Antimalarial Quinolines
Cinchona bark was used in Europe for the treatment of malaria beginning in the 1600s. Its active ingredient is a quinoline alkaloid called quinine. Synthesis of new quinolines was stimulated by the interruption of quinine supplies during the World War I and World War II and, after 1961, by the growing impact of drug-resistant falciparum malaria in several areas of the world. Among the most effective agents are those that share the double-ring structure of quinine.
Quinine and quinoline analogs active against malaria
Current analogs fall into three major groups: 4-aminoquinolines (including, chloroquine 8-aminoquinolines (including primaquine), and 4-quinolinemethanols (including mefloquine). All of them selectively destroy intracellular parasites by accumulating in parasitized host cells. Most of these agents appear to inhibit heme polymerase, leading to the buildup of toxic hemoglobin metabolites within the malarial parasite.
Accumulate in parasitized cells, block heme metabolism
Quinine, chloroquine, and mefloquine concentrate in parasitized erythrocytes and rapidly destroy the erythrocytic stage of the parasite that is responsible for the clinical manifestations of malaria. Thus, these agents can be used either prophylactically to suppress clinical illness if infection occurs or therapeutically to terminate an acute attack. They do not concentrate in tissue cells, and thus organisms sequestered in exoerythrocytic sites, particularly the liver, survive and may later reestablish erythrocytic infection and produce a clinical relapse. In contrast, primaquine accumulates in tissue cells, destroys hepatic parasites, and effects a full “radical” cure.
Quinine, 4-aminoquinolines (eg, chloroquine), and 4-quinolinemethanols suppress malarial infection in the human red blood cell
8-Aminoquinolines (eg, primaquine) effect radical cure by treating the liver
Chloroquine phosphate was the most widely used of the blood schizonticidal drugs for decades. In the doses used for long-term malaria prophylaxis it was remarkably free of untoward effects. Unfortunately, its heavy use led to widespread resistance in Plasmodium falciparum, and thus it is no longer recommended for prevention or treatment of falciparum malaria in most parts of the world (see Resistance below). Primaquine phosphate, the 8-aminoquinoline used to eradicate persistent hepatic parasites, has toxic effects related to its oxidant activity. Methemoglobinemia and hemolytic anemia are particularly frequent in patients with glucose-6-phosphate dehydrogenase deficiency, because they are unable to generate sufficient quantities of the reduced form of nicotinamide adenine dinucleotide to respond to this oxidant stress. Typically, the anemia is severe in patients of Mediterranean and Far Eastern ancestry and mild in patients of African ancestry.
Primaquine may have hematologic toxicity
Quinine is the oldest and most toxic of the quinolines. It is currently used primarily to treat strains of drug-resistant P falciparum that are spreading rapidly through Asia, Latin America, and Africa. Quinidine, a less cardiotoxic optical isomer of quinine, is more readily available in the United States and is preferred to quinine when parenteral administration is required. Mefloquine, an oral 4-quinolinemethanol analog, originally displayed a high level of activity against most chloroquine-resistant parasites; however, mefloquine-resistant strains of P falciparum are now widespread in Southeast Asia and are present to a lesser degree in South America and Africa. Concerns regarding psychiatric side effects of mefloquine have been generally overblown, but serve as another reason for the waning use of this medication.
Quinine is active against many chloroquine-resistant malarial strains
Phenanthrene methanols are not in the strict sense quinine analogs. Nevertheless, they are structurally similar to this group of agents and, together with them, were discovered to have antimalarial activity during the World War II. Halofantrine*, the most effective of the group, is an blood schizonticide effective against both sensitive and multidrug-resistant strains of P falciparum. Unfortunately, because of rare cases of fatal heart arrhythmias, it is not available in the United States. A related drug, lumefantrine, is much safer, but is unreliable when dosed alone. It is always administered as a coformulation with artemisinins (see below).
Phenanthrene methanols active against multidrug-resistant malaria
Qinghaosu (Artemisinin)
This natural extract of the plant Artemisia annua (qing hao, sweet wormwood) is a sesquiterpene lactone peroxide that is structurally distinct from all other known antiparasitic compounds. Extracts of qing hao were recommended for the treatment of fevers in China as early as AD 341; their specific antimalarial activity was defined by Chinese investigators in 1971. Although Qinghaosu has also been shown to be active against the free-living ameba Naegleria fowleri and several trematodes, including Schistosoma japonicum, S mansoni, and Clonorchis sinensis, its greatest impact to date has been in the treatment of malaria. Extensive investigations showed it to be schizonticidal for both chloroquine-sensitive and chloroquine-resistant strains of P falciparum. Several derivatives, among them artemether and artesunate, are significantly more active than the parent compound. All are concentrated in parasitized erythrocytes, where they decompose and release free radicals, which are thought to damage parasitic membranes. Artemisinin compounds act more rapidly than other antimalarial agents, stopping parasite development and preventing cytoadherence in falciparum malaria. Because of their relatively short half-life, they should be administered in coformulations with longer-acting agents such as lumefantrine. This “artemisinin combination therapy (ACT)” is so safe and effective that it has become the standard of care for treatment of acute malaria worldwide. Unfortunately, resistance has already been detected, especially among P falciparum isolates from the Thai–Myanmar border. Although depression of reticulocyte counts has been noted, these agents appear significantly less toxic than quinoline antimalarials. Because there is some evidence that they may possess teratogenic properties, they should be avoided in pregnancy. Note that they may be given orally, rectally (by suppository), or parenterally.
Plant derivative active against malaria, amebas, and Schistosoma
Concentrated in parasitized erythrocytes
ACT now treatment of choice for falciparum malaria
Quinones
Atovaquone is a novel hydroxynaphthoquinone that shows promise in the treatment of malaria and toxoplasmosis. Its antiparasitic activity appears to result from the specific blockade of pyrimidine biosynthesis secondary to the inhibition of the parasite’s mitochon-drial electron transport chain.
Efficacy trials established its capacity to affect rapid clearance of parasitemia in patients with chloroquine-resistant falciparum malaria. Frequent parasitic recrudescences were eliminated when atovaquone was administered in combination with the folate antagonist proguanil (see below). This coformulation (Malarone) is popular in malaria prophylaxis because it is effective and well tolerated—although, like mefloquine, it will not protect against malaria liver infection. Subsequently, this agent was shown to be effective for the treatment of toxoplasmosis in patients with acquired immunodeficiency syndrome (AIDS). Unlike other antitoxoplasma agents, atovaquone has been found to be active against Toxoplasma gondii cysts as well as tachyzoites, suggesting that this agent may produce radical cure. Supporting this is the infrequency with which cessation of atovaquone treatment of toxoplasmic cerebritis in AIDS patients has resulted in relapse. Relapse after atovaquone treatment of the fungus Pneumocystis jirovecii in this same patient population appears similarly uncommon.
Atovaquone stable and active against malaria and toxoplasmosis
Folate Antagonists
Folic acid is a critical coenzyme for the synthesis of purines and ultimately DNA. In protozoa, as in bacteria, the active form of folic acid is produced in vivo by a simple two-step process. The first step, the conversion of para-aminobenzoic acid to dihydrofolic acid, is blocked by sulfonamides. The second step, the transformation of dihydro- to tetrahydrofolic acid, is inhibited by folic acid analogs (folate antagonists), which competitively inhibit dihydrofolate reductase. Used together with sulfonamides, folate antagonists are very effective inhibitors of protozoan growth.
Sulfonamide and folate antagonists inhibit protozoa
Trimethoprim, an inhibitor of dihydrofolate reductase, is used in combination with sulfamethoxazole to treat toxoplasmosis. Another folate antagonist, pyrimethamine, has a high affinity for sporozoan dihydrofolate reductase and has been particularly effective, when used with a sulfonamide, in the management of clinical malaria and toxoplasmosis. A third folate antagonist, proguanil, is commonly taken in combination with atovaquone for malaria prophylaxis. Acquired protozoal resistance to sulfonamides coformulated with folate antagonists has greatly diminished their effectiveness for malaria prevention and treatment.
Sulfonamides effective in Toxoplasma infections
Folate antagonists may result in folate deficiency in individuals with limited folate reserves, such as newborns, pregnant women, and the malnourished. This is of greatest concern when large doses are used for prolonged periods, as in the treatment of acute toxoplasmosis. When folate antagonists are used with sulfonamides, the entire range of sulfonamide toxic effects may be seen. Patients with AIDS appear to suffer an unusually high incidence of toxic side effects to trimethoprim–sulfamethoxazole.
Folate deficiency and sulfonamide toxicities may occur during treatment
Nitroimidazoles
Metronidazole, a nitroimidazole, was introduced in 1959 for the treatment of trichomoniasis. Subsequently, it was found to be effective in the management of giardiasis, amebiasis, and a variety of infections produced by obligate anaerobic bacteria. Energy metabolism in all of them depends on the presence of low-redox–potential compounds, such as ferredoxin, to serve as electron carriers. These compounds reduce the 5-nitro group of the imidazoles to produce intermediate products responsible for the death of the protozoal and bacterial cells, possibly by alkylation of DNA. Resistance, though uncommon, has been noted in strains of Trichomonas vaginalis lacking nitroreductase activity. Nausea, dysguesia (taste perversion), and peripheral neuropathy are notable potential side effects.
Tinidazole, a newer nitroimidazole, appears to be both a more effective and better tolerated antiprotozoal agent. Its greater lipid solubility improves cerebrospinal fluid levels and in vitro activity. Either drug can be used for trichomoniasis, invasive amebiasis, and giardiasis.
Active against Protozoa at lowredox-potential
Eflornithine (Difluoromethylornithine)
Eflornithine is a specific, enzyme-activated, irreversible inhibitor of ornithine decarboxylase (ODC). In mammalian cells, decarboxylation of ornithine by ODC is a mandatory step in the synthesis of polyamines, compounds thought to play critical roles in cell division and differentiation. Originally developed as an antineoplastic agent, eflornithine proved ineffective in cancer chemotherapy trials. It was also marketed as a topical depilatory agent (anti-hair growth). With the discovery that polyamines of Trypanosoma species were also synthesized from ornithine, eflornithine was successfully tested in the treatment of animal trypanosomiasis. It has been used to treat advanced cases of human West African sleeping sickness due to T brucei gambiense. However, it is not effective against the more virulent T brucei rhodesiense, it is dosed intravenously, and it remains expensive. Eflornithine appears to be cytostatic and requires an intact host immune system for maximum effect.
Originally an anticancer drug
Active against West African sleeping sickness
Heavy Metals
Arsenic and antimonial compounds have been used since ancient times. They form stable complexes with sulfur compounds and probably exert their biologic effects by binding to sulfhydryl (–SH) groups. They are toxic to the host as well as to the parasite, and have their greatest impact on cells that are metabolically active such as neuronal, renal tubular, intestinal epithelial, and bone marrow stem cells. Their differential toxicity and therapeutic value are due to enhanced uptake by the parasite and its intense metabolic activity. However, significant host toxicity remains. Only one trivalent arsenical, melarsoprol (Mel B), is now used for African trypanosomiasis of the central nervous system, because of its penetration of the blood–brain barrier. Due to its toxicity, including a roughly 10% chance of fatal arsenic poisoning, it is used only when less toxic agents have failed or when the central nervous system is involved. Safer agents are desperately needed for this deadly disease.
Arsenic and antimonial compounds inactivate –SH groups
Some differential toxicity based on enhanced uptake by parasite, but still very toxic to humans
Melarsoprol active against all stages of trypanosomiasis, but highly toxic
Antimonial agents are now restricted to the management of leishmanial infections. Two pentavalent compounds, sodium stibogluconate (Pentostam) and meglumine antimoniate† (Glucantime), are used for all forms of leishmaniasis. In disseminated disease, prolonged therapy is usually required, and relapses often occur. In localized cutaneous leishmaniasis, cure is usually achieved with a relatively brief course. Toxic side effects are similar to those of the arsenicals, although less severe. However, visceral leishmaniasis is usually treated using intravenous amphotericin-lipid formulations, which are thought of as antifungal medications. In fact, these drugs are being used more frequently for cutaneous leishmaniasis as well, where they are often effective and better tolerated than the antimonials.
Antimonials used only for leishmania infections
DRUGS FOR HELMINTH INFECTIONS
The approach to treatment of most worm infections differs significantly from those applied to prokaryotic or protozoan infections. Helminths, with few exceptions, do not multiply within the human host, and severe infections usually require the repeated acquisition of infectious worms. Interestingly, the intensity of gastrointestinal worm burden does not follow a normal distribution in human populations. Most infected persons harbor fewer than a dozen adult worms; a small minority harbor very large worm numbers. Because there is a direct correlation between worm burden and clinical disease, only this minority suffers significant morbidity. Concentrating treatment on those few clinically ill patients could moderate the medical impact of a helminthic disease on the community at a cost dramatically lower than that required for mass treatment. Moreover, it is usually unnecessary to eradicate all gastrointestinal worms from treated patients; a significant decrease in the worm burden may be adequate to alleviate clinical symptoms. This can often be accomplished with short, subcurative doses that further reduce cost and minimize the likelihood of drug toxicity. Because this approach can dramatically decrease the total community worm burden, the number of worm progeny shed into the environment is similarly reduced, and the transmission of the disease slowed or—rarely—eliminated entirely. Resistance to antihelminthic agents is a real concern, although this has rarely been demonstrated to date.
For gastrointestinal worms, treatment efforts should concentrate on the most heavily parasitized individuals
Goal is reduced worm burden, not sustained eradication
Benzimidazoles
As their name implies, the basic structure of benzimidazoles consists of linked imidazole and benzene rings. Unlike their antiprotozoal cousins discussed previously, the benzimidazoles are broad-spectrum anthelmintic agents. The prototype drug, thiabendazole, acts against both adult and larval nematodes. Soon after its introduction in the early 1960s it was shown to be useful in the management of cutaneous larva migrans, trichinosis, and most intestinal nematode infections. The mechanism by which it exerts its anthelmintic action is uncertain. It is known to inhibit fumarate reductase, an important mitochondrial enzyme of helminths. The primary mode of action, however, may derive from the known capacity of all benzimidazoles to inhibit the polymerization of tubulin, the eukaryotic cytoskeletal protein. Mild side effects are related to the gastrointestinal tract or liver, and rapidly resolve with the discontinuation of the drug. Hypersensitivity reactions, induced either by the drug or by antigens released from the damaged parasite, may occur.
Broad-spectrum anthelmintics
Mebendazole, a carbamate benzimidazole introduced in 1972, has a spectrum similar to that of thiabendazole, but also has been found to be effective against a number of cestodes, including Taenia, Hymenolepsis, and Echinococcus. It irreversibly binds to worm tubulin, thus interfering with the assembly of cytoplasmic microtubules, structures essential for glucose uptake. This results in glycogen depletion, cessation of ATP formation, and worm paralysis or death. Unlike thiabendazole, mebendazole is not well absorbed from the gastrointestinal tract and may owe part of its effectiveness against intestine-dwelling adult worms to its high concentrations in the human gut. It does not appear to affect glucose metabolism in humans, and toxicity is uncommon. Teratogenic effects have been observed in experimental animals; its use in infants and pregnant women is relatively contraindicated.
Mebendazole blocks glucose uptake by adult and larval worms
Interferes with tubulin and cytoplasmic microtubules
Albendazole is a benzimidazole carbamate that is more highly absorbed and thus has a somewhat broader spectrum than that of its close relative, mebendazole, including more activity against Strongyloides stercoralis and several tissue nematodes. In addition to the vermicidal and larvicidal properties that it shares with other benzimidazoles, it is ovicidal, enhancing its effectiveness in tissue cestode infections such as echinococcosis and cysticercosis. Its activity against Giardia, one of the most common intestinal protozoa, makes it an appealing candidate for the treatment of polyparasitism. Although it shares the teratogenic potential of other benzimidazoles, it is otherwise extremely well tolerated. Single-dose therapy is effective in the management of many intestinal nematode infections.
Albendazole has broader spectrum
Avermectins
Avermectins are macrocyclic lactones produced as fermentation products of Streptomyces avermitilis. Structurally similar to the macrolide antibiotics, they are effective at extremely low concentration against a wide variety of nematodes and arthropods. The avermectins appear to induce neuromuscular paralysis by acting on a receptor of the parasite peripheral neurotransmitter, γ-aminobutyric acid (GABA). In mammals, GABA is confined to the central nervous system, and because the avermectins do not cross the blood–brain barrier in significant concentration, they do not appear to produce significant untoward effects in the mammalian host. Ivermectin, a derivative of avermectin B1, was originally developed and marketed as a horse dewormer. However, its effect on human health has been tremendous. It is currently the drug of choice for the treatment and suppression of onchocerciasis and is dosed on a massive scale for that purpose in West Africa. It is also effective in the treatment of strongyloidiasis, filariasis, and certain GI helminth infections, among others. It also has activity against ectoparasites, making it useful in the treatment of common syndromes such as head lice and scabies.
Antibiotics that influence nematode neurotransmitters
Activity against filariae
Ivermectin dosed on massive scale for onchocerciasis
Praziquantel
Praziquantel, a heterocyclic pyrazinoisoquinoline, is an important anthelmintic, effective against a broad range of cestodes and trematodes, many of which are poorly responsive to previously available agents. It is given in one to three doses. The drug is rapidly taken up by susceptible helminths, in which it appears to induce the loss of intracellular calcium, tetanic muscular contraction, and destruction of the tegument. The differential toxicity of this agent may be related to the inability of susceptible worms to metabolize the drug. Aside from transient, mild gastrointestinal symptoms, praziquantel appears remarkably free of side effects in humans. It is currently the drug of choice for the treatment of schistosomiasis, clonorchiasis, and opisthorchiasis. Good activity has been demonstrated against other common trematode and cestode infections. Its high level of safety suggests that it may play a significant role in future worldwide mass therapy campaigns.
Causes loss of intracellular calcium in cestodes and trematodes
Safety of praziquantel may allow use in mass therapy campaigns
Other Antiparasitic Agents
A number of other antiparasitic agents used in therapy, their properties, and their clinical uses are listed in Table 50–1.
TABLE 50–1 Miscellaneous Antiparasitic Agents
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