Antiprotozoal drugs
Dr. Rowan AlEjielat
Antimalaria
Antiamoeba
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1- CHEMOTHERAPY FOR AMEBIASIS
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Introduction
• Amebiasis (also called amebic dysentery) is an infection of
the intestinal tract caused by Entamoeba histolytica.
• E. histolytica is endemic in developing countries and is mainly
transmitted via the fecal–oral route or through ingestion of
contaminated food or water.
• Most infected individuals are asymptomatic but can exhibit
varying degrees of illness
• The diagnosis is established by isolating E. histolytica from
fresh feces
• Symptoms:
• from no symptoms to mild diarrhea to fulminating dysentery
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Introduction
• Entamoeba histolytica exists in two forms:
1. Cysts that can survive outside the body
2. Trophozoites that do not persist outside the body for a long
time
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Drugs
• Mixed amebicides (metronidazole and tinidazole)
• Systemic amebicides (Chloroquine, emetine, dehydroemetine)
• Luminal amebicides (Iodoquinol, Paromomycin)
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Mixed amebicides (metronidazole and tinidazole)
• Metronidazole undergoes a reductive bioactivation of its nitro
group by ferredoxin (present in anaerobic parasites) to form
reactive cytotoxic products.
• The mechanism of tinidazole is assumed to be similar.
• Note: Metronidazole is the drug of choice for the treatment of
pseudomembranous colitis caused by the anaerobic, grampositive bacillus Clostridium difficile
• Also used for several other bacterial infections for ex. Gram
negative bacilli
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Metronidazole, Adverse effects
• Gastrointestinal tract: including nausea, vomiting, epigastric
distress, and abdominal cramps.
• An unpleasant, metallic taste is commonly experienced.
• Other effects include oral moniliasis (candidiasis) (yeast
infection of the mouth)
• Rarely, neurotoxicologic problems, such as dizziness, vertigo,
and numbness or paresthesias in the peripheral nervous
systemmay necessiate discontinuation
• If taken with alcohol, a disulfiram-like effect occurs
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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, 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, or
paromomycin, should be administered for treatment of the
asymptomatic colonization state
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1. Iodoquinol
• Iodoquinol, a halogenated 8-hydroxyquinolone
• 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 luminal forms of E. histolytica, because it is not
significantly absorbed from the gastrointestinal tract.
• Gastrointestinal distress and diarrhea are the principal adverse
effects.
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C. Systemic amebicides
• These drugs are useful for treating extraintestinal amebiasis,
such as liver abscesses, and intestinal wall infections
caused by amoebas.
• Chloroquine, dehyrdroemetine
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1. Chloroquine
• Chloroquine is used in combination with metronidazole (or as
a substitute for one of the nitroimidazoles in the case of
intolerance) 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.
• Note: Chloroquine is also effective in the treatment of malaria.
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2. Dehydroemetine
• Dehydroemetine is an alternative agent for the treatment of
amebiasis.
• The drug inhibits protein synthesis by blocking chain
elongation.
• Intramuscular (IM) 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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2- ANTIMALARIAL AGENTS
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Introduction
• Malaria is one of the most common diseases worldwide and a
leading cause of death.
• Plasmodium species that infect humans (P falciparum, P
malariae, P ovale, P vivax, P knowlesi) undergo a primary
developmental stage in the liver and then move to
erythrocytes.
• P falciparum is responsible for the majority of serious
complications and deaths
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Life cycle of Malaria
• An anopheline mosquito inoculates plasmodium sporozoites to
initiate human infection
• Circulating sporozoites rapidly invade liver cells, and exoerythrocytic
stage tissue schizonts mature in the liver.
• Merozoites are subsequently released from the liver and invade
erythrocytes.
• Only erythrocytic parasites cause clinical illness.
• Repeated cycles of infection can lead to the infection of many
erythrocytes and serious disease.
• Sexual stage gametocytes also develop in erythrocytes before being
taken up by mosquitoes, where they develop into infective
sporozoites.
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Life cycle of Malaria
• In P falciparum and P malariae infection, only one cycle of
liver cell invasion and multiplication occurs, and liver infection
ceases spontaneously in less than 4 weeks.
• Thus, treatment that eliminates erythrocytic parasites will cure
these infections.
• In P vivax and P ovale infections, a dormant hepatic stage,
the hypnozoite, is not eradicated by most drugs, and
subsequent relapses can therefore occur after therapy
directed against erythrocytic parasites.
• Eradication of both erythrocytic and hepatic parasites is
required to cure these infections and usually requires two or
more drugs.
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• P falciparum malaria recurrence can occur by two different
mechanisms: reinfection and recrudescence.
• Reinfection usually occurs after day 14 of treatment and in
endemic areas. (new infection)
• Recrudescence (same parasite in the patient)can be due to
• (1) incomplete or inadequate treatment as a result of drug
resistance or improper choice of medication
• (2) an antigenic variation
• (3) multiple infection by different strains
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Symptoms
• In the early stages, malaria symptoms are sometimes similar
to those of many other infections caused by bacteria, viruses,
or parasites.
• Symptoms may include:
•
•
•
•
•
•
Fever.
Chills.
Headache.
Sweats.
Fatigue.
Nausea and vomiting.
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Symptoms
• Symptoms may appear in cycles. The time between episodes
of fever and other symptoms varies with the specific parasite
• Episodes of symptoms may occur:
• Every 48 hours if you are infected with P. vivax or P. ovale.
• Every 72 hours if you are infected with P. malariae.
• P. falciparum does not usually cause a regular, cyclic fever.
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Symptoms
• The cyclic pattern of malaria symptoms is due to the life cycle
of malaria parasites as they develop, reproduce, and are
released from the red blood cells and liver cells in the human
body. This cycle of symptoms is also one of the major signs of
a malaria infection.
• Other common symptoms of malaria include:
• Dry (nonproductive) cough.
• Muscle or back pain or both.
• Enlarged spleen.
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Drugs
• Primary tissue schizonticides kill schizonts in the liver
• Blood schizonticides kill these parasitic forms only in the
erythrocyte
• Those that kill sexual stages and prevent transmission to
mosquitoes are gametocides
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Primaquine
• Tissue schizonticide
• 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, which may remain in the liver in the exoerythrocytic form after
the erythrocytic form of the disease is eliminated
• The sexual (gametocytic) forms of all plasmodia are destroyed in the plasma or
are prevented from maturing later in the mosquito, thereby interrupting
transmission of the disease.
• Not effective against the erythrocytic stage of malaria and, therefore, is
often used in combination with a blood schizonticide, such as chloroquine,
quinine, mefloquine, or pyrimethamine
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MOA
• While not completely understood, metabolites of primaquine
are believed to act as oxidants that severely disrupt the
metabolic processes of plasmodial mitochondria.
• The metabolites are responsible for the schizonticidal action,
as well as for the hemolysis and methemoglobinemia
encountered as toxicities
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Primaquine
• Standard doses of primaquine may cause hemolysis or
methemoglobinemia (manifested by cyanosis), especially in
persons with G6PD deficiency or other hereditary metabolic
defects.
• 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.
• Avoid in these patients
• Should not be used in pregnancy
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Chloroquine
• Blood schizonticide mainly
• not active against liver stage parasites
• Uses:
• Treatment and prophylaxis (Weekly)
• Mainstay for P. falciparum malaria (only the sensitive type)
• The antidiarrheal agent kaolin and calcium- and magnesiumcontaining antacids interfere with the absorption of chloroquine
and should not be co-administered with the drug.
• Chloroquine is considered safe in pregnancy and for young
children.
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Chloroquine adverse effects
• Adverse effects are minimal at low prophylactic doses
• At higher doses, many more toxic effects occur, such as
gastrointestinal upset, pruritus, headaches, and blurred vision
• An ophthalmologic examination should be routinely performed
during extended use due to potential retinal toxicity
• Patients with psoriasis or porphyria should not be treated with
chloroquine, because an acute attack may be provoked.
• Discoloration of the nail beds and mucous membranes may be seen
on chronic administration.
• Chloroquine can prolong the QT interval
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Atovaquone–proguanil
(Malarone)
• The combination of atovaquone–proguanil is effective for chloroquineresistant strains of P. falciparum, and it is used in the prevention and
treatment of malaria for travelers from outside malaria endemic areas
• Atovaquone–proguanil is not routinely used in endemic areas due to
propensity for emergence of high-level resistance
• Atovaquone acts against plasmodia by disrupting mitochondrial electron
transport, as well as ATP and pyrimidine biosynthesis
• Proguanil : inhibitor of folate synthesis
• Cycloguanil, the active triazine metabolite of proguanil, inhibits plasmodial
dihydrofolate reductase, thereby preventing DNA synthesis
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Mefloquine
• structurally related to quinine,
• an effective agent for prophylaxis from all plasmodia, and for
treatment when used in combination with an artemisinin
derivative for infections caused by multidrug-resistant forms
of P. falciparum.
• ECG abnormalities and cardiac arrest are possible if taken
concurrently with quinine or quinidine.
• nausea, vomiting, and dizziness to disorientation,
hallucinations, and depression
• reserved for treatment of malaria when other agents cannot
be used.
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Quinine
• Quinine is derived from the bark of the cinchona tree ‫شجر الكينا او‬
‫الكافور‬, a traditional remedy for intermittent fevers from South
America.
• Interferes with heme polymerization, resulting in death of the
erythrocytic form of the plasmodial parasite.
• The major adverse effect of quinine is cinchonism, a syndrome
causing nausea, vomiting, tinnitus, and vertigo. These effects
are reversible and are not reasons for suspending therapy.
• However, quinine treatment should be suspended if
hemolytic anemia occurs. (especially with G6PD deficiency)
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Artemisinin
• Artemisinin (qinghaosu,
sweet wormwood) is the
active component of a
chinese herbal medicine
that has been used as an
antipyretic in China for
over 2000 years.
• analogs are Artesunate
and artemether
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Artemisinin
• Mechanism of action:
• The antimalarial activity of artemisinins may result from the
production of free radicals that follows the iron (heme)-catalyzed
cleavage of the artemisinin endoperoxide bridge in the parasite
food vacuole
• Artemisinin-based combination therapy is now the standard
for treatment of uncomplicated falciparum malaria in nearly
all areas endemic for falciparum malaria.
• Addition of another antimalarial agent, or artemisinin-based
combination therapy (ACT), is recommended to prevent the
development of resistance.
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Artemisinin
• Artemisinin based combination therapy:
• artemether with lumefantrine and is used for the treatment of
uncomplicated malaria.
• [Note: Lumefantrine is an antimalarial drug similar in action to
quinine or mefloquine.]
• Artesunate may be combined with sulfadoxine–
pyrimethamine, mefloquine, clindamycin, or others.
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Pyrimethamine
• Blood schizonticide and sporontocide
• It is an antifolate
• Fansidar: A fixed combination of the sulfonamide sulfadoxine
and pyrimethamine
• Resistance to this combination has developed, so it is usually
administered with other agents, such as artemisinin
derivatives
• If megaloblastic anemia occurs with pyrimethamine
treatment, it may be reversed with leucovorin
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Chemoprophylaxis
• When patients are counseled on the
prevention of malaria, it is imperative to
emphasize measures to prevent mosquito
bites (eg,with insect repellents,
insecticides, and bed nets), because
parasites are increasingly resistant to
multiple drugs and no chemoprophylactic
regimen is fully protective.
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Chemoprophylaxis
• these may change in response to changing resistance patterns
and increasing experience with new drugs
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