Lippincott Chapter 43: Antiprotozoal Drugs

Question 1

AMEBIASIS

Answer 1

Chloroquine ARALEN
Dehydroemetine DEHYDROEMETINE
Iodoquinol YODOXIN
Metronidazole FLAGYL
Paromomycin HUMATIN
Tinidazole TINDAMAX

Question 2

Malaria

Answer 2

Artemether/lumefantrine COARTEM
Chloroquine ARALEN
LARIAM
Primaquine
Pyrimethamine DARAPRIM
Quinine/Quinidine QUALAQUIN,
QUINIDINE GLUCONATE
Atovaquone-proguanil MALARONE
mefloquine

Question 3

TRYPANOSOMIASIS

Answer 3

Benznidazole RADANIL
Melarsoprol
Nifurtimox
Pentamidine NEBUPENT
Suramin GERMANIN
E
Eflornithine

Question 4

LEISHMANIASIS

Answer 4

Sodium stibogluconate
Miltefosine

Question 5

Toxoplasmosis

Answer 5

Pyrimethamine DARAPRIM

Question 6

Giardiasis

Answer 6

Metronidazole FLAGYL
Nitazoxanide ALINIA
Tinidazole TINDAMAX

Question 7

Mixed amebicides

Answer 7

Metronidazole: Metronidazole [me-troe-NYE-da-zole], a nitro-
imidazole, is the mixed amebicide of choice for treating amebic
infections. [Note: Metronidazole is also used in the treatment of infections caused by Giardia lamblia, Trichomonas vaginalis,
anaerobic cocci, and anaerobic gram-negative bacilli (for example,
Bacteroides species) and is the drug of choice for the treatment
of pseudomembranous colitis caused by the anaerobic, gram-
positive bacillus Clostridium difficile.]
a. Mechanism of action: Amebas possess ferredoxin-like,
low-redox-potential, electron transport proteins that participate
in metabolic electron removal reactions. The nitro group of
metronidazole is able to serve as an electron acceptor, forming
reduced cytotoxic compounds that bind to proteins and DNA,
resulting in death of the E. histolytica trophozoites.
b. Pharmacokinetics: Metronidazole is completely and rapidly
absorbed after oral administration. [Note: For the treatment of
amebiasis, it is usually administered with a luminal amebicide,
such as iodoquinol or paromomycin. This combination provides
cure rates of greater than 90%.] Metronidazole distributes well
throughout body tissues and fluids. Therapeutic levels can be
found in vaginal and seminal fluids, saliva, breast milk, and
cerebrospinal fluid (CSF). Metabolism of the drug depends
on hepatic oxidation of the metronidazole side chain by mixed-function oxidase, followed by glucuronidation. Therefore,
concomitant treatment with inducers of the cytochrome P450,
such as phenobarbital, enhances the rate of metabolism, and
inhibitors, such as cimetidine, prolong the plasma half-life of
metronidazole. The drug accumulates in patients with severe
hepatic disease. The parent drug and its metabolites are
excreted in the urine.

Question 8

Metronidazole ADR and resistance

Answer 8

Adverse effects: The most common adverse effects are
nausea, vomiting, epigastric distress, and abdominal cramps
(Figure 43.3). An unpleasant, metallic taste is commonly expe-
rienced. Other effects include oral moniliasis (yeast infection
of the mouth) and, rarely, neurotoxicity (dizziness, vertigo, and
numbness or paresthesia), which may necessitate discontinua-
tion of the drug. If taken with alcohol, a disulfiram-like reaction
may occur (see Chapter 15).
d. Resistance: Resistance to metronidazole is not a therapeutic
problem for amebiasis, although strains of trichomonads resis-
tant to the drug have been reported.

Question 9

Tinidazole

Answer 9

Tinidazole: Tinidazole [tye-NI-da-zole] is a second-generation
nitroimidazole that is similar to metronidazole in spectrum of activ-
ity, 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 con-
sumption should be avoided during therapy

Question 10

Luminal amebicides

Answer 10

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 asymp-
tomatic colonization state.
1. Iodoquinol: Iodoquinol [eye-oh-doe-QUIN-ole], 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.
2. Paromomycin: Paromomycin [par-oh-moe-MYE-sin], an amino-
glycoside 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 prin-
cipal adverse effects.

Question 11

Systemic amebicides

Answer 11

These drugs are useful for treating liver abscesses and intestinal wall
infections caused by amebas.

1. Chloroquine: Chloroquine [KLOR-oh-kwin] is used in combina-
   tion with metronidazole (or as a substitute for one of the nitroimid-
   azoles 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. Chloroquine is also effective in the treatment
   of malaria.
2. Dehydroemetine: Dehydroemetine [de-hye-dro-EM-e-teen] is an
   alternative agent for the treatment of amebiasis. The drug inhibits
   protein synthesis by blocking chain elongation. Intramuscular injec-
   tion 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. A summary of the treatment of amebiasis is shown in
   Figure 43.4.

Question 12

Antimalarials
Primaquine

Answer 12

Primaquine
Primaquine [PRIM-a-kwin], an 8-aminoquinoline, is an oral antima-
larial drug that eradicates primary exoerythrocytic (tissue) forms of
plasmodia and the secondary exoerythrocytic forms of recurring
malarias (P. vivax and P. ovale). [Note: Primaquine is the only agent
that prevents relapses of the P. vivax and P. ovale malarias, which
may remain in the liver in the exoerythrocytic form after the eryth-
rocytic form of the disease is eliminated.] The sexual (gametocytic)
forms of all four plasmodia are destroyed in the plasma or are pre-
vented from maturing later in the mosquito, thereby interrupting trans-
mission of the disease. [Note: 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, chloroquine
and mefloquine).]
1. Mechanism of action: While not completely understood, metab-
olites of primaquine are believed to act as oxidants that are responsible for the schizonticidal action as well as for the hemoly-
sis and methemoglobinemia encountered as toxicities.
2. Pharmacokinetics: Primaquine is well absorbed after oral admin-
istration and is not concentrated in tissues. It is rapidly oxidized
to many compounds, primarily the deaminated drug. Which com-
pound possesses the schizonticidal activity has not been estab-
lished. The drug is minimally excreted in the urine.
3. Adverse effects: Primaquine is associated with drug-induced
hemolytic anemia in patients with glucose-6-phosphate dehydro-
genase deficiency (Figure 43.6). Large doses of the drug may
cause abdominal discomfort (especially when administered in com-
bination with chloroquine) and occasional methemoglobinemia.
Primaquine should not be used during pregnancy. All Plasmodium
species may develop resistance to primaquine.

Question 13

Chloroquine

Answer 13

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 used
in the prophylaxis of malaria for travel to areas with known chloro-
quine-sensitive malaria. [Note: Hydroxychloroquine is an alternative
to chloroquine for the prophylaxis and treatment of chloroquine-
sensitive malaria.] It is also effective in the treatment of extraintestinal
amebiasis.
1. Mechanism of action: Although the mechanism of action is
not fully understood, the processes essential for the antimalarial
action of chloroquine are outlined in Figure 43.7. After travers-
ing the erythrocytic and plasmodial membranes, chloroquine (a
diprotic weak base) is concentrated in the acidic food vacuole of
the malarial parasite, primarily by ion trapping. In the food vacuole,
the parasite digests the host cell’s hemoglobin to obtain essential
amino acids. However, this process also releases large amounts
of soluble heme, which is toxic to the parasite. To protect itself, the
parasite polymerizes the heme to hemozoin (a pigment), which is
sequestered in the food vacuole. Chloroquine specifically binds to
heme, preventing its polymerization to hemozoin. The increased
pH and the accumulation of heme result in oxidative damage to
the phospholipid membranes, leading to lysis of both the parasite
and the red blood cell.
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 oxi-
dase system, and some metabolic products retain antimalarial
activity. Both parent drug and metabolites are excreted predomi-
nantly in urine.
3. Adverse effects: Side effects are minimal at low prophylactic
doses. At higher doses, gastrointestinal upset, pruritus, head-
aches, and blurred vision may occur (Figure 43.8). [Note: 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 cau-
tiously in patients with hepatic dysfunction, severe gastrointestinal
problems, or neurologic disorders. Patients with psoriasis or por-
phyria should not be treated with chloroquine, because an acute
attack may be provoked. Chloroquine can prolong the QT interval,
and use of other drugs that also cause QT prolongation should be
avoided if possible.
4. Resistance: Resistance has become a serious medical prob-
lem throughout Africa, Asia, and most areas of Central and South
America. Chloroquine-resistant P. falciparum exhibits multigenic
alterations that confer a high level of resistance.

Question 14

Atovaquone–proguanil

Answer 14

The combination of atovaquone–proguanil [a-TOE-va-kwone pro-
GWA-nil] is effective for chloroquine-resistant strains of P. falciparum,
and it is used in the prevention and treatment of malaria. Atovaquone
inhibits mitochondrial processes such as electron transport, as well
as ATP and pyrimidine biosynthesis. Cycloguanil, the active metabo-
lite of proguanil, inhibits plasmodial dihydrofolate reductase, thereby
preventing DNA synthesis. Proguanil is metabolized via CYP2C19, an
isoenzyme that is known to exhibit a genetic polymorphism resulting
in poor metabolism of the drug in some patients. The combination
should be taken with food or milk to enhance absorption. Common
adverse effects include nausea, vomiting, abdominal pain, headache,
diarrhea, anorexia, and dizziness.

Question 15

Mefloquine

Answer 15

Mefloquine [MEF-lo-kwin] is an effective single agent for prophylaxis
and treatment of infections caused by multidrug-resistant forms of
P. falciparum. Its exact mechanism of action remains undetermined.
Resistant strains have been identified, particularly in Southeast Asia.
Mefloquine is well absorbed after oral administration and is widely
distributed to tissues. It has a long half-life (20 days) because of
enterohepatic circulation and its concentration in various tissues. The
drug undergoes extensive metabolism and is primarily excreted via
the bile into the feces. Adverse reactions at high doses range from
nausea, vomiting, and dizziness to disorientation, hallucinations, and
depression. Because of the potential for neuropsychiatric reactions,
mefloquine is usually reserved for treatment of malaria when other
agents cannot be used. ECG abnormalities and cardiac arrest are
possible if mefloquine is taken concurrently with quinine or quinidine.

Question 16

Quinine

Answer 16

Quinine [KWYE-nine], originally isolated from the bark of the cin-
chona tree, interferes with heme polymerization, resulting in death
of the erythrocytic form of the plasmodial parasite. It is reserved
for severe infestations and for chloroquine-resistant malarial strains. Quinine is usually administered in combination with doxycycline,
tetracycline, or clindamycin. Taken orally, quinine is well distributed
throughout the body. The major adverse effect of quinine is cincho-
nism, 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 hemo-
lytic anemia occurs. Drug interactions include potentiation of neu-
romuscular-blocking agents and elevation of digoxin levels if taken
concurrently. Quinine absorption is reduced by aluminum-containing
antacids.

Question 17

Artemisinin

Answer 17

Artemisinin [ar-te-MIS-in-in] is derived from the sweet wormwood
plant, which has been used in traditional Chinese medicine for many
centuries. Artemisinin and its derivatives are recommended first-line
agents for the treatment of multidrug-resistant P. falciparum malaria.
To prevent the development of resistance, these agents should not be
used alone. For instance, artemether is coformulated with lumefan-
trine [AR-te-meth-er/loo-me-FAN-treen] and used for the treatment of
uncomplicated malaria. [Note: Lumefantrine is an antimalarial drug
similar in action to quinine or mefloquine.] Artesunate [ar-TEZ-oo-
nate] may be combined with sulfadoxine–pyrimethamine, mefloquine,
clindamycin, or others. The antimalarial action involves the production
of free radicals resulting from cleavage of the drug’s endoperoxide
bridge by heme iron in the parasite food vacuole. These agents may
also covalently bind to and damage specific malarial proteins. Oral,
rectal, and intravenous (IV) preparations are available, but the short
half-lives preclude the use of these drugs for prophylaxis. Adverse
effects include nausea, vomiting, and diarrhea. High doses may
cause prolongation of the QT interval. Hypersensitivity reactions and
rash have occurred.

Question 18

Pyrimethamine

Answer 18

Pyrimethamine [peer-i-METH-a-meen] inhibits plasmodial dihydrofo-
late reductase required for the synthesis of tetrahydrofolate (a cofactor
needed for synthesis of nucleic acids). It acts as a blood schizonticide
and a strong sporonticide when the mosquito ingests it with the blood
of the human host. Pyrimethamine is not used alone for P. falciparum;
it is available as a fixed-dose combination with sulfadoxine. Resistance
to this combination has developed, so it is usually administered with
other agents, such as artemisinin derivatives. Pyrimethamine in com-
bination with sulfadiazine is also used against Toxoplasma gondii. If
megaloblastic anemia occurs with pyrimethamine treatment, it may
be reversed with leucovorin. Figure 43.9 shows some therapeutic
options in the treatment of malaria.

Question 19

TRYPANOSOMIASIS drugs

Pentamidine

Answer 19

Pentamidine
Pentamidine [pen-TAM-i-deen] is active against a variety of protozoal
infections, including African trypanosomiasis due to T. brucei gam-
biense, 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 Pneumocystis
jirovecii. [Note: P. jirovecii is an atypical fungus that causes pneumo-
nia in immunocompromised patients, such as those with HIV infec-
tion. Trimethoprim/sulfamethoxazole is preferred in the treatment of
P. jirovecii infections; however, pentamidine is an alternative in indi-
viduals who are allergic to sulfonamides.] Pentamidine is also an
alternative drug for the treatment of leishmaniasis.
1. Mechanism of action: T. brucei concentrates pentamidine by an
energy-dependent, high-affinity uptake system. [Note: Resistance
is associated with inability to concentrate the drug.] Although its
mechanism of action has not been defined, evidence exists that
the drug interferes with parasite synthesis of RNA, DNA, phospho-
lipids, and proteins.
2. Pharmacokinetics: Pentamidine is administered intramuscularly
or intravenously for the treatment of trypanosomiasis and pneu-
monia caused by P. jirovecii. [Note: For prophylaxis of P. jirovecii
pneumonia, pentamidine is administered via nebulizer.] The drug
distributes widely and is concentrated in the liver, kidney, adrenals,
spleen, and lungs. Because it does not enter the CSF, it is ineffec-
tive against the second stage (CNS involvement) of trypanosomia-
sis. The drug is not metabolized, and it is excreted very slowly in
the urine.
3. Adverse effects: Serious renal dysfunction may occur, which
is reversible on discontinuation. Other adverse reactions include
hyperkalemia, hypotension, pancreatitis, hypoglycemia, hypergly-
cemia, and diabetes.

Question 20

Suramin

Answer 20

Suramin [SOO-ra-min] is used primarily in the first stage (without
CNS involvement) of African trypanosomiasis due to T. brucei rho-
desiense. It is very reactive and inhibits many enzymes, especially
those involved in energy metabolism, which appears to be the mech-
anism 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. Although
infrequent, adverse reactions include nausea and vomiting, shock
and loss of consciousness, acute urticaria, blepharitis, and neuro-
logic problems, such as paresthesia, photophobia, and hyperesthe-
sia of the hands and feet. Renal insufficiency may occur but tends to resolve with discontinuation of treatment. Acute hypersensitivity
reactions may occur, and a test dose should be given prior to drug
administration.

Question 21

Melarsoprol

Answer 21

Melarsoprol [mel-AR-so-prol], a trivalent arsenical compound, 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. The drug reacts
with sulfhydryl groups of various substances, including enzymes in
both the organism and host. 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. The host read-
ily oxidizes melarsoprol to a relatively nontoxic, pentavalent arsenic
compound. 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. Other
adverse effects include peripheral neuropathy, hypertension, and
albuminuria. Hypersensitivity reactions may also occur, and febrile
reactions may follow injection. Hemolytic anemia has been seen in
patients with glucose-6-phosphate dehydrogenase deficiency.

Question 22

Eflornithine

Answer 22

Eflornithine [ee-FLOOR-nih-theen] is an irreversible inhibitor of orni-
thine decarboxylase. Inhibition of this enzyme halts the production
of polyamines in the parasite, thereby leading to cessation of cell
division. The IV formulation of eflornithine is a first-line treatment for
second-stage African trypanosomiasis caused by T. brucei gambiense.
[Note: Topical eflornithine is used as a treatment for unwanted facial
hair in women.] The short half-life of eflornithine necessitates frequent
IV administration, making the treatment regimen difficult to follow.
Eflornithine is less toxic than melarsoprol, although the drug is asso-
ciated with anemia, seizures, and temporary hearing loss.

Question 23

Nifurtimox

Answer 23

Nifurtimox [nye-FER-tim-oks] is used in the treatment of T. cruzi infec-
tions (Chagas disease), although treatment of the chronic stage of
such infections has led to variable results. It may also be useful for the
treatment of second-stage T. brucei gambiense in combination with
eflornithine. Being a nitroaromatic compound, nifurtimox undergoes
reduction and eventually generates intracellular oxygen radicals, such
as superoxide radicals and hydrogen peroxide (Figure 43.11). These
highly reactive radicals are toxic to T. cruzi. Nifurtimox is adminis-
tered orally. It is extensively metabolized, and the metabolites are
excreted mainly in the urine. Adverse effects are common following
chronic administration, particularly among the elderly. Major toxicities
include hypersensitivity reactions (anaphylaxis, dermatitis) and gas-
trointestinal problems that may be severe enough to cause weight
loss. Peripheral neuropathy is relatively common, and headache and
dizziness may also occur.

Question 24

Benznidazole

Answer 24

Benznidazole [benz-NI-da-zole] is a nitroimidazole derivative with a
mechanism of action similar to nifurtimox. It tends to be better toler-
ated than nifurtimox and is an alternative for the treatment of Chagas
disease. Adverse effects include dermatitis, peripheral neuropathy,
insomnia, and anorexi

Question 25

LEISHMANIASIS treatment
Sodium stibogluconate

Answer 25

Sodium stibogluconate
The pentavalent antimonial sodium stibogluconate [stib-o-GLOO-
koe-nate] is not effective in vitro. Therefore, it has been proposed that
reduction to the trivalent antimonial compound is essential for activity.
The exact mechanism of action has not been determined. Because it
is not absorbed after oral administration, sodium stibogluconate must
be administered parenterally, and it is distributed in the extravascu-
lar compartment. Metabolism is minimal, and the drug is excreted
in urine. Adverse effects include injection site pain, pancreatitis, ele-
vated liver enzymes, arthralgias, myalgias, gastrointestinal upset, and
cardiac arrhythmias. Renal and hepatic function should be monitored
periodically.

Question 26

Miltefosine

Answer 26

Miltefosine [mil-te-FOE-zeen] is the first orally active drug for visceral
leishmaniasis. It may also have some activity against cutaneous and
mucocutaneous forms of the disease. The precise mechanism of
action is not known, but miltefosine appears to interfere with phos-
pholipids in the parasitic cell membrane to induce apoptosis. Nausea
and vomiting are common adverse reactions. The drug is teratogenic
and should be avoided in pregnancy.

Question 27

TOXOPLASMOSIS treatment

Answer 27

One of the most common infections in humans is caused by the pro-
tozoan 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. The treatment of choice for this condition is a combination of sulfadiazine
and pyrimethamine. Leucovorin is commonly administered to pro-
tect against folate deficiency. [Note: At the first appearance of a rash,
pyrimethamine should be discontinued, because hypersensitivity to this
drug can be severe.] Pyrimethamine with clindamycin, or the combina-
tion of trimethoprim and sulfamethoxazole, are alternative treatments.
Trimethoprim/sulfamethoxazole is used for prophylaxis against toxoplas-
mosis (as well as P. jirovecii) in immunocompromised patients.

Question 28

GIARDIASIS treatment

Answer 28

Giardia lamblia is the most commonly diagnosed intestinal parasite
in the United States. It has two life cycle stages: the binucleate tro-
phozoite with four flagella and the drug-resistant, four-nucleate cyst
(Figure 43.12). 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. Although some infections are asymptomatic, severe diar-
rhea can occur, which can be very serious in immunocompromised
patients. 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 [nye-ta-ZOX-a-nide], a nitrothiazole derivative,
is also approved for the treatment of giardiasis. [Note: Nitazoxanide
may also be used for cryptosporidiosis (a diarrheal illness most com-
monly seen in immunocompromised patients) caused by the parasite
Cryptosporidium parvum.] For giardiasis, nitazoxanide is administered
as a 3-day course of oral therapy. The anthelmintic drug albendazole
may also be efficacious for giardiasis, and paromomycin is sometimes
used for treatment of giardiasis in pregnant patients.