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294 Antiparasitic Drugs

Antimalarials

The causative agents of malaria are plasmodia, unicellular organisms (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. These give rise to numerous merozoites that enter the blood. The preerythrocytic stage is asymptomatic. 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.

Different antimalarials selectively kill the parasite’s different developmental forms. The mechanism of action is known for some agents: Chloroquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme released from digested hemoglobin, free heme being toxic for the schizonts. Pyrimethamine in-

hibits protozoal

dihydrofolate

reductase

(p.274), as does

chlorguanide

(proguanil)

via its active metabolite cycloguanil. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p.274). Dihydrofolate reductase is also blocked by cycloguanil, the active form of proguanil. Atoquavone suppresses synthesis of pyrimidine bases, probably by interfering with mitochondrial electron transport. Artemesinin derivatives (artemether, artesunate) originate from the East Asian plant Qinghaosu (Artemisia sp.) Its antischizontal effect appears to involve a re-

action between heme iron and the epoxide group of these compounds.

Antimalarial drug choice takes tolerability and plasmodial resistance into account.

Tolerability. The oldest antimalarial, quinine, has the smallest therapeutic margin. All newer agents are rather well tolerated.

Plasmodium falciparum, responsibleforthe most dangerous form of malaria, is particularly prone to develop drug resistance. The prevalence of resistant strains rises with increasingfrequencyofdruguse.Resistancehas been reported for chloroquine and also 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, though not against infection. Primaquine would be effective against primary tissue schizonts of all plasmodial species; however, it is not used for long-term prophylaxis because of unsatisfactory tolerability and the risk of plasmodial resistance. Instead, prophylactic regimens employ agents against blood schizonts. Depending on the presence of resistant strains, use can be made of chloroquine, and/or proguanil, mefloquine, the tetracycline doxycycline, as well as the combination of atoquavone and proguanil.

These drugs do not prevent the (symp- tom-free) hepatic infection but only the dis- ease-causing infection of erythrocytes (“suppression therapy”). On a person’s return from an endemic malaria region, a two-week course of primaquine is adequate for eradication of the late hepatic stages (P. vivax and

P. ovale).

Protection from mosquito bites (with nets, skin-covering clothes, etc.) is a very important prophylactic measure.

Therapy. Antimalarial therapy employs the same agents, in addition to the combinations of artemether plus lumefantrine or pyrimethamine plus sulfadoxine.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

 

Antimalarials

295

A. Malaria: stages of the plasmodial life cycle in the human: therapeutic options

 

 

Sporozoites

 

 

 

 

 

Hepatocyte

 

 

 

Primary tissue schizont

 

Primaquine

cycle

 

Proguanil

 

Preerythrocytic 1-4 weeks

P. falciparum

 

 

 

Pyrimethamine

 

Hypnozoite

Merozoites

 

 

 

 

 

 

 

 

 

 

Only

 

 

 

 

P. vivax

 

Chloroquine

 

 

P. ovale

 

 

 

Erythrocyte

 

 

 

 

 

 

Blood

Mefloquine

 

 

 

Quinine

 

 

 

schizont

 

 

 

 

 

 

cycle

 

Lumefantrine

 

 

 

Artemether

 

 

Erythrocytic

 

 

 

 

Atovaquone

 

 

 

Proguanil

 

 

 

Pyrimethamine

 

 

 

 

 

 

 

 

Sulfadoxine

 

 

 

 

Fever

 

 

Fever

 

2 days :

 

 

 

Tertian malaria

 

 

 

 

P. vivax, P. ovale

 

 

 

 

3 days:

 

 

Primaquine

 

Quartan malaria

 

 

 

P. malariae

 

 

 

 

 

 

 

 

No fever

 

 

 

 

periodicity:

 

 

 

 

Pernicious malaria:

 

 

 

P. falciparum

 

 

not P. falciparum

 

 

 

Chloroquine

 

 

 

 

Gametocytes

 

 

 

 

Quinine

 

 

 

 

Fever

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

296 Antiparasitic Drugs

extrapyramidal motor disturbances, Parkin-

 

Other Tropical Diseases

son-like signs, coma, and death. Therapy:

 

 

 

In addition to malaria, other tropical diseases

Long-term suramine i.v. or pentamidine(less

 

and their treatment will be considered for

effective);

arsenicals

(e.g.,

melarsoprol,

 

the following reasons. (1) Owing to the tre-

highly toxic), when the CNS is involved.

 

mendous growth in global travel, inhabitants

T. cruzi is confined to Central and South

 

of temperate climatic zones have become

America and transmitted by blood-sucking

 

exposed to the hazard of infection with trop-

reduviid bugs. These parasites preferentially

 

ical disease pathogens. (2) The spread of

infiltrate the cardiac musculature, where

 

some tropical diseases is of unimaginable

they cause damage to muscle fibers and the

 

dimensions, with humans victims number-

specialized conducting tissue. Death results

 

ing in the millions. The pharmacotherapeutic

from cardiac failure. Therapy: unsatisfactory.

 

 

possibilitiesknown to date will be presented.

 

 

 

 

 

 

 

 

Schistosomiasis

(bilharziasis)

(see

also

 

Amebiasis. The causative agent, Entamoeba

p.292). The causative organisms are trema-

 

histolytica, lives and multiplies in the colon

todes with a complex life cycle that need

 

(symptom: diarrhea), its cyst form residing

(aquatic) snails as intermediate hosts. Free-

 

also in the liver among other sites. In tropical

swimming larval cercariae penetrate the in-

 

regions, up to half the population can be

tact skin of humans. The adult worms (Schis-

 

infested, transmission occurring by the fe-

tosoma mansoni, D) livein thevenousvascu-

 

cal–oral route. The most effective treatment

lature. Occurrence: tropical countries rich in

 

against both intestinal infestation and sys-

aquatic habitats. About 200 million humans

 

temic disease is administration of metroni-

are af icted. Therapy: praziquantel, 10–

 

dazole. If monotherapy fails, combination

40 mg/kg,singledose,ishighlyeffectivewith

 

therapy with chloroquine, emetine or tetra-

minimal adverse effects. Substancesreleased

 

cyclines may be indicated.

from decaying worms may cause problems.

 

Leishmaniasis. The causative agents are flag-

Filariasis. In its microform, Wuchereria ban-

 

ellated protozoa that are transmitted by

crofti istransmittedbymosquitoes;theadult

 

sand flies to humans. The parasites are taken

parasites live in the lymph system and cause

 

up into phagocytes, where they remain in

inflammations and blockage of lymph drain-

 

phagolysosomes and multiply until the cell

age leading to elephantiasis in extreme cases

 

dies and the parasites can infect new cells.

(B). Therapy: diethylcarbamazepine for sev-

 

Symptoms: A visceral form, known as kala-

eral weeks; adverse reactions are chiefly due

 

azar, and cutaneous or mucocutaneous

to products from disintegrating worms.

 

forms exist (A). An estimated 12 million hu-

 

 

 

 

 

 

 

mans are affected. Therapy is dif cult; pen-

Onchocerciasis (“River Blindness”). The

 

tavalent antimonial compounds, such as sti-

causative organism is Onchocerca volvulus,

 

bogluconate, must be given for extended

a filaria transmitted by black flies (genus

 

periods. Adverse effects are pronounced.

Simulium). The adult parasites (several cen-

 

 

timeters long) form tangles and proliferating

 

Trypanosomiasis. The pathogens, Trypano-

nodules (onchocercomas) in the skin and

 

soma brucei (sleeping sickness) and T. cruzi

have a particular propensity for invading

 

(Chagas disease), are flagellated protozoa. T.

the eyeball, resulting in blindness. About 20

 

brucei (C) is transmitted by the tsetse fly,

million people inhabiting banks of fast-flow-

 

distributed in West and East Africa. An initial

ing rivers are af

icted with river blindness.

 

stage (swelling of lymph nodes, malaise,

Therapy:

ivermectin

(0.15 mg/kg,

single

 

hepatosplenomegaly, among others) is fol-

dose); adverse reactions are in part caused

 

lowedLuellmann,by invasionColor ofAtlastheofCNSPharmacologywith lethargy,© 2005by disintegratingThieme

worms.

 

 

 

All rights reserved. Usage subject to terms and conditions of license.

 

 

 

 

 

 

 

 

Other Tropical Diseases

297

 

 

 

 

A. Cutaneous leishmaniasis

 

 

 

B. Elephantiasis

 

 

 

 

 

 

 

Causative agent: Leishmania major

 

 

Causative agent: Wuchereria bancrofti

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

C. Trypanosoma brucei

 

 

 

D. Schistosoma mansoni

 

 

Causative agent of sleeping sickness

 

 

Causative agent of bilharziasis

 

 

 

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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