Chapter: Modern Pharmacology with Clinical Applications: Antiprotozoal Drugs

Antimalarial Drugs

Chloroquine (Aralen) is one of several 4-aminoquino-line derivatives that display antimalarial activity.

Antimalarial Drugs



Chloroquine (Aralen) is one of several 4-aminoquino-line derivatives that display antimalarial activity. Chloroquine is particularly effective against intraeryth-rocytic forms because it is concentrated within the par-asitized erythrocyte. This preferential drug accumula-tion appears to occur as a result of specific uptake mechanisms in the parasite. Chloroquine appears to work by intercalation with DNA, inhibition of heme polymerase or by interaction with Ca++ –calmodulin-mediated mechanisms. It also accumulates in the para-site’s food vacuoles, where it inhibits peptide formation and phospholipases, leading to parasite death.


The drug is effective against all four types of malaria with the exception of chloroquine-resistant P. falci-parum. Chloroquine destroys the blood stages of the in-fection and therefore ameliorates the clinical symptoms seen in P. malariae, P. vivax, P. ovale, and sensitive P. fal-ciparum forms of malaria. The disease will return in P. vivax and P. ovale malaria, however, unless the liver stages are sequentially treated with primaquine after the administration of chloroquine. Chloroquine also can be used prophylactically in areas where resistance does not exist. In addition to its use as an antimalarial, chloroquine has been used in the treatment of rheuma-toid arthritis and lupus erythematosus , extraintestinal amebiasis, and photoallergic reactions.


The absorption of chloroquine from the gastroin-testinal tract is rapid and complete. The drug is distrib-uted widely and is extensively bound to body tissues, with the liver containing 500 times the blood concentra-tion. Such binding is reflected in a large volume of dis-tribution (Vd). Desethylchloroquine is the major metabolite formed following hepatic metabolism, and both the parent compound and its metabolites are slowly eliminated by renal excretion. The half-life of the drug is 6 to 7 days.


Dizziness, headache, itching (especially in dark-skinned people), skin rash, vomiting, and blurring of vi-sion may occur following low doses of chloroquine. In higher dosages these symptoms are more common, and exacerbation or unmasking of lupus erythematosus or discoid lupus, as well as toxic effects in skin, blood, and eyes can occur. Since the drug concentrates in melanin-containing structures, prolonged administration of high doses can lead to blindness. Chloroquine should not be used in the presence of retinal or visual field changes.




Hydroxychloroquine (Plaquenil), like chloroquine, is a 4-aminoquinoline derivative used for the suppressive and acute treatment of malaria. It also has been used for rheumatoid arthritis and discoid and systemic lupus ery-thematosus. Hydroxychloroquine has not been proved to be more effective than chloroquine. Adverse reac-tions associated with its use are similar to those de-scribed for chloroquine. The drug should not be used in patients with psoriasis or porphyria, since it may exac-erbate these conditions.




Amodiaquine (Camoquin) is another 4-aminoquinoline derivative whose antimalarial spectrum and adverse re-actions are similar to those of chloroquine, although chloroquine-resistant parasites may not be amodi-aquine-resistant to the same degree. Prolonged treat-ment with amodiaquine may result in pigmentation of the palate, nail beds, and skin. There is a 1:2000 risk of agranulocytosis and hepatocellular dysfunction when the drug is used prophylactically.




Primaquine is the least toxic and most effective of the 8-aminoquinoline antimalarial compounds. The mecha-nism by which 8-aminoquinolines exert their antimalar-ial effects is thought to be through a quinoline–quinone metabolite that inhibits the coenzyme Q–mediated res-piratory chain of the exoerythrocytic parasite.


Primaquine is an important antimalarial because it is essentially the only drug effective against the liver (exo-erythrocytic) forms of the malarial parasite. The drug also kills the gametocytes in all four species of human malaria. Primaquine is relatively ineffective against the asexual erythrocyte forms. Primaquine finds its greatestuse in providing a radical cure for P. vivax and P. ovale malaria.


Primaquine is readily absorbed from the gastroin-testinal tract, and in contrast to chloroquine, it is not bound extensively by tissues. It is rapidly metabolized, and the metabolites are reported to be as active as the parent drug itself. Peak plasma levels are reached in 4 to 6 hours after an oral dose, with almost total drug elimi-nation occurring by 24 hours. The half-life is short, and daily administration is usually required for radical cure and prevention of relapses.


Although primaquine has a good therapeutic index, a number of important side effects are associated with its administration. In individuals with a genetically de-termined glucose 6-phosphate dehydrogenase defi-ciency, primaquine can cause lethal hemolysis of red cells. This genetic deficiency occurs in 5 to 10% of black males, in Asians, and in some Mediterranean peoples. With higher dosages or prolonged drug use, gastroin-testinal distress, nausea, headache, pruritus, and leukopenia can occur. Occasionally, agranulocytosis also has been observed.





Pyrimethamine (Daraprim) is the best of a number of 2,4-diaminopyrimidines that were synthesized as potential antimalarial and antibacterial compounds. Trimethoprim (Proloprim) is a closely related compound.


Pyrimethamine is well absorbed after oral adminis-tration, with peak plasma levels occurring within 3 to 7 hours. An initial loading dose to saturate nonspecific binding sites is not required, as it is with chloroquine. However, the drug binds to tissues, and therefore, its rate of renal excretion is slow. Pyrimethamine has a half-life of about 4 days. Although the drug does un-dergo some metabolic alterations, the metabolites formed have not been totally identified.


The only antimalarial drugs whose mechanisms of action are reasonably well understood are the drugs that inhibit the parasite’s ability to synthesize folic acid. Parasites cannot use preformed folic acid and therefore must synthesize this compound from the following pre-cursors obtained from their host: p-aminobenzoic acid (PABA), pteridine, and glutamic acid. The dihydrofolic acid formed from these precursors must then be hydro-genated to form tetrahydrofolic acid. The latter com-pound is the coenzyme that acts as an acceptor of a va-riety of one-carbon units. The transfer of one-carbon units is important in the synthesis of the pyrimidines and purines, which are essential in nucleic acid synthesis.


Whereas the sulfonamides and sulfones inhibit the initial step whereby PABA and the pteridine moiety combine to form dihydropteroic acid , pyrimethamine and trimethoprim inhibit the conversion of dihydrofolic acid to tetrahydrofolic acid, a reaction

catalyzed by the enzyme dihydrofolate reductase. The basis of pyrimethamine selective toxicity resides in the preferential binding of the drug to the parasite’s reduc-tase enzyme.


The combined use of sulfonamides or sulfones with dihydrofolate reductase inhibitors, such as trimetho-prim (Bactrim, Septra) or pyrimethamine (Fansidar), is a good example of the synergistic possibilities that exist in multiple-drug chemotherapy. This type of impair-ment of the parasite’s metabolism is termed sequential blockade. Using drugs that inhibit at two different points in the same biochemical pathway produces parasite lethality at lower drug concentrations than are possible when either drug is used alone.


Pyrimethamine has been recommended for prophy-lactic use against all susceptible strains of plasmodia; however, it should not be used as the sole therapeutic agent for treating acute malarial attacks. As mentioned previously, sulfonamides should always be coadminis-tered with pyrimethamine (or trimethoprim), since the combined antimalarial activity of the two drugs is sig-nificantly greater than when either drug is used alone. Also, resistance develops more slowly when they are used in combination. Sulfonamides exert little or no ef-fect on the blood stages of P. vivax, and resistance to the dihydrofolate reductase inhibitors is widespread.


In addition to its antimalarial effects, pyrimethamine is indicated (in combination with a sulfonamide) for the treatment of toxoplasmosis. The dosage required is 10 to 20 times higher than that employed in malarial infections.


Relatively few side effects are associated with the usual antimalarial dosages. However, signs of toxicity are evident at higher dosages, particularly those used in the management of toxoplasmosis. Many of these reactions reflect the interference of pyrimethamine with host folic acid metabolism, especially that occurring in rapidly di-viding cells. Toxic symptoms include anorexia, vomiting, anemia, leukopenia, thrombocytopenia, and atrophic glossitis. CNS stimulation, including convulsions, may fol-low an acute overdose.The side effects associated with the pyrimethamine–sulfadoxine combination include those associated with the sulfonamide and pyrimethamine alone. In addition, there is evidence of a greater incidence of allergic reactions, particularly toxic epidermal necroly-sis and Stevens-Johnson syndrome, with the combination. This carries an estimated mortality of 1:11,000 to 1:25,000 when used as a chemoprophylactic.


Chloroguanide (Proguanil)


Chloroguanide hydrochloride (Paludrine) is activated to a triazine metabolite, cycloguanil, which also inter-feres with parasite folic acid synthesis. It is a dihydrofo-late reductase inhibitor that is used for the prophylaxis of malaria caused by all susceptible strains of plas-modia. Chloroguanide is rapidly absorbed from the gas- trointestinal tract. Peak plasma levels occur 2 to 4 hours after oral administration, and the drug is excreted in the urine with an elimination half-life of 12 to 21 hours. Its side effects and spectrum of antimalarial activity are quite similar to those of pyrimethamine. The conversion of chloroguanide to the active metabolite is decreased in pregnancy and also as a result of genetic polymor-phism in 3% of whites and Africans and 20% of Asians.




Quinine is one of several alkaloids derived from the bark of the cinchona tree. The mechanism by which it exerts its antimalarial activity is not known. It does not bind to DNA at antimalarial dosages. It may poison the parasite’s feeding mechanism, and it has been termed a general protoplasmic poison, since many organisms are affected by it.


Quinine is rapidly absorbed following oral inges-tion, with peak blood levels achieved in 1 to 4 hours. About 70 to 93% of the drug is bound to plasma pro-teins, depending on the severity of the infection. Quinine is extensively metabolized, with only about 20% of the parent compound eliminated in the urine.


The primary present-day indication for quinine and its isomer, quinidine, is in the intravenous treatment of severe manifestations and complications of chloro-quine-resistant malaria caused by P. falciparum.


Aside from its use as an antimalarial compound, quinine is used for the prevention and treatment of noc-turnal leg muscle cramps, especially those resulting from arthritis, diabetes, thrombophlebitis, arteriosclero-sis, and varicose veins.


Cinchonism describes the toxic state induced by ex-cessive plasma levels of free quinine. Symptoms include sweating, ringing in the ears, impaired hearing, blurred vision, nausea, vomiting, and diarrhea. Quinine is a po-tent stimulus to insulin secretion and irritates the gas-trointestinal mucosa. Also, a variety of relatively rare hematological changes occur, including leukopenia and agranulocytosis. Quinine is potentially neurotoxic in high dosages, and severe hypotension may follow its rapid intravenous administration.




Quinacrine is no longer used extensively as an anti-malarial drug and has been largely replaced by the 4-aminoquinolines.




Although dapsone (Avlosulfon) was once used in the treatment and prophylaxis of chloroquine-resistant P. falciparum malaria, the toxicities associated with its administration (e.g., agranulocytosis, methemoglobine-mia, hemolytic anemia) have severely reduced its use.

Occasionally dapsone has been added to the usual chloroquine therapeutic regimen for the prophylaxis of chloroquine-resistant P. falciparum malaria. It is also used in combination therapy for leprosy.



Mefloquine (Lariam) is a 4-quinolinemethanol deriva-tive used both prophylactically and acutely against re-sistant P. falciparum malaria. It is ineffective against the liver stage of P. vivax malaria.


While its detailed mechanism of action is unknown, it is an effective blood schizonticide; that is, it acts against the form of the parasite responsible for clinical symptoms. Orally administered mefloquine is well ab-sorbed and has an absorption half-life of about 2 hours; the elimination half-life is 2 to 3 weeks. Among its side effects are vertigo, visual alterations, vomiting, and such CNS disturbances as psychosis, hallucinations, confu-sion, anxiety, and depression. It should not be used con-currently with compounds known to alter cardiac con-duction or prophylactically in patients operating dangerous machinery. It should not used to treat severe malaria, as there is no intravenous formulation.




Atovaquone is a naphthoquinone whose mechanism of action involves inhibition of the mitochondrial electron transport system in the protozoa. Malaria parasites de-pend on de novo pyrimidine biosynthesis through dihy-droorotate dehydrogenase coupled to electron trans-port. Plasmodia are unable to salvage and recycle pyrimidines as do mammalian cells.


Atovaquone is poorly absorbed from the gastroin-testinal tract, but absorption is increased with a fatty meal. Excretion of the drug, mostly unchanged, occurs in the feces. The elimination half-life is 2 to 3 days. Low plasma levels persist for several weeks. Concurrent ad-ministration of metoclopramide, tetracycline, or ri-fampin reduces atovaquone plasma levels by 40 to 50%.


Atovaquone has good initial activity against the blood but not the hepatic stage of P. vivax and P. ovale malaria parasites. It is effective against erythrocytic and exoerythrocytic P. falciparum, and therefore, daily sup-pressive doses need to be taken for only 1 week upon leaving endemic areas. When used alone, it has an unac-ceptable (30%) rate of recrudescence and selects for re-sistant organisms. It and proguanil are synergistic when combined and no atovaquone resistance is seen. This combination (Malarone) is significantly more effective than mefloquine, amodiaquine, chloroquine, and combi-nations of chloroquine, pyrimethamine, and sulfadox-ine. In addition to using the combination of atovaquone and proguanil for the treatment and prophylaxis of P. falciparum malaria, atovaquone is also used for the treatment and prevention of P. carinii pneumonia and babesiosis therapy.

Atovaquone is well tolerated and produces only rare instances of nausea, vomiting, diarrhea, abdominal pain, headache, and rash of mild to moderate intensity.



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