Antiparasitic Agents

Drugs for Treating Endo- and
Ectoparasitic Infestations
Adverse hygienic conditions favor human
infestation with multicellular organisms
(referred to here as parasites).
Skin and hair are colonization sites for
arthropod ectoparasites, such as insects
(lice, fleas) and arachnids (mites).
Against these, insecticidal or arachnicidal
agents, respectively, can be used.
Endoparasites invade the intestines or
even internal organs, and are mostly
members of the phyla of flatworms and
roundworms. They are combated with
anthelmintics.
Anthelmintics. As shown in the table,
the newer agents praziquantel and
mebendazole are adequate for the treatment
of diverse worm diseases. They
are generally well tolerated, as are the
other agents listed.
Insecticides. Whereas fleas can be
effectively dealt with by disinfection of
clothes and living quarters, lice and
mites require the topical application of
insecticides to the infested subject.
Chlorphenothane (DDT) kills insects
after absorption of a very small
amount, e.g., via foot contact with
sprayed surfaces (contact insecticide).
The cause of death is nervous system
damage and seizures. In humans DDT
causes acute neurotoxicity only after
absorption of very large amounts. DDT
is chemically stable and degraded in the
environment and body at extremely
slow rates. As a highly lipophilic substance,
it accumulates in fat tissues.
Widespread use of DDT in pest control
has led to its accumulation in food
chains to alarming levels. For this reason
its use has now been banned in
many countries.
Lindane is the active γ-isomer of
hexachlorocyclohexane. It also exerts a
neurotoxic action on insects (as well as
humans). Irritation of skin or mucous
membranes may occur after topical use.
Lindane is active also against intradermal
mites (Sarcoptes scabiei, causative
agent of scabies), besides lice and fleas.
It is more readily degraded than DDT.
Permethrin, a synthetic pyrethroid,
exhibits similar anti-ectoparasitic
activity and may be the drug of choice
due to its slower cutaneous absorption,
fast hydrolytic inactivation, and rapid
renal elimination.


Antimalarials
The causative agents of malaria are plasmodia,
unicellular organisms belonging
to the order hemosporidia (class protozoa).
The infective form, the sporozoite,
is inoculated into skin capillaries when
infected female Anopheles mosquitoes
(A) suck blood from humans. The sporozoites
invade liver parenchymal cells
where they develop into primary tissue
schizonts. After multiple fission, these
schizonts produce numerous merozoites
that enter the blood. The preerythrocytic
stage is symptom free. In
blood, the parasite enters erythrocytes
(erythrocytic stage) where it again multiplies
by schizogony, resulting in the
formation of more merozoites. Rupture
of the infected erythrocytes releases the
merozoites and pyrogens. A fever attack
ensues and more erythrocytes are infected.
The generation period for the
next crop of merozoites determines the
interval between fever attacks. With
Plasmodium vivax and P. ovale, there can
be a parallel multiplication in the liver
(paraerythrocytic stage). Moreover,
some sporozoites may become dormant
in the liver as “hypnozoites” before entering
schizogony. When the sexual
forms (gametocytes) are ingested by a
feeding mosquito, they can initiate the
sexual reproductive stage of the cycle
that results in a new generation of
transmittable sporozoites.
Different antimalarials selectively
kill the parasite’s different developmental
forms. The mechanism of action is
known for some of them: pyrimethamine
and dapsone inhibit dihydrofolate
reductase (p. 273), as does chlorguanide
(proguanil) via its active metabolite. The
sulfonamide sulfadoxine inhibits synthesis
of dihydrofolic acid (p. 272). Chloroquine
and quinine accumulate within
the acidic vacuoles of blood schizonts
and inhibit polymerization of heme, the
latter substance being toxic for the
schizonts.
Antimalarial drug choice takes into
account tolerability and plasmodial resistance.
Tolerability. The first available
antimalarial, quinine, has the smallest
therapeutic margin. All newer agents
are rather well tolerated.
Plasmodium (P.) falciparum, responsible
for the most dangerous form
of malaria, is particularly prone to develop
drug resistance. The incidence of
resistant strains rises with increasing
frequency of drug use. Resistance has
been reported for chloroquine and also
for the combination pyrimethamine/
sulfadoxine.
Drug choice for antimalarial
chemoprophylaxis. In areas with a risk
of malaria, continuous intake of antimalarials
affords the best protection
against the disease, although not
against infection. The drug of choice is
chloroquine. Because of its slow excretion
(plasma t1/2 = 3d and longer), a single
weekly dose is sufficient. In areas
with resistant P. falciparum, alternative
regimens are chloroquine plus pyrimethamine/
sulfadoxine (or proguanil,
or doxycycline), the chloroquine analogue
amodiaquine, as well as quinine
or the better tolerated derivative mefloquine
(blood-schizonticidal). Agents active
against blood schizonts do not prevent
the (symptom-free) hepatic infection,
only the disease-causing infection
of erythrocytes (“suppression therapy”).
On return from an endemic malaria region,
a 2 wk course of primaquine is adequate
for eradication of the late hepatic
stages (P. vivax and P. ovale).
Protection from mosquito bites
(net, skin-covering clothes, etc.) is a
very important prophylactic measure.
Antimalarial therapy employs the
same agents and is based on the same
principles. The blood-schizonticidal
halofantrine is reserved for therapy only.
The pyrimethamine-sulfadoxine
combination may be used for initial selftreatment.
Drug resistance is accelerating in
many endemic areas; malaria vaccines
may hold the greatest hope for control
of infection.