Lecture: T.L. Kirley, Ph.D.

Syllabus prepared by L.K. Lane, Ph.D.

Wednesday, October 22, 2008; 10:40-11:30
Room 5154 MSB, 558-2353
Pharmacology & Cell Biophysics

ANTIPROTOZOAL & ANTIMALARIAL DRUGS

Knowledge Objectives

1) Describe and compare the drugs currently used to prevent and to treat malaria
caused by different strains of Plasmodium (i.e., with respect to specificity,
resistance, significant adverse effects and contraindications).

2) Identify drugs used to treat selected protozoal infections (particularly those

you might see in the USA), and describe their significant adverse effects or
contraindications.

Drug List

Antimalarial Drugs: atovaquone-proguanil

chloroquine
mefloquine
primaquine
doxycycline*

others: quinidine, clindamycin*, artemisinins

Antiprotozoal Drugs: metronidazole*

trimethoprim-sulfamethoxazole (TMP/SMX)*

others: paromomycin, iodoquinol, suramin, pyrimethamine, sulfadiazine,

nifurtimox

[* drugs also on Antibiotics list]

Q-1
 T.L. Kirley, Ph.D.
Antiprotozoal & Antimalerial Drugs

Malaria is the world's most devastating human parasitic infection, affecting nearly
500 million people and causing approximately 2 million deaths each year.

Antimalarial Drugs
The ancient treatment for malaria was powdered bark of the cinchona tree, which grows
in the Andes mountains. Jesuits introduced it to Europe in the 1600’s and 200 years later
the active ingredient, quinine, was isolated from the bark. The English used this remedy
to create the British Empire and the gin and tonic (quinine was mixed with gin to make it
palatable). Currently, the stereoisomer of quinine, quinidine, is used in the USA for
treating serious malaria. Except for doxycycline and proguanil, the required antimalarial
drugs are all quinoline derivatives, and their generic names include “quine” or “quone”.

These drugs are used in 3 ways:

1) prophylaxis – traveler takes drug before/during/after trip to “prevent malaria”

(doesn’t prevent infection, but kills Plasmodia when it invades the patient’s
erythrocytes)
2) self-medication – traveler carries drug with them to self-medicate if malaria
symptoms occur. (If already using one drug for prophylaxis, use a different
drug for emergency self-medication.)
3) physician treatment of malaria

To prescribe effective antimalarial drugs, you need to know which Plasmodia

species the traveler will be or has been exposed to, as well as the drug-resistance of
that Plasmodia. www.cdc.gov/travel is an excellent source of information for
both physicians and patient travelers. The CDC provides current information
about Plasmodia distribution and resistance and it also provides difficult to find
drugs for malaria and other protozoal diseases.

Antimalarial drugs are classified into 2 categories:

1) Primaquine, the only drug that kills dormant Plasmodium vivax and
ovale in hepatocytes (tissue schizonticide), and
2) all others, that kill only the erythrocytic forms of Plasmodia (blood
schizonticides).

Chloroquine -- The Prototype

It’s the 1st synthetic antimalarial and the primary drug for prophylaxis and
treatment of malaria since the 1940’s. Its usefulness is now limited, since
most P. falciparum in the world is resistant and P. vivax resistance is
increasing. [FYI: Sensitive- P. falciparum still exist in Haiti, Dominican Republic,
Mexico & south to Panama Canal, and most of Middle East. Insensitive P. Vivax exist in
Indonesia & New Guinea]

Q-2
 T.L. Kirley, Ph.D.
Antiprotozoal & Antimalerial Drugs

Its long half-life (30-60 days) permits a weekly dose for prophylaxis.

It kills the erythrocytic form only of all four disease-causing Plasmodia species,
and has no activity against the dormant liver forms of ovale and vivax.

It’s the only antimalarial drug that everyone agrees is safe for kids and
pregnant women.

Adverse effects: antimalarial doses are very well tolerated

common: pruritus (itching), particularly with darker skin, as drug accumulates
in melanin-containing cells
occasional: nausea, headache, blurred vision
rare: hemolysis in G6PD-deficient patients (at high doses), confusion,
hypotension, and exfoliate dermatitis

Contraindications: allergy to chloroquine, psoriasis or prophyria. retinal abnormalities

use cautiously in patients with liver disease or G6PD-deficiency

Drug interactions: Ca++ and Mg++ in supplements and antacids, and

kaolin/pectin (antidiarrheal) interfere with chloroquine’s
intestinal absorption

Mefloquine (Lariam) -- Current drug of choice of U.S. government

It’s the primary chloroquine-substitute for prophylaxis and treatment of

chloroquine-resistant P. falciparum malaria, and it’s also active against
P. vivax, ovale and malariae. Resistance to mefloquine is increasing,
particularly in southeast Asia.

Its long half-life (20 days) permits weekly dose for prophylaxis.

It kills only the erythrocytic forms of Plasmodia

Adverse effects: frequent: nausea & diarrhea; 30-50% have some signs of CNS
toxicity (dizziness, depression, insomnia, nightmares, altered
motor function)
rare: seizures, hallucinations, severe anxiety

Contraindications: allergy to drug, epilepsy or other seizure disorder, psychiatric

disorders, cardiac conduction abnormalities
use with caution in patients with liver disease (extended half-life)

Q-3
 T.L. Kirley, Ph.D.
Antiprotozoal & Antimalerial Drugs

Pregnancy: Animal studies suggest mefloquine is teratogenic and embryotoxic.

FDA recommends no use in pregnant or nursing women and infants
CDC & Katzung: limited experience suggests it’s safe to take during
pregnancy, including the 1st trimester, although there are reports
of increased stillbirths with the drug. OK for nursing mothers
because little drug is transmitted.

Drug Interactions: increases risk of EKG abnormalities and arrhythmias

Doxycycline

A tetracycline antibiotic that’s active against only the erythrocytic form of all
four malaria-causing Plasmodia species

A daily dose is required for prophylaxis.

It’s used with quinidine to treat severe falciparum malaria and as a substitute
for chloroquine- or mefloquine-prophylaxis, particularly in southeast
Asia, where mefloquine resistance is growing.

Adverse effects: GI distress, vaginal yeast infections, photosensitivity

Contraindications: Pregnant and nursing women, children under 8 y.o.

Drug Interactions: Mg2+, Ca2+ and Al3+ (in supplements and antacids) interfere
with absorption

Atovaquone-Proguanil (Malarone)

A fixed combination of two old antiprotozoal drugs with synergistic effects.

Neither drug used alone is an effective antimalarial drug.

It’s an alternative to mefloquine for prophylaxis and treatment of

chloroquine-resistant P. falciparum and P. vivax malaria

It’s active against erythrocytic forms only, and it requires a daily dose

Q-4
 T.L. Kirley, Ph.D.
Antiprotozoal & Antimalerial Drugs

Atovaquone -- interferes with Plasmodia ATP synthesis & oxidative

phosphorylation
-- active against other protozoa (e.g., Pneumocyctis carinii, Toxoplasma
gondii, Entamoeba histolytica, Trichomonas vaginalis, Leishmania sp.,
and microsporidia)
Proguanil -- a prodrug – transformed by P450 2C19 into active metabolite (cycloguanil)
that inhibits folic acid synthesis

Adverse effects: abdominal pain, nausea, vomiting, headache, dizziness

Contraindications: small children, kidney disease, and pregnant* & nursing women
(* if malaria risk requires use, add folate supplementation to
prevent neural tube birth defects)

Drug Interactions: rifampin decreases atovaquone levels

Primaquine

The only drug that can kill the dormant liver forms of P. vivax and ovale,
Resulting in a “Radical Cure”

It’s not active against erythrocytic forms of Plasmodia and is, therefore, always
used in conjunction with chloroquine, mefloquine or atovaquone-proguanil.

[The patient uses an erythrocytic active drug before, during and after visiting a
malaria area, and then follows up with primaquine; or the patient with vivax or
ovale malaria is treated 1st with an erythrocytic active drug and then with
primaquine.]

Adverse effects: nausea, abdominal cramps, headache

rare: cardiac arrhythmias, leukopenia, leukocytosis, agranulocytosis

!! IMPORTANT !!
Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are
at high risk for hemolytic anemia (hemolysis) and methemoglobinemia. Two
of primaquine’s metabolites are more oxidative than primaquine, and much
more so than chloroquine. The G6PD gene is on the X chromosome, so males
are more likely to be affected than females.
Approximately 10% of African-American males in the USA are G6PD-
deficient. The G6PD mutations in dark-skinned caucasians from the
Mediterranean region (e.g., Sardinians, Sephardic Jews, Iranians & Greeks)
and in some Asians (southern China)) cause a greater G6PD-deficiency (and
therefore primaquine sensitivity) than does the African mutation.

Q-5
 T.L. Kirley, Ph.D.
Antiprotozoal & Antimalerial Drugs

Screen for G6PD-deficiency before using primaquine. Some G6PD-

deficient patients infected with P. vivax and ovale will not be able to take
primaquine, and will have to be treated with other malaria drugs when the
disease flares up. Some patients with a lesser G6PD-deficiency may be able to
tolerate lower primaquine doses taken for a longer time, but at the first sign of
hemolysis or anemia (dark urine, fatigue, decreased hemoglobin) stop the drug.

Contraindications: allergy to quinolones, pregnancy, patients with a history of

hematological disease, systemic lupus erythematosus, rheumatoid
arthritis, G6PD-deficiency, or any condition involving bone
marrow suppression

Drug Interactions: bone marrow suppressants and hemolytic drugs increase risk
of adverse hematological effects

Other important drugs used to treat malaria (not for prophylaxis): Board info only

quinidine – stereoisomer of quinine; both isolated from Cinchona bark

-- used to treat severe P. falciparum malaria; active on

erythrocytic form only (+ doxycycline or clindamycin)
-- not used for malaria prophylaxis due to its cardiac toxicity
-- quinidine has a narrow therapeutic index. It can exacerbate
existing cardiac problems, and many drugs alter its half-life
and its various biological effects
-- “cinchonism” = toxicity: tinnitus, dizziness, headache, nausea,
visual disturbances (can get severe)

artemisinin – ancient Chinese antipyretic from ginghausu (sweet wormwood)

-- artemisinin and its analogs, artemether & artesunate, now
recommended by UN & WHO for use in regions with drug-
resistant malaria
-- active against erythrocytic forms only
-- available in combination with mefloquine or lumefantrine to
decrease development of resistant Plasmodia

Q-6
 T.L. Kirley, Ph.D.
Antiprotozoal & Antimalerial Drugs

Antiprotozoal Drugs
Metronidazole (Flagyl)

-- very useful antiprotozoal drug; recommended for:

amebiasis (Entamoeba histolytica) – kills trophozoites, not cysts

giardiasis (Giardia lamblia)
trichomoniasis (Trichomonas vaginalis)

-- also effective against anaerobic bacteria

Mechanism of action: Reduction of drug’s nitro group by anaerobic bacteria and

by sensitive protozoa produces reactive intermediates that disrupt DNA structure
and inhibit DNA repair and synthesis

Adverse effects: common: nausea, headache, dry mouth, & metallic taste in mouth
occasional: GI distress
rare: peripheral neuropathy

Metronidazole is mutagenic in bacteria and tumorigenic in mice. Its use in

pregnancy, particularly the 1st trimester, is NOT recommended.

Drug Interactions: --disulfiram-like reaction with alcohol

--confusion/psychoses in presence of disulfiram
--inhibits the P450 metabolism of some drugs (e.g., warfarin)
--half-life is altered by drugs that induce/inhibit P450 enzymes

Trimethoprim-Sulfamethoxazole (TMP-SMX, Co-trimoxazole,

Bactrim)

--widely used anti-folate antibiotic drug combination

--also used for Cyclospora infections and for treating Pneumocystis pneumonia
in AIDS patients

Adverse effects: are due to both drugs in the mixture

common: --hypersensitivity reactions to sulfonamides, including fever and
rashes, are increased by trimethoprim
--GI distress & photosensitivity due to sulfonamides
--AIDS patients on TMP/SMX have a high incidence of fever,
rashes, diarrhea and leukopenia

Q-7
 T.L. Kirley, Ph.D.
Antiprotozoal & Antimalerial Drugs

rare: --sulfonamides can precipitate in urine and form crystals

--hepatotoxicity is rare, but more frequent in G6PD-deficient patients
--trimethoprim can cause severe blood disorders (anemia, leukopenia)
(supplement with folic acid to ¯ incidence)

Avoid during pregnancy, particularly the 3rd trimester

sulfonamides can cause kernicterus (bilirubin encephalopathy) in
newborns

Drug interactions: Sulfonamides increase the serum levels of some other

drugs (including warfarin, phenytoin, sulfonylurea) by inhibiting
both
their hepatic P450 metabolism and their binding to albumin

---------------------------------------------------------------------------------------------------------

Antiprotozoal and Antimalarial Drug Summary

Protozoan Disease Drug

Entamoeba histolytica amebiasis metronidazole + a
luminal amebicide:
paromomycin, iodoquinol
Giardia lamblia giardiasis Metronidazole
Trichomonas vaginalis vaginitis Metronidazole
Trypanosoma cruzi acute Chagas disease Nifurtimox
Trypanosoma brucei African sleeping Suramin
sickness
*Pneumocystis carinii pneumonia in AIDS TMP-SMX
Cyclospora cayetanesis diarrhea/flu symptoms TMP-SMX
Cryptosporidium diarrhea try paromomycin in AIDS
Toxoplasma gondii toxoplasmosis sulfonamide +
pyrimethamine
Plasmodium: falciparum chloroquine, mefloquine,
malariae malaria atavaquone+proguanil,
doxycycline, quinidine
------------------------------ ------------------------------
vivax one of above +
ovale primaquine
* now classified as a fungus

Q-8
 T.L. Kirley, Ph.D.
Antiprotozoal & Antimalerial Drugs

Antiprotozoal and Antimalarial Drug Study Questions

(not in standard examination format)

1. What is the best choice prophylactic drug for someone traveling to a malaria-risk
region with no reported drug resistance?

2. If P. vivax or P. ovale is present in the above malaria-risk region, what second drug
should you prescribe for the traveler at the end of the trip?

3. Which antimalarial drugs can provide effective prophylaxis against chloroquine-

resistant P. falciparum?

4. A female patient who planned to leave next month for a vacation in a region known
to contain chloroquine-resistant P. falciparum and vivax, discovers that she’s
pregnant and asks for your advice. What should you warn her about?

5. A business traveler taking medication to prevent malaria becomes depressed and

experiences insomnia and nightmares. Which antimalarial drug is he likely to be
taking?

6. A second year medical student who spent his term break backpacking in the Rocky
Mountains returns to school with diarrhea, vomiting and abdominal pain that persists
for several days. Fecal examination (in the lab) reveals the presence of Giardia
trophozoites. A) Which drug should you prescribe? B) What should you advise
this student to avoid ingesting while taking this drug?

Q-9
 T.L. Kirley, Ph.D.
Antiprotozoal & Antimalerial Drugs

Answers to Study Questions

1. chloroquine: It’s effective, convenient to take, and has the fewest side effects

2. primaquine: It’s the only drug that is effective against the dormant liver form of
P. vivax and ovale

3. mefloquine, doxycycline, and atovaquone-proguanil are all effective against

chloroquine-resistant P. falciparum

4. Malaria and all of the drugs that you could prescribe for prophylaxis or treatment of
malaria due to chloroquine-resistant P. falciparum and P. vivax will place her fetus at
risk. It would be prudent for her to cancel this vacation.

5. mefloquine frequently causes some symptoms of CNS toxicity

6A. metronidazole
6B. ingesting alcohol while taking metronidazole will cause a disulfiram-like reaction

References:

www.cdc.gov/travel

Basic and Clinical Pharmacology, 10th edition (2007), B.G. Katzung, Chapter 53.

Q-10