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ANTIPROTOZOAL DRUGS II
PHARMACOLOGY IV
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CHEMOTHERAPY FOR MALARIA

Blood schizonticide: Chloroquine
Chloroquine is a synthetic 4-aminoquinoline that 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 extra intestinal
amebiasis.
The anti-inflammatory action of chloroquine explains its
occasional use in rheumatoid arthritis and discoid lupus
erythematosus.
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Action of chloroquine on the formation of

hemozoin by Plasmodium species
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Mechanism of action
The following processes are essential for the drug’s lethal
action:
After traversing the erythrocytic and plasmodial membranes,
chloroquine (a diprotic weak base) is concentrated in the
organism’s acidic food vacuole, primarily by ion trapping. 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 (ferriprotoporphyrin IX), 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.
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Mechanism of action
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 antiplasmodial activity, which
may represent a unifying mechanism for such diverse
compounds as chloroquine, quinidine, and mefloquine.
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Pharmacokinetics
Chloroquine is rapidly and completely absorbed following oral
administration. Usually, 4 days of therapy suffice to cure the
disease.
The drug has a very large volume of distribution and
concentrates in erythrocytes, liver, spleen, kidney, lung,
melanin-containing tissues, and leukocytes.
The drug also penetrates the central nervous system (CNS)
and traverses the placenta.
Chloroquine is de-alkylated by the hepatic mixed-function
oxidase system, but some metabolic products retain
antimalarial activity.
Both parent drug and metabolites are excreted predominantly
in urine, the excretion rate is enhanced with acidified urine.
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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, headaches, 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 or severe gastrointestinal problems and in patients
with neurologic or blood disorders.
Chloroquine can cause electrocardiographic (ECG) changes,
because it has a quinidine-like effect.
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Resistance
Resistance of plasmodia to available drugs has become a
serious medical problem .
Chloroquine-resistant P. falciparum exhibit multigenic
alterations that confer a high level of resistance.
Quinine is the standard drug for oral treatment of acute
attacks of malaria caused by chlorquine resistance P.
falciparum .
It should be used in combination with another antimalarial
agents such as doxycycline, clindamycin or pyrimethamine
plus sulfadoxine.
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Blood schizonticide: Mefloquine

Mefloquine appears to be promising as an effective single agent
for suppressing and curing infections caused by multidrug
resistant forms of P. falciparum.
Like quinine, it can apparently damage the parasite’s
membrane.
Resistant strains have been identified.
Mefloquine is absorbed well after oral administration and
concentrates in the liver and lung.
It has a long half-life (17 days) because of its concentration in
various tissues and its continuous circulation through the
enterohepatic and enterogastric systems.
The drug undergoes extensive metabolism. Its major excretory
route is through the feces.
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Blood schizonticide: Mefloquine

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

• 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.
• Taken orally, quinine is well distributed throughout the body and
can reach the fetus in pregnant patients.
• Alkalinization of urine decreases its excretion.
• 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.
• Quinine treatment should be suspended if hemolytic anemia
occurs.
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Blood schizonticides: Quinine

• Drug interactions include potentiation of neuromuscular-
blocking agents and elevation of digoxin levels if taken
concurrently with quinine.
• Quinine absorption is retarded when the drug is taken with
aluminum-containing antacids.
• Quinine is fetotoxic.
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Blood schizonticide: Artemisinin

• Artemisinin (or one of its derivatives) is available for the treatment
of severe, multidrug-resistant P. falciparum malaria.
• Artemisinin (or one of its derivatives) are metabolized in the food
vacuole of the parasite forming toxic free radicals.
• It is also believed to covalently bind to and damage specific
malarial proteins.
• Oral, rectal, and intravenous (IV) preparations are available.
• They are metabolized in the liver and are excreted primarily in bile.

• Adverse effects include nausea, vomiting, and diarrhea, but,

overall, artemisinin is remarkably safe.
• Extremely high doses may cause neurotoxicity and
prolongation of the QT interval.
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Blood schizonticide and sporontocide:

Pyrimethamine
It acts as a strong sporonticide in the mosquito’s gut when
the mosquito ingests it with the blood of the human host.

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 purines and
pyrimidines and in the inter conversions of certain amino acids.
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Blood schizonticide and sporontocide:

Pyrimethamine
• Pyrimethamine alone is effective 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.
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Summary of trypanosomiasis Treatment and prevention of

malaria
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CHEMOTHERAPY FOR TRYPANOSOMIASIS

Trypanosomiasis refers to African sleeping sickness and

American sleeping sickness, two chronic and, eventually,
fatal diseases caused by species of Trypanosoma .

In African sleeping sickness, the causative organisms, T.

brucei gambiense and T. brucei rhodiense, initially live and
grow in the blood. The parasite invades the CNS, causing an
inflammation of the brain and spinal cord that produces the
characteristic lethargy and, eventually, continuous sleep.

Chagas disease (American sleeping sickness) is caused by

T. cruzi and occurs in South America.
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Melarsoprol
Its use is limited to the treatment of trypanosomal infections
(usually in the late stage with CNS involvement), and it is lethal
to these parasites.
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Mechanism of action
The drug reacts with sulfhydryl groups of various substances,
including enzymes in both the organism and host.
The parasite's enzymes may be more sensitive than those of the
host. There is evidence that mammalian cells may be less
permeable to the drug and, thus, are protected from its toxic
effects.

Trypanosomal resistance may also be due to decreased

permeability of the drug.
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Pharmacokinetics
Melarsoprol usually is slowly administered intravenously
through a fine needle, even though it is absorbed from the
gastrointestinal tract. Because it is very irritating, care should
be taken not to infiltrate surrounding tissue.
Adequate trypanocidal concentrations appear in the CSF, in
contrast to nonpenetration of the CSF by pentamidine.
Melarsoprol is the agent of choice in the treatment of T. brucei
rhodesiense, which rapidly invades the CNS, as well as for
meningoencephalitis caused by T. brucei gambiense.
The host readily oxidizes melarsoprol to a relatively nontoxic,
pentavalent arsenic compound.
The drug has a very short half-life and is rapidly excreted into
the urine .
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Adverse effects
• CNS toxicities are the most serious side effects of melarsoprol
treatment.
• Encephalopathy may appear soon after the first course of treatment
but usually subsides. It may, however, be fatal.
• Hypersensitivity reactions may also occur, and fever may follow
injection.
• Gastrointestinal disturbances, such as severe vomiting and
abdominal pain, can be minimized if the patient is in the fasting state
during drug administration and for several hours thereafter.
• Melarsoprol is contraindicated in patients with influenza because of
heightened probability of febrile episodes in influenza. It has been
associated with an increased in incidence of reactive arsenic
encephalopathy when given to febrile patients.
• Hemolytic anemia has been seen in patients with glucose 6-
phosphate dehydrogenase deficiency.
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Pentamidine isethionate
• Pentamidine is active against a variety of protozoal infections,
including many trypanosomes, such as T. brucei gambiense,
for which pentamidine is used to treat and prevent the
organism's hematologic stage.
• Some trypanosomes, including T. cruzi, are resistant.
• Pentamidine is also effective in the treatment of systemic
blastomycosis (caused by the fungus Blastomyces
dermatitidis) and in treating infections caused by
Pneumocystis jiroveci .
• Trimethoprim-sulfamethoxazole is preferred in the treatment of
P. jiroveci infections.
• Pentamidine is the drug of choice in treating patients with
pneumonia caused by P. jiroveci who have failed to respond to
trimethoprim-sulfamethoxazole.
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Pentamidine isethionate
• The drug is also used in treating P. jiroveci infected individuals
who are allergic to sulfonamides.

• Because of the increased incidence of pneumonia caused by

this organism in immunocompromised patients, such as those
infected with human immunodeficiency virus, pentamidine has
assumed an important place in chemotherapy.

• Pentamidine is also an alternative drug to stibogluconate in

the treatment of leishmaniasis.
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Mechanism of action
• The drug binds to the parasite's DNA and interferes with the
synthesis of RNA, DNA, phospholipid, and protein by the
parasite.
• Trypanosoma brucei concentrates pentamidine by an
energy-dependent, high-affinity uptake system.
• Resistance is associated with an inability of the trypanosome to
concentrate the drug.
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Pharmacokinetics
• Fresh solutions of pentamidine are administered intramuscularly
or as an aerosol.
• The intravenous route is avoided because of severe adverse
reactions, such as a sharp fall in blood pressure and tachycardia
• The drug is concentrated and stored in the liver and kidney for a
long period of time.
• Because it does not enter the CSF, it is ineffective against the
meningoencephalitic stage of trypanosomiasis.
• The drug is not metabolized, and it is excreted very slowly into
the urine.
• Its half-life in the plasma is about 5 days.
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Adverse effects
Serious renal dysfunction may occur, which reverses on
discontinuation of the drug.
Other adverse reactions are hypotension, dizziness, rash, and
toxicity to β cells of the pancreas.
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Nifurtimox
Nifurtimox has found use only in the treatment of acute T. cruzi
infections (Chagas disease).
Nifurtimox is suppressive, not curative.
Being a nitroaromatic compound, nifurtimox undergoes reduction
and eventually generates intracellular oxygen radicals, such as
superoxide radicals and hydrogen peroxide.
These highly reactive radicals are toxic to T. cruzi.

Mammalian cells are partially protected from such substances

by the presence of enzymes, such as catalase, glutathione
peroxidase, and superoxide dismutase.
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Nifurtimox
Nifurtimox is administered orally and is rapidly absorbed and
metabolized to unidentified products that are excreted in the
urine.
Adverse effects are common following chronic administration,
particularly among the elderly.
Major toxicities include immediate hypersensitivity reactions
such as anaphylaxis; delayed hypersensitivity reactions, such as
dermatitis and icterus(jaundice); and gastrointestinal problems
that may be severe enough to cause weight loss.
Peripheral neuropathy is relatively common, and disturbances in
the CNS may also occur.
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Suramin
• Suramin is used primarily in the early treatment and,
especially, the prophylaxis of African trypanosomiasis.
• It is very reactive and inhibits many enzymes, among them
those involved in energy metabolism (for example, glycerol
phosphate dehydrogenase), which appears to be the
mechanism most closely correlated with trypanocidal activity.
• The drug must be injected intravenously.
• It binds to plasma proteins and remains in the plasma for a
long time, accumulating in the liver and in the proximal tubular
cells of the kidney.
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Suramin
The severity of the adverse reactions demands that the patient be
carefully followed.
Although infrequent, adverse reactions include
1. nausea and vomiting (which cause further debilitation of the patient)
2. shock and loss of consciousness
3. acute urticaria
4. neurologic problems(paresthesia)
5. photophobia
6. palpebral edema (edema of the eyelids)
7. hyperesthesia of the hands and feet

Albuminuria tends to be common, but when cylindruria (the

presence of renal casts in the urine) and hematuria occur,
treatment should cease.
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Benznidazole
Benznidazole is a nitroimidazole derivative that inhibits protein
and RNA synthesis in T. cruzi cells.
• It is an alternative choice for treatment of acute and
indeterminate phases of Chagas disease, but therapy with
benznidazole does not offer any significant efficacy or toxicity
advantages over that with nifurtimox.
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CHEMOTHERAPY FOR LEISHMANIASIS

• There are three types of leishmaniasis:
cutaneous, mucocutaneous, and visceral.
• In the visceral type (liver and spleen), the parasite is in the
bloodstream and can cause very serious problems.
• Leishmaniasis is transmitted from animals to humans (and
between humans) by the bite of infected sand flies.
• The diagnosis is established by demonstrating the parasite in
biopsy material and skin lesions.
• The treatments of leishmaniasis and trypanosomiasis are
difficult, because the effective drugs are limited by their toxicities
and failure rates.
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CHEMOTHERAPY FOR LEISHMANIASIS

Sodium stibogluconate (pentavalent antimony), the primary
drug in all forms of the disease, appears to kill the parasite
by inhibition of glycolysis or effects on nucleic acid metabolism.
Stibogluconate must be administered parenterally and is
potentially cardiotoxic (QT prolongation).
Alternative agents include pentamidine (for visceral
leishmaniasis), fluconazole or metronidazole (for cutaneous
lesions), and amphotericin B (for mucocutaneous
leishmaniasis).
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CHEMOTHERAPY FOR TOXOPLASMOSIS

One of the most common infections in humans is caused by the
protozoan Toxoplasma gondii, which is transmitted to humans when
they consume raw or inadequately cooked infected meat.
An infected pregnant woman can transmit the organism to her fetus.
Cats are the only animals that shed oocysts, which can infect other
animals as well as humans.
The treatment of choice for this condition is a combination of
sulfadiazine and pyrimethamine.
Leucovorin is commonly administered to protect against folate
deficiency.
At the first appearance of a rash, pyrimethamine should be
discontinued, because hypersensitivity to this drug can be severe.
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Life cycle of Giardia lamblia

• Giardia lamblia is the most commonly diagnosed intestinal
parasite. Ingestion, usually from contaminated drinking water,
leads to infection.
• The trophozoites exist in the small intestine and divide by binary
fission.
• Occasionally, cysts are formed that pass out in stools.
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CHEMOTHERAPY FOR GIARDIASIS

Although some infections are asymptomatic, severe diarrhea can
occur, which can be very serious in immune-suppressed
patients.
The treatment of choice is metronidazole for 5 days.
One alternative agent is tinidazole, which is equally effective as
metronidazole in the treatment of giardiasis but with a much
shorter course of therapy (2 grams given once).
Nitazoxanide, a nitrothiazole derivative structurally similar to
aspirin, was recently approved for the treatment of giardiasis.
Nitazoxanide is also equally efficacious as metronidazole and,
in comparison, has a two-day-shorter course of therapy.
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