Antiprotozoal Drugs

Group members :
• Asfa
• Alisha
• Laraib
• Moazama
• Noor–e-sehar
 Table of Contents
• Introduction
• Chemotherapy for Amebiasis
• Chemotherapy For Malaria
• Chemotherapy For Trypanosomiasis
• Chemotherapy For Leishmaniasis
• Chemotherapy For Toxoplasmosis
• Chemotherapy For Giardiasis
 Introduction:
• Protozoal infections are common among people in underdeveloped
tropical and subtropical countries, where
• sanitary conditions,
• hygienic practices, and
• control of the vectors of transmission are inadequate.

• However, with increased world travel, protozoal diseases are no longer

confined to specific geographic locales.

• Because they are unicellular eukaryotes, the protozoal cells have metabolic
processes closer to those of the human host than to prokaryotic bacterial
pathogens.
• Therefore, protozoal diseases are less easily treated than bacterial
infections, and many of the antiprotozoal drugs cause serious toxic
effects in the host, particularly on cells showing high metabolic
activity.

• Most antiprotozoal agents have not proven to be safe for pregnant

patients.

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 II. CHEMOTHERAPY FOR AMEBIASIS

•Amebiasis (also called amebic dysentery) is an infection of the

intestinal tract caused by Entamoeba histolytica.

The disease can be acute or chronic, with varying degrees of illness, from
no symptoms to mild diarrhea to fulminating dysentery.

The diagnosis is established by isolating E. histolytica from feces.

Therapy is indicated for acutely ill patients and asymptomatic carriers,

since dormant E. histolytica may cause future infections in the carrier and
be a potential source of infection for others.
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 Therapeutic agents for amebiasis are classified as
• luminal,
• systemic, or
• mixed amebicides according to the site of action.

 For example, luminal amebicides act on the parasite in the lumen of

the bowel, whereas systemic amebicides are effective against
amoebas in the intestinal wall and liver.
 Mixed amebicides are effective against both the luminal and
systemic forms of the disease, although luminal concentrations are
too low for single-drug treatment.
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 A. Mixed amebicides

 Metronidazle:

 Tinidazole:

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 1. Metronidazole:
 Nitroimidazole is the mixed amebicide of choice for treating amebic
infections.
Acts on trophozoites.
Has no effect on cysts

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 a. Mechanism of action:

 Amebas possess ferredoxin-like, low-redox-potential,

electron transport proteins that participate in metabolism
electron removal reactions. The nitro group of
metronidazole is able to serve as an electron acceptor,
forming reduced cytotoxic compounds that binds to
proteins and DNA, resulting in death of the E. histolytica
trophozoites.

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 b. Pharmacokinetics:
•Given orally or IV.
•Absorption is rapid and complete.
•Due to rapid absorption from GIT, not reliably effective against luminal
parasites.
•Wide distribution to all tissues and body fluids (CSF, saliva, milk).
•Plasma protein binding is low ( < 20%).
•Plasma half life is 8 h
•Metabolized in liver by mixed function oxidase followed by glucouroidation.
•Excreted in urine as unchanged drug plus metabolites.

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 c. Adverse effects:

 The most common adverse effects are nausea, vomiting, epigastric

distress, and abdominal cramps

 An unpleasant, metallic taste is commonly experienced.

 Other effects include oral moniliasis (yeast infection of the mouth)

and, rarely, neurotoxicity (dizziness, vertigo, and numbness or
paresthesia), which may necessitate discontinuation of the drug.

 If taken with alcohol, a disulfiram-like reaction may occur.

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 2. Tinidazole:

 Tinidazole is a second-generation nitroimidazole that is similar to metronidazole

in spectrum of activity, absorption, adverse effects, and drug interactions.
 It is used for treatment of amebiasis, amebic liver abscess, giardiasis, and
trichomoniasis.
 Tinidazole is as effective as metronidazole, with a shorter course of
treatment, but it is more expensive.
 Alcohol consumption should be avoided during therapy.
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 B. Luminal amebicides

 After treatment of invasive intestinal or extraintestinal

amebic disease is complete, a luminal agent, such as
• iodoquinol,
• diloxanide furoate, or
• paromomycin, should be administered for treatment of
the asymptomatic colonization state.

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 1. Iodoquinol:

 A halogenated 8-hydroxyquinolone, is amebicidal against E. histolytica

and is effective against the luminal trophozoite and cyst forms.
 Adverse effects of iodoquinol include rash, diarrhea, and dose-related
peripheral neuropathy, including a rare optic neuritis.
 Long-term use of this drug should be avoided.

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 2. Paromomycin:

 Paromomycin an aminoglycoside antibiotic, is only effective against the

intestinal (luminal) forms of E. histolytica, because it is not
significantly absorbed from the gastrointestinal tract.
 Paromomycin is directly amebicidal and also exerts its antiamebic
actions by reducing the population of intestinal flora.
 It is also an alternative agent for cryptosporidiosis and giardiasis.
Gastrointestinal distress and diarrhea are the principal adverse
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 C. Systemic amebicides

1. Chloroquine:

 It is used in combination with metronidazole to treat amebic liver

abscesses.
 It eliminates trophozoites in liver abscesses, but it is not useful in
treating luminal amebiasis.
 Therapy should be followed with a luminal amebicide.
 Chloroquine is also effective in the treatment of malaria.
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2. Dehydroemetine:
 It is an alternative agent for the treatment of amebiasis.
 The drug inhibits protein synthesis by blocking chain elongation.
 Intramuscular injection is the preferred route, since it is an irritant when taken
orally.
 The use of this ipecac alkaloid is limited by its toxicity, and it has largely been
replaced by metronidazole.
 Adverse effects:include pain at the site of injection, nausea, cardiotoxicity
(arrhythmias and congestive heart failure), neuromuscular weakness,
dizziness, and rash.

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 III. CHEMOTHERAPY FOR MALARIA

 Malaria is an acute infectious disease caused by four species of the

protozoal genus Plasmodium.
 It is transmitted to humans through the bite of a female Anopheles
mosquito.
 Plasmodium falciparum is the most dangerous species, causing an acute,

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 P. falciparum infection can lead to capillary obstruction and
death without prompt treatment.

 Plasmodium vivax causes a milder form of the disease.

 Plasmodium malariae is common to many tropical regions,

but Plasmodium ovale is rarely encountered.

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 A. Primaquine

 Primaquine,is an oral antimalarial drug

 Primaquine is the only agent that prevents relapses of the P. vivax and P. ovale
malarias.

 The sexual (gametocytic) forms of all four plasmodia are destroyed in the plasma or
are prevented from maturing later in the mosquito, thereby interrupting transmission
of the disease.
 Primaquine is not effective against the erythrocytic stage of malaria and, therefore,
is used in conjunction with agents to treat the erythrocytic form (for example,2
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1. Mechanism of action:
• While not completely 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.

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2. Pharmacokinetics:

• Primaquine is well absorbed after oral administration and is

not concentrated in tissues.
• It is rapidly oxidized to many compounds, primarily the
deaminated drug. Which compound possesses the
schizonticidal activity has not been established.
• The drug is minimally excreted in the urine. 2
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3. Adverse effects:

Cardiac Arrhythmias, Hemolysis ,GI disturbance, Headache

It is never given parenterally because it may induce marked hypotension.
It should be avoided in pregnancy because the fetus is relatively G6PD-
deficient and thus at risk of hemolysis.

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 B. Chloroquine

 Chloroquine 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 used in the prophylaxis of malaria for travel to areas with known
chloroquine- sensitive malaria.
 Hydroxychloroquine is an alternative to chloroquine for the prophylaxis and treatment of
chloroquine-sensitive malaria. It is also effective in the treatment of extraintestinal
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 1. Mechanism of action
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

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 2. Pharmacokinetics:

 Chloroquine is rapidly and completely absorbed following oral administration.

 The drug has a very large volume of distribution and concentrates in
erythrocytes, liver, spleen, kidney, lung, and melanin-containing tissues, and
leukocytes.
 It persists in erythrocytes.
 The drug also penetrates the central nervous system (CNS) and traverses the
placenta.
 Chloroquine is dealkylated by the hepatic mixed-function oxidase system, and
some metabolic products retain antimalarial activity.
 Both parent drug and metabolites are excreted predominantly in urine.
 3. Adverse effects:

• Usually very well tolerated

• Pruritus, GI disturbance, headache, malaise, blurring of vision,
and urticaria

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 C. Mefloquine

•Used in chloroquine-resistant strains of P falciparum and other species.

•Is chemically related to quinine.
•Can only be given orally because severe local irritation occurs with parenteral use.
•Has strong blood schizonticidal activity against P falciparum and P vivax,
•it is not active against hepatic stages or gametocytes.

MOA: is unknown.

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 D. Quinine

•First-line therapies for falciparum malaria.

•Oral administration.
•Higher plasma levels and half-life in infected persons than in healthy
controls, but toxicity is not increased, apparently because of increased
protein binding.
•MOA: is unknown, it may act like chloroquine

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 E. Artemisinin

 Artemisinin: used orally.

 They are very rapidly acting blood schizonticides against all human malaria
parasites, no effect on hepatic stages.

 Mechanism of action :

 The parasite when it infects a RBC, it consumes Hb within its digestive

vacuole, liberating free heme, The iron in heme interacts with Artemisinin
producing reactive oxygen radicals which damage the parasite leading to its
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• Or inhibition of a parasite calcium transporter.

• Artemisinin-based combination therapy is now the standard for treatment

of uncomplicated falciparum malaria in nearly all areas endemic for
falciparum malaria.

 Adverse effects include nausea, vomiting, and diarrhea. High doses

may cause prolongation of the QT interval. Hypersensitivity reactions
and rash have occurred.
 IV. CHEMOTHERAPY FOR TRYPANOSOMIASIS

 African trypanosomiasis (sleeping sickness) and American

trypanosomiasis (also known as Chagas disease) are two chronic and,
eventually, fatal diseases caused by species of Trypanosoma

 In African sleeping sickness, T. brucei gambiense and T. brucei

rhodesiense initially live and grow in the blood.

 The parasite later invades the CNS, causing inflammation of the brain
and spinal cord that produces the characteristic lethargy and,
eventually, continuous sleep.

 Chagas disease is caused by T. cruzi and is endemic in Central and

South America. 3
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 A. Pentamidine

 Pentamidine is active against a variety of protozoal infections,

including African trypanosomiasis due to T. brucei gambiense, for
which it is used to treat the first stage (hemolymphatic stage without
CNS involvement).
 Pentamidine is also an alternative for prophylaxis or treatment of
infections caused by P.neumocystis jirovecii.
 Pentamidine is also an alternative drug for the treatment of
leishmaniasis. 3
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 The drug distributes widely and is concentrated in the
liver, kidney, adrenals, spleen, and lungs.

 Because it does not enter the CSF, it is ineffective against

the second stage (CNS involvement) of trypanosomiasis.

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 B. Suramin

 It is used primarily in the first stage (without CNS involvement) of

African trypanosomiasis due to T. brucei rhodesiense.
 It is very reactive and inhibits many enzymes, especially those involved
in energy metabolism, which appears to be the mechanism correlated
with trypanocidal activity.
 Suramin must be injected intravenously.
 It binds to plasma proteins and does not penetrate the blood–brain barrier
well.
 It has a long elimination half-life (more than 40 days) and is mainly
excreted unchanged in the urine.
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 C. Melarsoprol

 It is used for the treatment of African trypanosomal infections in the

second stage (CNS involvement).
 It is the only drug available for second stage trypanosomiasis due to T.
brucei rhodesiense.
 Some resistance has been noted, and it may be due to decreased
transporter uptake of the drug.
 Melarsoprol is administered by slow IV injection and can be very
irritating to the surrounding tissue.
 Adequate trypanocidal concentrations appear in the CSF, making
melarsoprol the agent of choice in the treatment of T. brucei
rhodesiense, which rapidly invades the CNS. 3
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 The drug has a very short half-life and is rapidly excreted in urine.
 The use of melarsoprol is limited by CNS toxicity.
 Reactive encephalopathy may occur, which can be fatal in 10% of
cases.
 Hemolytic anemia has been seen in patients with glucose-6-
phosphate dehydrogenase deficiency.

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 E. Nifurtimox

 It is used in the treatment of T. cruzi infections (Chagas disease),

although treatment of the chronic stage of such infections has led to
variable results.
 Nifurtimox is administered orally.
 Major toxicities include hypersensitivity reactions (anaphylaxis,
dermatitis) and gastrointestinal problems that may be severe enough to
cause weight loss.
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 F. Benznidazole

 It tends to be better tolerated than nifurtimox and is an

alternative for the treatment of Chagas disease.
 Adverse effects include dermatitis, peripheral neuropathy,
insomnia, and anorexia.

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CHEMOTHERAPHY FOR
LEISHMANIASIS:
 Leishmaniasis is transmitted from animals to humans (and between
humans) by the bite of infected sandflies.
 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.

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TREATMENT STRATEGY:

 Pentavalent antimonials such as:

 Sodium stibogluconate are the conventional therapy
used in the treatment of leishmaniasis with
pentamidine and amphotericin B as the backup agent.
 Allopurinol has also been reported to be effective.
SODIUM STIBOGLUCONATE

 It is an anti-leishmaniasis agent.

MECHANISM OF ACTION:
 The mode of action of sodium stibogluconate is unknown.
 Inhibit parasite glycolysis and fatty acid oxidation, leading to
decreased energy and reduction in ATP and GTP synthesis.
 Decrease in parasite DNA, RNA protein.
 ADVERSE EFFECTS:

 Loss of appetite
 Fever
 Nausea  Sweating
 Vomiting  Flushing
 Abdominal pain  Spinning sensation (vertigo)
 Bleeding from nose or gum
 ECG changes  Yellowing skin and eyes
 Headache (jaundice)
 Rash
 Lethargy
 Anaphylaxis (rare)
 Muscle pain
 MILTEFOSINE

 It is the first orally active drug for visceral leishmaniasis.

 It may also have some activity against cutaneous and
mucocutaneous forms of the disease.
Adverse effects:
 Nausea
 Vomiting
 The drug is teratogenic and should be avoided in pregnancy.
 TOXOPLASMOSIS

 One of the most common infections in humans is caused by the

protozoan T. 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.

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• The treatment of choice for this condition is a combination of
sulfadiazine and pyrimethamine.

• Leucovorin is commonly administered to protect

against folate deficiency.

• Pyrimethamine with clindamycin, or the combination

of trimethoprim
and sulfamethoxazole, are alternative treatments.

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GIARDIASIS

 Giardia lamblia is the most commonly diagnosed intestinal parasite in

the United States.

 Ingestion, usually from contaminated drinking water, leads to

infection.

 The trophozoites exist in the small intestine and divide by binary

fission.
 Although some infections are asymptomatic, severe diarrhea can
occur, which can be very serious in immunocompromised patients.
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 The treatment of choice is oral metronidazole for 5 days.
 An alternative is tinidazole, which is as effective as metronidazole in the
treatment of giardiasis.
 This agent is administered orally as a single dose.
 Nitazoxanide is also approved for the treatment of giardiasis.
 For giardiasis, nitazoxanide is administered as a 3-day course of oral therapy.

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 REFERENCE:
• Lippincott Pharmacology