single agents
• Tetracycline and doxycycline are active against erythrocytic schizonts
of all human malaria parasites.
• Doxycycline is commonly used in the treatment of falciparum
malaria in conjunction with quinidine or quinine, allowing a shorter
and better-tolerated course of quinine.

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 Antibiotics…
• Doxycycline has also become a standard chemoprophylactic
drug, especially for use in areas with high rates of resistance
to other antimalarials, including mefloquine.

• Clindamycin is slowly active against erythrocytic schizonts and

can be used in conjunction with quinine or quinidine in those
for whom doxycycline is not recommended
– Children and Pregnant women.

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 Others
• Halofantrine & Lumefantrine
– Halofantrine:
• Effective against erythrocytic stages of all for human malaria species
• Oral absorption is variable & is enhanced with food
• Plasma half-life 4 days
– Is generally well tolerated
• Altered cardiac conduction

– Lumefantrine:
• Available in fixed dose combination with artemether as Coartem
• Plasma half-life= 4 days
• Coartem is very effective for Rx of P. falciparum [mild to moderate
infection]

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Thank you

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